Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[CH:7][CH:8]=1.[C-:10]#[N:11].[Na+].[Cl-].[NH4+]>CN(C=O)C>[CH3:9][C:4]1[C:3]([CH2:2][C:10]#[N:11])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: [C-]#N
Reactant: Cc1ncccc1CCl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ncccc1CC#N
Temperature: 45 °C
Reaction time: 8 h

Procedure:
970 mg (6.85 mmol) of the compound from Example 37A are initially introduced into 10 ml DMF, 336 mg (6.85 mmol) sodium cyanide are added and the mixture is stirred overnight at 45° C. The reaction mixture is introduced on to 75 ml saturated ammonium chloride solution and extracted several times with methylene chloride. The combined organic phases are dried over sodium sulfate, filtered and concentrated. The residue is purified by means of flash chromatography on silica gel (mobile phase: methylene chloride/methanol 20:1).
Reaction SMILES: C([NH:5][C:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([NH:18][C:19]3[CH:24]=[C:23]([C:25](=[O:37])[NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=4)[CH:22]=[CH:21][C:20]=3[CH3:38])=[O:17])[C:10]=2[CH:9]=[CH:8][N:7]=1)(C)(C)C.[Cl:39]C1C=CC(N)=CC=1C(F)(F)F>>[NH2:5][C:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([NH:18][C:19]3[CH:24]=[C:23]([C:25](=[O:37])[NH:26][C:27]4[CH:32]=[CH:31][C:30]([Cl:39])=[C:29]([C:33]([F:34])([F:35])[F:36])[CH:28]=4)[CH:22]=[CH:21][C:20]=3[CH3:38])=[O:17])[C:10]=2[CH:9]=[CH:8][N:7]=1
Reactant: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1NC(=O)c1cccc2c(NC(C)(C)C)nccc12
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Product: Cc1ccc(C(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1NC(=O)c1cccc2c(N)nccc12
Yield: 24 %

Procedure:
The procedures of Steps (1), (2) and (3) of Example 2 and Step (4) of Example 1 were repeated step by step, except for using 4-chloro-3-(trifluoromethyl)aniline instead of aniline in Step (1) of Example 2 to obtain the title compound (30 mg, 24%).
Reaction SMILES: Cl.[F:2][C:3]([F:29])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:30]1([N:36]=[C:37]=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[F:29][C:3]([F:2])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][N:12]([C:37]([NH:36][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:38])[CH2:11][C@H:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Reactant: O=C=Nc1ccccc1
Agent: Cl
Product: O=C(Nc1ccccc1)N1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](c2ccccc2)C1
Yield: 67 %

Procedure:
The compound (0.15 g) obtained in Example 1 and phenyl isocyanate (0.074 ml) were reacted and treated in the same maimer as in the method described in Example 6 to obtain the title compound as colorless oil (0.12 g, 67%).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:9]1([OH:16])[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]1.N1C=CN=C1>CN(C)C=O.O1CCCC1.[Cl-].[Na+].O>[C:4]([Si:1]([CH3:3])([CH3:2])[O:15][CH:12]1[CH2:13][CH2:14][CH:9]([OH:16])[CH2:10][CH2:11]1)([CH3:7])([CH3:6])[CH3:5]
Reactant: OC1CCC(O)CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC1CCC(O)CC1
Yield: 65.6 %

Procedure:
A solution of tert-butyldimethylsilyl chloride (1.5 g, 9.9 mmol) in anhydrous N,N-dimethylformamide (5 mL) was added, dropwise, at 0° C., to a solution of 1,4-cyclohexanediol (1.0 g, 8.6 mmol) and imidazole (1.5 g, 22.0 mmol) in anhydrous tetrahydrofuran (5 mL). After completion of the addition brine was added and the resulting mixture was extracted 3 times with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified on a silica gel plug (hexane/EtOAc, 80/20) to afford 1.3 g (66% yield) of 4-(tert-butyl-dimethyl-silanyloxy)-cyclohexanol as a colorless oil.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([CH2:9][CH2:10][CH3:11])[NH:5][C:6]=1[CH:7]=[O:8].C1(C)C=CC=CC=1.[C:19]1(B(O)O)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[C:27]1([C:2]2[N:3]=[C:4]([CH2:9][CH2:10][CH3:11])[NH:5][C:6]=2[CH:7]=[O:8])[C:28]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: CCCc1nc(I)c(C=O)[nH]1
Reactant: OB(O)c1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCc1nc(-c2cccc3ccccc23)c(C=O)[nH]1
Reaction time: 0.08 h

Procedure:
A solution of 2.64 g (0.01 mol) of 4-iodo-2-n-propylimidazole-5-carboxaldehyde, toluene (40 mL), and 0.33 g (0.00029 mol) of tetrakistriphenylphosphine palladium (0) was stirred at room temperature under nitrogen, while a solution of 3.44 g (0.022 mol) of 1-naphthylboronic acid in 50 mL of ethanol was slowly added. The reaction was stirred for 5 minutes, after which 12 mL of 2M sodium carbonate was slowly added. After the addition was completed, the reaction was refluxed for 48 h and cooled. The reaction was filtered, the filtrate was evaporated under reduced pressure, and the resulting residue was dissolved in 300 mL of methylene chloride, washed twice with 100 mL of saturated sodium chloride solution, washed twice with 100 mL of distilled water, and washed twice with 300 mL of 10% HCl. The HCl layer was made basic with 50% sodium hydroxide until the pH=10. At this point, the basic water layer was extracted three times with 300 mL of methylene chloride, the methylene chloride layer was dried over sodium sulfate and evaporated under reduced pressure. Yield: 0.90 g (0.0034 mol, 34%) of product. NMR (CDCl3) δ 11.45 (m, 1H); 9.42 (s, 1H); 7.28 (m, 7H); 2.82 (t, 2H); 1.85 (m, 2H); 1.01 (t, 3H). ##STR75##
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][N:15]([CH3:24])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:32][CH2:31]1)=[O:29])[CH3:26]>>[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH2:14][N:15]([CH3:24])[CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:4][CH:3]=3)=[CH:35][CH:34]=2)[CH2:31][CH2:32]1)=[O:29])[CH3:26]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CN(C)CCc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CN(C)CCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylmethyl]-methyl-phenethyl-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][NH:13]3)[NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH:28]([NH:32][C:33]([O:35][CH2:36][CH:37]2[C:49]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=3[C:43]3[C:38]2=[CH:39][CH:40]=[CH:41][CH:42]=3)=[O:34])[C:29](O)=[O:30])=[CH:23][CH:22]=1)(=[O:20])[NH2:19].O.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH:48]1[C:49]2[CH:37]([CH2:36][O:35][C:33](=[O:34])[NH:32][CH:28]([CH2:27][C:24]3[CH:23]=[CH:22][C:21]([C:18](=[O:20])[NH2:19])=[CH:26][CH:25]=3)[C:29](=[O:30])[N:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH:12]3[C:9]3[NH:10][CH:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=3)[C:38]3[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:44]=2[CH:45]=[CH:46][CH:47]=1
Reactant: NC(=O)c1ccc(CC(NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Reactant: c1ccc(-c2c[nH]c(C3CCCCN3)n2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1ccc(CC(NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)N2CCCCC2c2nc(-c3ccccc3)c[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 138 mg (0.5 mmol) of 2-(4-Phenyl-1H-imidazol-2-yl)-piperidine, 215 mg (0.5 mmol) of 3-(4-Carbamoyl-phenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-propionic acid, 135 mg (1.0 mmol) of hydroxybenzotriazole hydrate, 115 mg (0.6 mmol) of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride was added 2 mL of dimethylformamide. The resulting mixture was allowed to stir at room temperature under argon overnight. The mixture was then partitioned between ethyl acetate and water. The organic layer was separated, dried over MgSO4 and concentrated to a yellow oil which was used for the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].[I-].[Na+].Cl[C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27]>CN(C=O)C.[Cu]I.[Cu]>[Cl:25][C:23]1[CH:22]=[CH:21][C:20]([N+:26]([O-:28])=[O:27])=[C:19]([CH:24]=1)[O:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Reactant: COC(=O)c1cc(OC)ccc1O
Agent: [Cu]
Agent: [Cu]I
Agent: [H-]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OC)ccc1Oc1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 85 °C
Reaction time: 16 h

Procedure:
To a solution of 61.8 g of 2-hydroxy-5-methoxybenzoic acid, methyl ester in 700 ml DMF was added 14.96 g of a 60% suspension of sodium hydride in mineral oil. This was followed by addition of 50.88 g of sodium iodide, 64.64 g of copper(I)iodide, and 2.16 g of finely powdered copper metal. The mixture was heated to 85° C., for 15 minutes, then 71.7 g of 2,4-dichloronitrobenzene was added, and the reaction was stirred at 85° C. for 16 hours. The mixture was filtered, and the filtrate concentrated to an oily residue. Sodium thiosulfate, 400 ml of a 20% solution was added, followed by extraction with ethyl acetate (3×400 ml). The combined ethyl acetate extracts were washed with water (2×325 ml), dried over anhydrous sodium sulfate, then evaporated to afford a pale yellow solid, which was triturated with cyclohexane and filtered giving the title compound, mp 114°-116° C.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1(Cl)[NH:10][C:9]([Cl:11])=[CH:8][S:7]1)(=[O:5])=[O:4].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[CH3:1][N:2]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[S:3]([C:6]1[S:7][CH:8]=[C:9]([Cl:11])[N:10]=1)(=[O:5])=[O:4]
Reactant: Nc1ccccc1
Reactant: CNS(=O)(=O)C1(Cl)NC(Cl)=CS1
Solvent: ClCCl
Product: CN(Nc1ccccc1)S(=O)(=O)c1nc(Cl)cs1
Yield: 15 %

Procedure:
In analogy to Example 5, the N-methyl-2-N-phenylamino-4-chlorothiazole-sulphonamide was prepared by reacting N-methyl-2,4-dichlorothiazole-sulphonamide from Example 2 with aniline. Following chromatography on silica gel using methylene chloride as the eluent, the product having a melting point of 157-8° C. was obtained in 15% yield.
Reaction SMILES: [BrH:1].C(O)(=O)C.[N:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:34])[C:14]2[CH:19]=[CH:18][C:17]([C@H:20]([NH:22]C(OCC3C=CC=CC=3)=O)[CH3:21])=[C:16]([Cl:33])[CH:15]=2)=[CH:8][CH:7]=1>>[BrH:1].[BrH:1].[N:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:34])[C:14]2[CH:19]=[CH:18][C:17]([C@H:20]([NH2:22])[CH3:21])=[C:16]([Cl:33])[CH:15]=2)=[CH:8][CH:7]=1
Reactant: C[C@@H](NC(=O)OCc1ccccc1)c1ccc(C(=O)Nc2ccncc2)cc1Cl
Agent: Br
Solvent: CC(=O)O
Product: C[C@@H](N)c1ccc(C(=O)Nc2ccncc2)cc1Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A 25% hydrogen bromide-acetic acid solution (7 ml) was added to (R)-N-(4-pyridyl)-4-(1-benzyloxycarbonylaminoethyl)-3-chlorobenzamide (630 mg), and the mixture was stirred at room temperature for 6 hours. After the reaction, the solvent was evaporated under reduced pressure. The obtained crystals were washed with ether, and recrystallized from methanol to give 243 mg of (R)-(+)-N-(4-pyridyl)-4-(1-aminoethyl)-3-chlorobenzamide dihydrobromide having a melting point of more than 300° C.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=3)=[CH:10]2)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1.CN1CCCC1=O>O>[CH:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([OH:2])[CH:12]=2)[CH:7]=[CH:8][C:9]=1[C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1
Reactant: COc1ccc2ccc(-c3ccc4ccccc4c3)cc2c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CN1CCCC1=O
Solvent: O
Product: Oc1ccc2ccc(-c3ccc4ccccc4c3)cc2c1
Temperature: 200 °C
Reaction time: 7 h

Procedure:
Under the nitrogen atmosphere, 7-methoxy-2,2′-binaphthalen (31.0) as the sixth intermediate compound, pyridine hydrochloride (63.0 g) and N-methylpyrrolidone (20 ml) were added to a flask and then stirred for 7 hours at 200° C. Once the heating is completed, it was cooled to 100° C. or less and added with water. The solid precipitated by adding water was collected by suction filtration. The obtained solid was purified by silica gel column chromatography (solvent: toluene) to give [2,2′-binaphthalen]-7-ol (22.0 g) as a seventh intermediate compound. The scheme is shown in the following “Reaction 12”.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[CH:2].[Li]CCCC.[CH3:14][C:15](=[O:36])[C@@H:16]1[C@:33]2([CH3:34])[C@H:19]([C@H:20]3[C@H:30]([CH2:31][CH2:32]2)[C@:28]2([CH3:29])[C@@H:23]([CH2:24][C:25](=[O:35])[CH2:26][CH2:27]2)[CH2:22][CH2:21]3)[CH2:18][CH2:17]1.C(Cl)Cl>C1COCC1>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]#[C:2][C@@:25]1([OH:35])[CH2:26][CH2:27][C@@:28]2([CH3:29])[C@H:23]([CH2:22][CH2:21][C@@H:20]3[C@@H:30]2[CH2:31][CH2:32][C@@:33]2([CH3:34])[C@H:19]3[CH2:18][CH2:17][C@@H:16]2[C:15](=[O:36])[CH3:14])[CH2:24]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: C#Cc1ccccn1
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@@](O)(C#Cc5ccccn5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-ethynylpyridine (270 mg, 2.6 mmol) in dry THF (15 mL) was treated with a n-BuLi (2.5 M in THF, 2.5 mmol, 1 mL) at −60° C. After stirring the mixture at −78° C. for 0.5 hr, a solution of 5β-pregnan-3,20-dione, cyclic 20-(1,2-ethanediyl acetal)170 mg, 047 mmol) in THF (15 mL) was added and the mixture was stirred at −78° C. for 1 hr. The cooling bath was removed and the mixture was quenched with NH4Cl solution (3 mL). The solvent was removed and the residue was then dissolved in acetone (25 mL). After adding 2N HCl (2 mL) the solution was stirred at rt for 15 min. Sat. NaHCO3 soln. was added to neutralize the acid. The solvents were removed and the residue was extracted with EtOAc. The organic layer was washed with water, and brine. After drying over anhyd. MgSO4 the solution was filtered and evaporated to yield the crude product (360 mg). This crude product was then dessolved in a small amount of CH2Cl2 and poured on a column of silica gel. Elution with toluene:acetone mixture (95:5) gave the unreacted ethynlpyridine as a first fraction. Further elution with the same solvent mixture yielded 3β-(2-pyridyl)ethynyl-3α-hydroxy-5β-pregnan-20-one (107 mg) as a colorless solid; mp 192-195° C.; TLC Rf (toluene:acetone 87:13)=0.21.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:6][CH:5]=1.I[CH2:21][CH2:22][CH2:23][CH3:24].Cl>CN(C=O)C>[CH2:21]([N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:19]=[C:11]1[CH2:10][C:7]1[CH:8]=[CH:9][C:4]([Br:3])=[CH:5][CH:6]=1)[CH2:22][CH2:23][CH3:24]
Reactant: Brc1ccc(Cc2cc3ccccc3[nH]2)cc1
Reactant: CCCCI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCn1c(Cc2ccc(Br)cc2)cc2ccccc21
Reaction time: 0.17 h

Procedure:
A mixture of sodium hydride (0.32 g) in DMF (50 ml) was cooled in an ice bath. A solution of 2-(p-bromophenylmethyl)indole (2.0 g), prepared, e.g., as described in Preparation 3, in DMF, was added, and the mixture stirred for 10 minutes. 1-Iodobutane (0.9 ml) in DMF was added dropwise, and the mixture stirred for 30 minutes. It was then poured into cold dilute HCl and extracted with ether. The extract was washed three times with cold water, dried over magnesium sulphate, and the solvent evaporated to afford an orange-red oil, 1-(n-butyl)-2-(p-bromophenylmethyl)indole (2.5 g), a compound of Formula (9).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](=O)[CH3:13])=[CH:7][CH:6]=1.[OH:15][CH:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([F:27])[CH:20]=1)[CH2:17][NH2:18]>>[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([NH:18][CH2:17][CH:16]([OH:15])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([F:27])[CH:20]=2)[CH3:13])=[CH:7][CH:6]=1
Reactant: COc1ccc(C(O)CN)cc1F
Reactant: CC(=O)Cc1ccc(OCCO)cc1
Product: COc1ccc(C(O)CNC(C)Cc2ccc(OCCO)cc2)cc1F

Procedure:
The compound was prepared as in Example 7, from 1-[4-(2-hydroxyethoxy)phenyl]propan-2-one (3.9 g) and 2-hydroxy-2-(3-fluoro-4-methoxyphenyl)-ethanamine (3.75 g) and crystallised from ether-hexane, mp 112°-115° C. as a 82:18 mixture of diastereoisomers.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.C(N(CC)CC)C.[CH3:16][C:17]([CH3:22])([CH3:21])[C:18](Cl)=[O:19]>ClCCl>[CH3:16][C:17]([CH3:22])([CH3:21])[C:18]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1)=[O:19]
Reactant: Cc1cccc(N)n1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(NC(=O)C(C)(C)C)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 82.2 %

Procedure:
2-amino-6-picoline (26 g) was dissolved in dichloromethane (280 ml) and the reactor was cooled to 0° C., followed by adding triethylamine (30 g) thereto. To the obtained solution was slowly added dropwise a solution of trimethylacetylchloride (31.8 g) in dichloromethane (20 ml) and the mixture was stirred at room temperature for 3 hours. The resulting mixture was filtered, washed with water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure and then crystallized (dichloromethane/petroleum ether) to yield a pale yellow solid (38 g, 82%).
Reaction SMILES: Br[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[N:6][CH:7]=1.[B:9]1(B2OC(C)(C)C(C)(C)O2)[O:13]C(C)(C)C(C)(C)[O:10]1.C([O-])(=O)C.[K+].C(Cl)Cl>O>[NH2:8][C:3]1[C:2]([B:9]([OH:13])[OH:10])=[CH:7][N:6]=[CH:5][N:4]=1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: Nc1ncncc1Br
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: Nc1ncncc1B(O)O
Temperature: 105 °C
Reaction time: 18 h

Procedure:
To a vial was added 5-bromopyrimidin-4-amine (0.200 g, 1.149 mmol), bis(pinacolato)diboron (0.438 g, 1.724 mmol), and potassium acetate (0.338 g, 3.45 mmol). The vial was capped with a rubber septum and then evacuated and backfilled with N2. Dioxane (0.120 ml) was added via syringe through the septum. The reaction mixture was sparged with N2, then PdCl2(dppf).CH2Cl2 (0.042 g, 0.057 mmol) was added. The septum was then replaced with a Teflon screw valve and the vial was sealed. The reaction mixture was heated at 105° C. in a metal pie block. After 18 h, reaction mixture was allowed to cool to room temperature. The reaction mixture was filtered through a disposable fritted funnel and the filter cake washed with EtOAc. The filtrate was concentrated to afford a brown solid. MS (ESI): m/z=140.0 [M+H]+ HPLC Peak ret. T=0.24 minutes was product (HPLC conditions: Column:Luna C18 4.6×30 mm 3 u A:10:90 H2O:ACN NH4OAc/B:10:90 H2O:ACN NH4OAc; 0%-95% B in 2 min; 4 mL/min flow).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=[O:12])[CH:2]=1.[BH4-].[Na+].O>C(O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11][OH:12])[CH:2]=1
Reactant: O=Cc1cnc2ccccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OCc1cnc2ccccc2c1
Reaction time: 0.5 h

Procedure:
3-Quinolinecarbaldehyde (Aldrich) (1.04 g, 6.64 mmol) was dissolved in anhydrous ethanol (20 mL), NaBH4 (0.250 g, 3.95 mmol) was then added in small portions over 10 min and the resulting solution allowed to stir for a further 30 min. Water (20 mL) was then added and the resulting solution extracted with ethyl acetate (2×30 mL). The combined organics were dried (MgSO4), filtered and the solvent removed under reduced pressure to give the sub-title compound.
Reaction SMILES: [C:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH2:14][N:15]2[C:19]3[CH:20]=[C:21]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)[CH:22]=[C:23]([C:24]([NH2:26])=[O:25])[C:18]=3[N:17]=[C:16]2[CH:34]([CH3:36])[CH3:35])=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].[CH2:37]([N:39](CC)CC)[CH3:38].C(OC(=N)C)C>CO>[C:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH2:14][N:15]2[C:19]3[CH:20]=[C:21]([N:27]([CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)[C:37](=[NH:39])[CH3:38])[CH:22]=[C:23]([C:24]([NH2:26])=[O:25])[C:18]=3[N:17]=[C:16]2[CH:34]([CH3:36])[CH3:35])=[CH:6][CH:5]=1)(=[NH:2])[NH2:3]
Reactant: CC(C)c1nc2c(C(N)=O)cc(NC3CCNCC3)cc2n1Cc1ccc(C(=N)N)c2ccccc12
Reactant: CCN(CC)CC
Agent: CCOC(C)=N
Solvent: CO
Product: CC(=N)N(c1cc(C(N)=O)c2nc(C(C)C)n(Cc3ccc(C(=N)N)c4ccccc34)c2c1)C1CCNCC1
Reaction time: 3 h

Procedure:
To 1-(4-amidinonaphth-1-yl)methyl-2-isopropyl-4-aminocarbonyl-6-(piperidin-4-ylamino)benzimidazole (1 g) in methanol (50 mL) was added triethylamine (3 mL) and ethylacetimidate (1 g). After stirring for 3 hours, the reaction was concentrated. The residue was purified by HPLC on a C18 Dynamax column with a 3-25% acetonitrile in water gradient with 0.1% trifluoroacetic acid to afford 1-(4-amidinonaphth-1-yl)methyl-2-isopropyl-4-aminocarbonyl-6-(N-(1-iminoethyl)piperidin-4-ylamino)benzimidazole, 1H NMR (DMSO, 300 MHz) δ 9.70 (s, 2H), 9.58 (s, 2H), 9.40 (s, 1H), 9.35 (s, 1H), 8.82 (s, 1H), 8.62-7.20 (m, 9H), 6.10 (s, 2H), 4.10-3.50 (m, 6H), 2.50 (s, 3H), 2.26 (m, 2H), 1.70 (m, 2H), 1.60 (d, 6H), as white solid after freeze drying removal of the solvent.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[Cl-].[Al+3].[Cl-].[Cl-].[NH:12]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][C:13]1=[O:14]>C(=S)=S>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:19]1[CH:18]=[C:17]2[C:22](=[CH:21][CH:20]=1)[NH:12][C:13](=[O:14])[CH2:15][CH2:16]2)=[O:6]
Reactant: O=C(Cl)CCCCl
Reactant: O=C1CCc2ccccc2N1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: O=C1CCc2cc(C(=O)CCCCl)ccc2N1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
120 Milliliters of γ-chlorobutyryl chloride and 160 g of pulverized anhydrous aluminium chloride were suspended in 300 ml of carbon disulfide. The suspension was refluxed by heating and another suspension of 29.4 g of 3,4-dihydrocarbostyril in 100 ml of carbon disulfide was added dropwise to the firt suspension in 1 hour and the reaction was continued for 4 hours under refluxing condition by heating. After the reaction was completed, the reaction mixture was poured into ice-water and the precipitates thus formed were collected by filtration, washed with water and with ether. Then the washed precipitates were recrystallized from acetone to obtain 25.5 g of 6-(4-chloro-1-oxobutyl)-3,4-dihydrocarbostyril in yellow needle-like crystals. Melting point: 158°-160° C.