Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.[CH3:13][C:14]([CH3:16])=[O:15].[OH-].[Na+].O>C(O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[CH:13][C:14](=[O:15])[CH:16]=[CH:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1
Reactant: O=Cc1ccc2ccccc2c1
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(C=Cc1ccc2ccccc2c1)C=Cc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 69.4 %

Procedure:
2-Naphthaldehyde (24, 1.56 g, 10.0 mmol) and acetone (19, 0.37 ml, 5.0 mmol) were combined in ethanol (10 ml) and stirred for 15 min at room temperature. A solution of sodium hydroxide (0.60 g, 15.0 mmol) and water (10 ml) was added and the mixture stirred for 18 hr at room temperature. The resulting precipitate was filtered and recrystallized from ethanol to give 1.16 g (69%) of a yellow solid: mp 244-246° C. [expected mp 243-244° C.]; 1H NMR: δ 7.23 (d, 2H, J=15.9 Hz), 7.52 (m, 4H), 7.83 (m, 8H), 7.93 (d, 2H, J=15.9 Hz), 8.03 (s, 2H); 13C NMR: δ 123.6, 125.7, 126.7, 127.3, 127.8, 128.6, 128.7, 130.5, 132.3, 133.3, 134.3, 143.1, 190.0.
Reaction SMILES: C([O:8][CH2:9][C@@H:10]1[CH2:15][N:14]([CH3:16])[CH2:13][CH2:12][N:11]1[C:17]1[CH:18]=[CH:19][C:20]([O:41][C:42]([F:45])([F:44])[F:43])=[C:21]([NH:23][C:24]2[N:33]=[CH:32][C:31]3[CH2:30][CH2:29][C:28]4[C:34]([C:38]([NH2:40])=[O:39])=[N:35][N:36]([CH3:37])[C:27]=4[C:26]=3[N:25]=2)[CH:22]=1)C1C=CC=CC=1.B(Cl)(Cl)Cl.CO>C(Cl)Cl>[OH:8][CH2:9][C@@H:10]1[CH2:15][N:14]([CH3:16])[CH2:13][CH2:12][N:11]1[C:17]1[CH:18]=[CH:19][C:20]([O:41][C:42]([F:43])([F:44])[F:45])=[C:21]([NH:23][C:24]2[N:33]=[CH:32][C:31]3[CH2:30][CH2:29][C:28]4[C:34]([C:38]([NH2:40])=[O:39])=[N:35][N:36]([CH3:37])[C:27]=4[C:26]=3[N:25]=2)[CH:22]=1
Reactant: CN1CCN(c2ccc(OC(F)(F)F)c(Nc3ncc4c(n3)-c3c(c(C(N)=O)nn3C)CC4)c2)[C@H](COCc2ccccc2)C1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(c2ccc(OC(F)(F)F)c(Nc3ncc4c(n3)-c3c(c(C(N)=O)nn3C)CC4)c2)[C@H](CO)C1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 8-[5-((S)-2-benzyloxymethyl-4-methyl-piperazin-1-yl)-2-trifluoromethoxy-phenylamino]-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (53 mg, 0.08 mmol) in DCM (1.7 mL) under an atmosphere of N2, at −78° C. 1M BCl3 in DCM (0.17 mL) was added dropwise. Under complete addition the solution was stirred at 0° C. for 30 min and at room temperature overnight. Then 2 mL of MeOH was added. The solvent was removed under reduced pressure and the residue was diluted with Et2O and decanted to give the desired compound in quantitative yield (46 mg) as a brown solid.
Reaction SMILES: [C:1]1([S:7]([N:10]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:11]2[CH:12]=[C:13]([O:25]C(=O)C3C=CC=CC=3)[CH:14]=[CH:15][C:16]=2[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>C1COCC1.CO.O>[CH2:34]([N:10]([C:11]1[CH:12]=[C:13]([OH:25])[CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:9])=[O:8])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(Oc1ccc(OCc2ccccc2)c(N(Cc2ccccc2)S(=O)(=O)c2ccccc2)c1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=S(=O)(c1ccccc1)N(Cc1ccccc1)c1cc(O)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.1 %

Procedure:
To a stirred solution of benzoic acid 3-(benzenesulfonyl-benzyl-amino)-4-benzyloxy-phenyl ester (which was obtained in Example 18) (1.80 g, 3.28 mmol) in THF (10 ml) and methanol (10 mL) was added 10% of sodium hydroxide (10 mL). The mixture was stirred at room temperature for 1.5 hours, acidified, with concentrated hydrochloric acid and diluted with water (200 mL). The aqueous solution was extracted with CH2Cl2. The organic phase was dried over MgSO4 and concentrated. The product was purified by flash silica gel chromatography eluting with ethyl acetate and hexanes to give the title compound as a white solid (1.20 g, 82%); 1H NMR (300 MHz, CDCl3) δ 4.71(brs, 4 H), 6.49(d, J=3.0 Hz, 1 H), 6.62(dd, J=9.0, 3.0 Hz, 1 H), 6.84(d, J=9.0 Hz, 1 H), 7.10–7.70(m, 15 H), 9.07(brs, 1 H); MS (ES) m/z: 444.0 ((M−H)−, 100%); HRMS Calcd. for C26H22NO4S(M−H)−: 444.1275. Found: 444.1270.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]([OH:15])=O)=[C:11]([CH3:16])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.C(N=C=NCCCN(C)C)C.[F:29][C:30]([F:44])([F:43])[C:31]1[CH:32]=[C:33]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:34]=[CH:35][CH:36]=1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]([N:40]3[CH2:39][CH2:38][N:37]([C:33]4[CH:34]=[CH:35][CH:36]=[C:31]([C:30]([F:43])([F:44])[F:29])[CH:32]=4)[CH2:42][CH2:41]3)=[O:15])=[C:11]([CH3:16])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: Cc1onc(-c2cccc(F)c2)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1onc(-c2cccc(F)c2)c1C(=O)N1CCN(c2cccc(C(F)(F)F)c2)CC1
Yield: 63.6 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 3-(3-fluorophenyl)-5-methylisoxazol-4-carboxylic acid (407 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(3-(trifluoromethyl)phenyl)piperazine (424 mg, 1.84 mmol), a white solid required compound (506 mg, 1.17 mmol, 64%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([C:13]([O:15]C)=O)[CH:4]=1.O.[NH2:18][NH2:19]>CC(O)C>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([C:13]([NH:18][NH2:19])=[O:15])[CH:4]=1
Reactant: NN
Reactant: COC(=O)c1cc(OC)c2ccccc2n1
Solvent: CC(C)O
Solvent: O
Product: COc1cc(C(=O)NN)nc2ccccc12
Temperature: 80 °C

Procedure:
The methyl 4-methoxyquinoline-2-carboxylate (1 eq) was dissolved in i-PrOH (0.75 M) and then hydrazine monohydrate (10 eq) was added. The reaction mixture was heated at 80° C. overnight and then the solvent was evaporated under reduced pressure and the crude product was used in the next step without purification. MS (ES) C11H11N3O2 required: 217, found: 218 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([CH2:14][C:15]2[C:20]([Cl:21])=[CH:19][N:18]=[CH:17][C:16]=2[Cl:22])=[N:4][N:3]=1.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>CN(C=O)C>[Cl:22][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([Cl:21])[C:15]=1[CH2:14][C:5]1[C:6]2[C:11](=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=2)[C:2]([N:27]2[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]2)=[N:3][N:4]=1
Reactant: CN1CCNCC1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(Cl)c2c1
Solvent: CN(C)C=O
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(N3CCN(C)CC3)c2c1
Temperature: 25 °C
Yield: 33.9 %

Procedure:
A solution of 4-chloro-1-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-phthalazine (1 g, 2.82 mmoles), prepared as described in example 45, in DMF (25 ml) was stirred under dry N2 at room temperature, and dropwise added with 1-methylpiperazine (0.848 g, 8.46 mmoles). The mixture was heated at 100° C. for 20 hours, then brought to small volume and partitioned between water and CH2Cl2. The organic phase was washed with water, anhydrified and concentrated to give a residue which was flash chromatographed (eluent: CH2Cl2/CH3OH/NH4OH 95:5:0.5). The resultant solid was crystallised from tert-butyl-methyl ether (35 ml) to give 0.4 g of the title compound (yield: 34%). m.p.: 160-162° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([CH3:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([NH:24][CH3:25])[CH:21]([CH3:23])[CH3:22]>CS(C)=O>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:24]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH3:25])[C:11]([CH3:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNCC(C)C
Reactant: Cc1cc([N+](=O)[O-])c(NC(=O)OC(C)(C)C)cc1Cl
Solvent: CS(C)=O
Product: Cc1cc([N+](=O)[O-])c(NC(=O)OC(C)(C)C)cc1N(C)CC(C)C

Procedure:
The title compound was prepared from (5-chloro-4-methyl-2-nitro-phenyl)-carbamic acid tert-butyl ester (Example B8) (3.01 g, 10.5 mmol) and N-isobutyl-methylamine (4.56 g, 52.3 mmol) in DMSO (30 mL) at 55° C. according to the general procedure C. Obtained as a yellow oil (1.84 g, 52%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)#[CH:2].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:13][CH:12]=1
Reactant: C#Cc1ccccc1
Reactant: COc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: COc1ccc(C#Cc2ccccc2)cc1
Reaction time: 24 h
Yield: 97 %

Procedure:
112 mg (1.1 mmol) of ethynylbenzene, 259 mg (1.1 mmol) of 4-methoxy-iodobenzene, 2 mg (10 μmol) of cupric iodide and 8 mg (10 μmol) of bis(triphenylphosphine)palladium(II) chloride were added to a round-bottomed flask. The round-bottomed flask was then purged 3 times with argon. 20 ml of distilled triethylamine were then added and the mixture was then stirred for 24 hours. The reaction medium was then diluted with 20 ml of a 6M solution of hydrochloric acid then extracted three times with 20 ml of dichloromethane. The organic phase was washed with 40 ml of a 1M solution of sodium hydroxide, then dried over sodium sulfate and the solvent was evaporated under reduced pressure. The crude product of the reaction was then purified by column chromatography using, as eluent, a petroleum ether/dichloromethane (7/3; v/v) mixture. The expected product was then isolated in the form of a yellow powder (m=201 mg; yield=97%).
Reaction SMILES: C(OC([NH:8][C:9]1[CH2:10][C:11]([C:33](O)=[O:34])=[CH:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:27])=[CH:22][CH:21]=3)=[CH:16][C:14]=2[N:15]=1)=O)(C)(C)C.[Si]([O:43][CH2:44][CH2:45][NH:46][CH2:47][CH2:48][CH3:49])(C(C)(C)C)(C)C.C(NCCO)CC>>[NH2:8][C:9]1[CH2:10][C:11]([C:33]([N:46]([CH2:45][CH2:44][OH:43])[CH2:47][CH2:48][CH3:49])=[O:34])=[CH:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[CH:22][C:23]([C:26]([N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:27])=[CH:24][CH:25]=3)=[CH:16][C:14]=2[N:15]=1
Reactant: CC(C)(C)OC(=O)NC1=Nc2cc(-c3ccc(C(=O)N4CCCC4)cc3)ccc2C=C(C(=O)O)C1
Reactant: CCCNCCO[Si](C)(C)C(C)(C)C
Agent: CCCNCCO
Product: CCCN(CCO)C(=O)C1=Cc2ccc(-c3ccc(C(=O)N4CCCC4)cc3)cc2N=C(N)C1

Procedure:
The title compound was prepared by the procedures as described in Example 104 using (1E,4E)-2-(tert-butoxycarbonylamino)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylic acid and N-(2-(tert-butyldimethylsilyloxy)ethyl)propan-1-amine that was prepared by the procedure as described in Example 104 (Step A) using 2-(propylamino)ethanol. MS APCI (+) m/z 461 (M+1) detected; 1H-NMR (400 MHz, CDCl3) δ 7.68 (d, 2H), 7.60 (d, 2H), 7.49 (s, 1H), 7.29-7.35 (m, 2H), 6.88 (s, 1H), 3.84 (s, 2H), 3.67 (t, 4H), 3.50 (t, 4H), 2.84 (s, 2H), 1.88-2.00 (m, 4H), 1.66-1.72 (m, 2H), 0.93 (t, 3H).
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]([C:7]1[CH:12]=[C:11]([SH:13])[CH:10]=[C:9]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:8]=1[OH:18])([CH3:6])[CH3:5].C([O:21][C:22](=[O:27])[CH2:23][CH2:24][CH2:25]Br)C.O>CC(C)=O>[CH3:6][C:4]([C:7]1[CH:12]=[C:11]([S:13][CH2:25][CH2:24][CH2:23][C:22]([OH:27])=[O:21])[CH:10]=[C:9]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:8]=1[OH:18])([CH3:3])[CH3:5]
Reactant: CCOC(=O)CCCBr
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)c1cc(SCCCC(=O)O)cc(C(C)(C)C)c1O
Reaction time: 1.5 h

Procedure:
Potassium hydroxide flakes (2.52g, 0.045 mole) were added to a clear solution of 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (3.57 g, 0.0165 mole) and ethyl-4-bromo-butyrate (3.23 g, 0.0165 mole) in acetone (10 ml). Water (20 ml) was added and the solution stirred for 1.5 hours, the solvent removed on a rotary evaporator and water (50 ml) added, and the mixture was extracted with ethyl ether (3×75 ml). The aqueous layer was acidified with concentrated hydrochloric acid, extraced with ethyl ether (2×50 ml), the combined organic extracts were washed with water (50 ml), dried over sodium sulfate, filtered and the solvents removed, leaving an oil, which was purified by chromatography on silica, recrystallized from ethyl ether/Skellysolve B, filtered and the product dried in vacuo at room temperature for 12 hours, m.p. ca. 112°-113.5° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[CH:11][CH:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].[ClH:36].[N:37]12[CH2:44][CH2:43][CH:40]([CH2:41][CH2:42]1)[C@@H:39]([NH:45][C:46]([C:48]1[S:49][C:50]3[C:56](Br)=[CH:55][CH:54]=[CH:53][C:51]=3[CH:52]=1)=[O:47])[CH2:38]2.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[ClH:36].[N:37]12[CH2:42][CH2:41][CH:40]([CH2:43][CH2:44]1)[C@@H:39]([NH:45][C:46]([C:48]1[S:49][C:50]3[C:56]([C:2]4[CH:7]=[CH:6][CH:5]=[C:4]([N:8]5[CH:12]=[CH:11][CH:10]=[CH:9]5)[CH:3]=4)=[CH:55][CH:54]=[CH:53][C:51]=3[CH:52]=1)=[O:47])[CH2:38]2
Reactant: Brc1cccc(-n2cccc2)c1
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(Br)c2s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(-c3cccc(-n4cccc4)c3)c2s1

Procedure:
124.4 mg (0.56 mmol) of 1-(3-bromophenyl)-1H-pyrrole, 142.2 mg (0.56 mmol) of bis(pinacolato)diboron, 119.1 mg (1.21 mmol) of potassium acetate, 13.7 mg (0.02 mmol) of PdCl2(dppf), 150.0 mg (0.37 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A), 0.93 ml of 2 M sodium carbonate solution and a further 13.7 mg (0.02 mmol) of PdCl2(dppf) in 2.0 ml of DMF are reacted by general method D. Drying under high vacuum results in 86.9 mg (48% of theory) of the title compound.
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([CH2:27][CH3:28])([CH2:25][CH3:26])[C:23]#[N:24])=[C:18]([F:29])[CH:17]=3)[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:30][C:31]1[CH:36]=[C:35]([CH3:37])[N:34]2[N:38]=[C:39]([CH:41]=O)[N:40]=[C:33]2[N:32]=1>CO>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([CH2:27][CH3:28])([CH2:25][CH3:26])[C:23]#[N:24])=[C:18]([F:29])[CH:17]=3)[CH2:11][C:10](=[O:12])[CH:9]([CH2:41][C:39]3[N:40]=[C:33]4[N:32]=[C:31]([CH3:30])[CH:36]=[C:35]([CH3:37])[N:34]4[N:38]=3)[C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(C)n2nc(C=O)nc2n1
Reactant: CCC(C#N)(CC)c1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1F
Solvent: CO
Product: CCC(C#N)(CC)c1ccc(CCC2(C3CCCC3)CC(=O)C(Cc3nc4nc(C)cc(C)n4n3)C(=O)O2)cc1F
Reaction time: 12 h

Procedure:
A solution of 2-{4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-2-ethyl-butyronitrile (300 mg, 0.75 mmol) in anhydrous MeOH (3.0 mL) was treated with 5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde (198 mg, 1.1 mmol), followed by borane-dimethylamine complex (62 mg, 1.05 mmol) at room temperature. The reaction was stirred for 12 hours before it was quenched by the addition of CH2Cl2 (30 mL) and Amberlite IR 120(plus) (3 g). The reaction was stirred for 30 minutes, and then filtered. The filtrate was concentrated to an oil, dissolved in CH2Cl2 (25 mL, and then washed with 10 mL 1 N HCl. The aqueous layer was extracted with 2×25 mL CH2Cl2. The organic layers were combined and dried over Na2SO4. After removing the solids by filtration, the liquid was concentrated to an oil. The desired product was isolated by preparatory HPLC (76 mg, 18%). 1H NMR (400 MHz, CDCl3) δ: 0.74 (t, J=7.45 Hz, 6 H), 1.37–1.59 (m, 8 H), 1.79–1.88 (m, 4 H), 1.94–2.03 (m, 2 H), 2.21 (t, J=8.84 Hz, 3 H), 2.36 (d, J=17.94 Hz, 1 H), 2.47–2.55 (m, 5 H), 2.59–2.63 (m, 4 H), 3.95 (d, J=3.54 Hz, 2 H), 6.66 (dd, J1=13.26 Hz, J2=1.64 Hz, 1 H), 6.72–6.75 (m, 2 H), 7.23 (t, J=8.21 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([F:27])[CH:18]=2)([NH2:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[CH3:28][C:29]1[N:30]=[CH:31][NH:32][C:33]=1[CH:34]=O.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:24])[F:25])[CH:20]=[C:19]([F:27])[CH:18]=2)([NH:16][CH2:34][C:33]2[NH:32][CH:31]=[N:30][C:29]=2[CH3:28])[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:6][CH:7]=1
Reactant: Cc1nc[nH]c1C=O
Reactant: NC(Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: Cc1nc[nH]c1CNC(Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 93.8 %

Procedure:
To a solution of 1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethanamine (0.02 g, 0.051 mmol) in dichloroethane (0.5 mL) in a two dram vial was added 4-methyl-1H-imidazole-5-carbaldehyde (6 mg, 0.051 mmol), followed by a drop of acetic acid. The reaction mixture was shaken for 20 minutes at room temperature and then NaBH(OAc)3 was added (12 mg, 0.056 mmol). The reaction was stirred at room temperature overnight. The solvents were removed and the residue was purified by preparative HPLC (phenominex C18 column, 21×100 mm, 5μ) using MeOH/H2O (with 0.1% TFA) to give 1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-N-((4-methyl-1H-imidazol-5-yl)methyl)-2-phenylethanamine as a white solid (23.4 mg, 76% yield). LCMS: 3.6 min [M+1] 489.2 (4 min gradient, MeOH/H2O 0.1% TFA); 1H NMR (400 MHz, CDCl3) δ ppm 2.27 (s, 3 H), 3.45-3.52 (m, 1 H), 3.88-3.99 (m, 2 H), 4.01-4.07 (m, 1 H), 6.64 (d, J=7.09 Hz, 2 H), 7.02 (d, J=8.56 Hz, 1 H), 7.10 (t, J=7.46 Hz, 2 H), 7.18 (t, J=7.46 Hz, 1 H), 7.49 (d, J=7.58 Hz, 1 H), 7.61 (d, J=9.54 Hz, 1 H), 7.69 (s, 1 H), 7.76 (dd, J=8.56, 2.45 Hz, 1 H), 8.28 (s, 1 H), 8.60 (d, J=1.96 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[C:13](=[O:39])[CH2:14][C:15]([C:17]1[C:18](O)=[C:19]([CH:27]2[CH2:31][CH2:30][N:29]([CH3:32])[CH:28]2[CH2:33][O:34]C(=O)C)[C:20]([O:25][CH3:26])=[CH:21][C:22]=1[O:23][CH3:24])=[O:16].C([O-])([O-])=O.[Na+].[Na+]>Cl>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[C:13]1[O:39][C:18]2[C:17]([C:15](=[O:16])[CH:14]=1)=[C:22]([O:23][CH3:24])[CH:21]=[C:20]([O:25][CH3:26])[C:19]=2[C@@H:27]1[CH2:31][CH2:30][N:29]([CH3:32])[C@H:28]1[CH2:33][OH:34]
Reactant: COc1cc(OC)c(C2CCN(C)C2COC(C)=O)c(O)c1C(=O)CC(=O)c1ccc(N2CCCC2)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1cc(OC)c2c(=O)cc(-c3ccc(N4CCCC4)cc3Cl)oc2c1[C@@H]1CCN(C)[C@H]1CO
Reaction time: 3 h

Procedure:
To a solution of n-BuLi (1.6 M in hexane, 3 mL, 4.8 mmol) in THF (10 mL), maintained at 0° C. under nitrogen atmosphere, hexamethyldisilazane (1 mL, 4.75 mmol) was added dropwise and stirred for 15 min. To this, a solution of the compound of example (55)(1.37 g, 2.45 mmol) in THF (5 mL) was added drop wise, maintaining the temperature at 0° C. After the addition, the reaction mixture was allowed to warm to room temperature and stirred for 2.5 hrs. The reaction mixture was acidified with dilute HCl, and basified with 10% sodium bicarbonate to pH 8-9. The aqueous layer was extracted with chloroform (3×50 mL). The organic layer was washed with water (25 mL), brine (25 mL) and dried over anhydrous Na2SO4. The organic layer was concentrated under reduced pressure and dried under vacuum to yield acetic acid 3-{3-[3-(2-chloro-4-pyrrolidin-1-yl-phenyl)-3-oxo-propionyl]-2-hydroxy-4,6-dimethoxy-phenyl}-1-methyl-pyrrolidin-2-ylmethyl ester as a brown solid (0.97 g, 70.8%). This ester was dissolved in 5 mL conc. HCl and stirred for 3 hrs. to effect cyclisation. At the end of 3 hrs, the reaction mixture was basified with solid Na2CO3 to pH 10. The aqueous layer was extracted with chloroform (3×25 mL) and washed with water (10 mL) and brine (10 mL). The organic layer was dried over anhydrous Na2SO4, concentrated under reduced pressure and dried over vacuum. The residue was purified by column chromatography with 3% methanol in chloroform and 0.1% ammonia as eluent to yield the compound, (+)-trans-2-(2-chloro-4-pyrrolidin-1-yl-phenyl)-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-5,7-dimethoxy-chromen-4-one as a brown solid.
Reaction SMILES: C([Li])CCC.[CH3:6][S:7]([CH2:9][S:10][CH3:11])=[O:8].Br[CH2:13][CH:14]([CH2:23]Br)[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCCCCC.C1COCC1.ClCCl>[CH3:6][S:7]([C:9]1([S:10][CH3:11])[CH2:13][CH:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:23]1)=[O:8]
Reactant: CSCS(C)=O
Reactant: BrCC(CBr)OCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: ClCCl
Product: CSC1(S(C)=O)CC(OCc2ccccc2)C1
Reaction time: 3 h
Yield: 55.5 %

Procedure:
2.5 M of n-butyllithium in hexane (19 mL) was added to a solution of (methylsulfinyl)(methylthio)methane (5.0 g, 0.040 mol) in THF (10 mL) dropwise at −10° C. and the mixture was stirred for 3 h. To the resultant solution was added dropwise [2-bromo-1-(bromomethyl)ethoxy]methylbenzene (4.9 g, 0.016 mol) at −70° C. over 30 min. The mixture was stirred at this temperature for 3 h and then at rt over night. The reaction was diluted with dichloromethane and washed with water. The aqueous phases were extracted with dichloromethane. The organic layers were combined, washed with brine, dried over MgSO4, concentrated and purified with Combiflash (silica gel, 0-55% EtOAc/Hex) to give the desired product (2.4 g, 56%) as brown oil. LCMS (M+Na) 293.3. 1H NMR (400 MHz, CDCl3): δ 7.30 (5H, m), 4.45 (2H, s), 4.33 (1H, m), 2.75 (2H, m), 2.65 (2H, m), 2.41 (3H, s), 2.12 (3H, s) ppm.
Reaction SMILES: [ClH:1].[NH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([NH2:15])=[NH:14])[C:3]([NH2:5])=[NH:4].NCCCCCCN.Cl>>[Cl-:1].[NH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([NH2:15])=[NH:14])[C:3]([NH2:5])=[NH:4]
Reactant: Cl
Agent: N=C(N)NCCCCCCNC(=N)N
Agent: NCCCCCCN
Product: [Cl-]
Temperature: 80 °C
Reaction time: 2 h

Procedure:
The diguanidinium salts may be prepared by the conventional method of reacting a diamine salt (XH.H2N--R--NH2.HX) with cyanamid (H2N--C≡N, R and X being as hereinabove mentioned). An amine salt or a mixture of amine salts may also be used. The molar ratio between the diamine salt and the cyanamid is at least 1:2. By way of example, 1,6-bisguanidinohexane hydrochloride, having the formula: ##STR2## is prepared from 1,6-diaminohexane and cyanamid by introducing 1 mole of diamine, which has been previously dried and dissolved in isopropyl alcohol, into a flask equipt with a stirrer, a thermometer and an outlet tube linked to a Dan and Stark decanter provided with a water cooler. Then, 3 moles of hydrochloric acid are slowly introduced into the flask. After reaction, the water and isopropyl alcohol are removed. Xylene is then added and the mixture is heated under reflux in order to remove any remaining traces of water. When the mixture has cooled down to about 80° C., 2 moles of cyanamid are added to it and the reaction mixture is heated to 140° C. and held there for 2 hours. After cooling, the reaction mixture is filtered, washed with alcohol, stirred at 60° C. for 30 minutes in the presence of alcohol containing about 1% active carbon, and filtered on a millipore filter. After elimination of residual solvent, 1,6-bisguanidinohexane chloride is obtained with a purity of about 98%.