Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([CH:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)[C:3]([OH:5])=[O:4].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>>[C:13]([NH:1][CH:2]([CH:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)[C:3]([OH:5])=[O:4])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NC(C(=O)O)C1CCC(O)CC1
Reactant: O=C(Cl)c1ccccc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: O=C1CCC(C(NC(=O)c2ccccc2)C(=O)O)CC1

Procedure:
Bicyclic diamines of general formula (32), wherein P2 is a nitrogen protecting group, can be prepared as described in (Org. Mass Spectrum. (1984) 19(9), 459-460). Amino(4-hydroxyphenyl)acetic acid, purchased commercially, can be treated with Raney nickel and heat to provide amino(4-hydroxycyclohexyl)acetic acid. Amino(4-hydroxycyclohexyl)acetic acid can be treated with benzoyl chloride and then oxidized with Jones' reagent to provide (benzoylamino)(4-oxocyclohexyl)acetic acid. (Benzoylamino)(4-oxocyclohexyl)acetic acid can be subjected to a Beckmann rearrangement using hydroxyl amine and a sulfonyl chloride such as phenyl sulfonyl chloride to provide (benzoylamino)(7-oxo-4-azepanyl)acetic acid. (Benzoylamino)(7-oxo-4-azepanyl)acetic acid can be treated with concentrated HCl and heat to provide 2-amino-3-(2-aminoethyl)hexanedioic acid. 2-Amino-3-(2-aminoethyl)hexanedioic acid can be distilled at 180-200° C./0.1 torr to provide octahydro[1,7]naphthyridine-2,8-dione. Octahydro[1,7]naphthyridine-2,8-dione can be treated with lithium aluminum hydride and monoprotected with a nitrogen protecting reagent such as acetyl chloride/acetic anhydride, di-tert-butyl dicarbonate, benzyloxycarbonyl chloride, or benzyl bromide to provide bicyclic diamines of general formula (32).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].[Br:31][CH2:32][CH2:33][CH2:34][CH2:35]Br>CN(C)C=O.[Cl-].[Na+].O>[Br:31][CH2:32][CH2:33][CH2:34][CH2:35][N:19]1[C:18]([O:22][CH3:23])=[N:17][C:16]2[C:20]1=[N:21][C:13]([O:12][CH2:8][CH2:9][CH2:10][CH3:11])=[N:14][C:15]=2[NH2:24]
Reactant: BrCCCCBr
Reactant: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCBr)c2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The compound obtained in Example 2-1 step (v) (0.5 g) was added to potassium carbonate (0.92 g) and 1,4-dibromobutane (0.85 ml) in dimethylformamide (5 ml), and the mixture was stirred at room temperature for 16 hours. To the reaction solution was added brine and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and concentrated to dryness. The residue was purified by flash column chromatography (ethyl acetate) to give the titled compound, as a white solid. Yield: 370 mg (70%).
Reaction SMILES: [N:1]1[CH2:2][CH2:3][N:4]2[C:8]=1[CH2:7][S:6][C:5]2=[O:9].[F:10][C:11]([F:32])([F:31])[C:12]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:13]=1[CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([CH:21]=O)[CH2:17][CH2:16]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:32][C:11]([F:10])([F:31])[C:12]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:13]=1[CH2:14][N:15]1[CH2:20][CH2:19][CH:18](/[CH:21]=[C:7]2/[C:8]3[N:4]([CH2:3][CH2:2][N:1]=3)[C:5](=[O:9])[S:6]/2)[CH2:17][CH2:16]1
Reactant: O=C1SCC2=NCCN12
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: O=c1s/c(=C\C2CCN(Cc3ccc(C(F)(F)F)cc3C(F)(F)F)CC2)c2n1CCN=2
Temperature: 60 °C
Reaction time: 8 h
Yield: 16.5 %

Procedure:
To a solution of 2,7-dihydro-3H-imidazo[1,2-c][1,3]thiazol-5-one (260 mg) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (620 mg) in 2-propanol (5 mL) was added piperidinium acetate (292 mg) at room temperature. The reaction mixture was stirred at 60° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) and recrystallized from heptane to give the title compound (140 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[N:7]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH2:22])[N:17]=3)[C:6]=2[CH:23]=1.[CH3:24][C:25]1[O:29][N:28]=[C:27]([C:30]([OH:34])([C:32]#[CH:33])[CH3:31])[CH:26]=1>CS(C)=O.C(N(CC)CC)C.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>[NH2:22][C:18]1[N:17]=[C:16]([N:7]2[C:6]3[CH:23]=[C:2]([C:33]#[C:32][C:30]([C:27]4[CH:26]=[C:25]([CH3:24])[O:29][N:28]=4)([OH:34])[CH3:31])[CH:3]=[CH:4][C:5]=3[N:9]=[C:8]2[O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:21]=[CH:20][N:19]=1
Reactant: Nc1nccc(-n2c(OCC(F)(F)F)nc3ccc(Br)cc32)n1
Reactant: C#CC(C)(O)c1cc(C)on1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(C(C)(O)C#Cc2ccc3nc(OCC(F)(F)F)n(-c4ccnc(N)n4)c3c2)no1
Yield: 38.7 %

Procedure:
A mixture of 4-[6-bromo-2-(2,2,2-trifluoroethoxy)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine (120 mg, 0.31 mmol), 2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol (120 mg, 0.79 mmol) and bis(triphenylphosphine)palladium(II) dichloride (200 mg, 0.28 mmol) in dimethylsulfoxide (2 mL) and triethylamine (1 mL) kept in a 10-mL vial under nitrogen was irradiated with microwave radiation for 2 h at 70° C. The reaction mixture was concentrated in vacuo. The crude product (120 mg) was purified by preparative HPLC to give 55 mg (39%) of 4-[1-(2-aminopyrimidin-4-yl)-2-(2,2,2-trifluoroethoxy)-1H-1,3-benzodiazol-6-yl]-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol as a light yellow solid: 1H NMR (400 MHz, DMSO) delta 8.45 (d, J=5.2 Hz, 1H), 8.17 (s, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.17 (s, 2H), 6.86 (d, J=5.2 Hz, 1H), 6.46 (s, 1H), 6.38 (s, 1H), 5.37-5.30 (m, 2H), 2.41 (s, 3H), 1.82 (s, 3H); LC-MS: m/z=+459 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([N+:16]([O-:18])=[O:17])[CH:4]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[OH:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([N+:16]([O-:18])=[O:17])[CH:4]=1
Reactant: CCOC(=O)COc1ccc(OC)cc1[N+](=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)COc1ccc(O)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a solution of ethyl 2-(4-methoxy-2-nitrophenoxy)acetate 11 (1.0 g, 0.004 mol) in 10 mL dichloromethane cooled in an ice-bath was added aluminum chloride (1.6 g, 0.0133 mol) portion wise. The resulting mixture was gradually warmed to room temperature and then refluxed for 4 h. The progress of the reaction was monitored by thin layer chromatography (TLC). The reaction mixture was washed with saturated sodium bicarbonate solution and dried over sodium sulfate to give ethyl 2-(4-hydroxy-2-nitrophenoxy)acetate 12 which was purified by silica gel column chromatography using a gradient of hexane and ethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([F:14])[C:11]=1[CH:12]=[O:13])[O:5][CH2:6][C:7]#[N:8].[BH4-].[Na+]>CCO>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([F:14])[C:11]=1[CH2:12][OH:13])[O:5][CH2:6][C:7]#[N:8]
Reactant: N#CCOc1cc(F)c(C=O)c(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: N#CCOc1cc(F)c(CO)c(F)c1
Reaction time: 1 h
Yield: 49.3 %

Procedure:
A mixture of 2-(3,5-difluoro-4-formylphenoxy)acetonitrile (531 mg, 2.69 mmol) and NaBH4 (123 mg, 3.20 mmol) in EtOH (7 mL) was stirred 1 h, processed as described previously, and purified by flash chromatography (80% EtOAc/Hex) to afford the title compound (264 mg, 49%). GCMS (EI) m/z 199.0 (M+).
Reaction SMILES: C(Cl)(=O)OC.C(N(CC)CC)C.[CH2:13]([C:15]1[C:20]([O:21]C(OC)=O)=[CH:19][C:18]([O:26]C(OC)=O)=[C:17]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=2)[C:16]=1[CH2:39][C:40]([O:42][CH3:43])=[O:41])[CH3:14].[BH4-].[Na+].N>CO.O1CCCC1.O>[CH2:13]([C:15]1[C:20]([OH:21])=[CH:19][C:18]([OH:26])=[C:17]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=2)[C:16]=1[CH2:39][C:40]([O:42][CH3:43])=[O:41])[CH3:14]
Reactant: CCc1c(OC(=O)OC)cc(OC(=O)OC)c(-c2cccc(OC)c2)c1CC(=O)OC
Agent: COC(=O)Cl
Agent: N
Agent: [BH4-]
Solvent: CO
Solvent: O
Solvent: CCN(CC)CC
Product: CCc1c(O)cc(O)c(-c2cccc(OC)c2)c1CC(=O)OC
Yield: 55 %

Procedure:
In the same manner as in Example 118, methyl 2-acetyl-3,5-bis(methoxycarbonyloxy)-6-(3-methoxyphenyl)phenylacetate was obtained from methyl 2-acetyl-3,5-dihydroxy-6-(3-methoxyphenyl)phenylacetate (320 mg, 0.97 mmol) obtained in the above, using methyl chlorocarbonate (0.2 mL, 2.6 mmol), triethylamine (0.4 mL, 2.9 mmol) and tetrahydrofuran (5.0 mL); and from the resulting compound, obtained was methyl 2-ethyl-3,5-bis(methoxycarbonyloxy)-6-(3-methoxyphenyl)phenylacetate, using sodium borohydride (210 mg, 5.5 mmol), water (3.0 mL) and tetrahydrofuran (5.0 mL). Then, the resulting compound was treated with methanol solution (5.0 mL) of 7 mmol/L ammonia to obtain Compound 142 (170 mg, 55%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][N:16]=3)[NH:11][CH:10]=2)=[O:8])=[CH:5][C:4]=1[CH3:22].Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=1.C[Si](C)(C)N[Si](C)(C)C.[K]>C1COCC1>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][N:16]=3)[N:11]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=3)[CH:10]=2)=[O:8])=[CH:5][C:4]=1[CH3:22]
Reactant: Cc1cccc(CBr)n1
Reactant: COc1ccc(C(=O)c2c[nH]c3cccnc3c2=O)cc1C
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [K]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2cn(Cc3cccc(C)n3)c3cccnc3c2=O)cc1C
Yield: 37.9 %

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1 using 75 mg (0.255 mmol) of 3-(4-Methoxy-3-methyl-benzoyl)-1H-[1,5]naphthyridin-4-one, 56.9 mg (0.306 mmol) of 2-bromomethyl-6-methyl-pyridine, 0.61 mL (0.306 mmol, 0.5 M in toluene) of potassium hexamethyldisilazane, and 2.5 mL of THF. The crude product was purified by flash column chromatography using a gradient of 20-100% ethyl acetate in hexane and further purified on the reverse phase HPLC with a C18 column, gradient of 20-70% acetonitrile—0.1% TFA to yield 38.6 mg of 3-(4-Methoxy-3-methyl-benzoyl)-1-(6-methyl-pyridin-2-ylmethyl)-1H-[1,5]naphthyridin-4-one. LC-MSD, m/z for C24H21N3O3 [M+H]: 400.16 LC retention time on HPLC, C18 column gradient 20-95% acetonitrile with 0.1% TFA in 4 minutes: 1.8 min.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[N:10]=[CH:11][NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C=O)C>[C:3]1([C:9]2[N:10]=[CH:11][N:12]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:13]=2[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)CBr
Reactant: c1ccc(-c2nc[nH]c2-c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cnc(-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.4 %

Procedure:
To a stirred suspension of 9.6 (0.24 mol) of 60% sodium hydride-mineral oil in 100 mL of DMF under nitrogen at 0° C. was added dropwise 50.0 g (0.226 mol) of 4,5-diphenylimidazole in 400 mL DMF. The mixture was allowed to warm, stirred at room temperature 1 hr, and 26.6 mL (0.24 mol) of ethyl bromoacetate was added. The reaction was stirred 18 hr at room temperature, heated on a steam bath 2 hr, cooled, and stripped. The residue was partitioned between water and methylene chloride, dried over MgSO4, and filtered through a silica gel column eluting with methylene chloride-ethyl acetate to provide 50.1 g of an oil that solidified on standing. It may be used in further reactions as is, or it may be recrystallized from ether to yield 35.1 g of product mp 89°-90° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[C:4]([Cl:10])=[N:5][C:6](Cl)=[N:7][CH:8]=1.[CH3:13][N:14]([CH3:22])[C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1.C(N(CC)CC)C>CCOCC.ClCCCl.CC(O)(C)C.[Cl-].[Zn+2].[Cl-]>[Cl:10][C:4]1[C:3]([C:2]([F:12])([F:11])[F:1])=[CH:8][N:7]=[C:6]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([N:14]([CH3:22])[CH3:13])=[CH:16][CH:17]=2)[N:5]=1
Reactant: CN(C)c1ccc(N)cc1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Product: CN(C)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Reaction time: 1 h

Procedure:
To a solution of 5-trifluoromethyl-2,4-dichloropyrimidine (500 mg; 2.3 mmol) in 1:1 DCE/t-BuOH (20 mL) was added Zinc chloride (5.1 mL of a 1 M solution in ether; 2.2 eq) at 0° C. After 1 hour, N,N-dimethyl-1,4-phenylenediamine (313 mg; 1 eq) was added followed by dropwise addition of a solution of triethylamine (279 mg; 1.1 eq) in 5 mL of DCE/t-BuOH. After stirring for 24 hours the reaction was concentrated. The product was obtained as a pale green solid (531 mg; 73%) following crystallization from 25% H2O/methanol. 1H NMR (DMSO-d6, 400 MHz) δ 2.83 (s, 6H), 6.69 (m, 2H), 7.39 (m, 2H), 8.65 (s, 1H), 10.32 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 161.3, 158.8 (br), 158.5 (br), 148.3, 128.2, 123.8 (q, J=268 Hz), 123.0, 113.1, 110.8 (br), 41.0; HPLC ret. time: 7.901 min. LRMS (M+) 317.3, 319.3.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:20]([NH:22][CH2:23][CH2:24][C:25]([F:49])([F:48])[CH2:26][C@@H:27]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[N:28](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[O:21])[CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>ClCCl>[CH3:1][O:2][C:3]([NH:5][C@H:6]([C:20]([NH:22][CH2:23][CH2:24][C:25]([F:48])([F:49])[CH2:26][C@@H:27]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[NH2:28])=[O:21])[CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:4]
Reactant: CCOC(=O)[C@H](CC(F)(F)CCNC(=O)[C@@H](NC(=O)OC)C(c1ccccc1)c1ccccc1)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)[C@@H](N)CC(F)(F)CCNC(=O)[C@@H](NC(=O)OC)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102 %

Procedure:
To a stirred solution of the material from Step 7 (290 mg, 0.419 mmol) in dichloromethane (1.8 mL) at 0° C. were added anisole (0.137 mL, 1.258 mmol) and TFA (0.388 mL, 5.03 mmol). The reaction mixture was stirred at room temperature for 2 hours, poured into saturated aqueous NaHCO3, and extracted with dichloromethane (2×). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to afford 210 mg of the title compound as a colorless foam. LCMS (M+1)=492.
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1O.CCN=C=NCCCN(C)C.CS(O)(=O)=O>O.C(Cl)(Cl)Cl>[F:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:5]([C:6]2[O:8][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=2)=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16]
Reactant: Nc1ccccc1O
Reactant: O=C(O)c1cc([N+](=O)[O-])c(F)c(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CS(=O)(=O)O
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)cc(C(F)(F)F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.6 %

Procedure:
4-Fluoro-3-nitro-5-trifluoromethyl benzoic acid (1.00 g, 4.0 mmol), 2-aminophenol (0.47 g, 4.4 mmol), CHCl3 (20 mL), and WSC (0.83 g, 4.4 mmol) were added together and stirred at room temperature for 1 hour. Water was added, and this was extracted with chloroform/acetone (3:1). After the organic layer obtained was dried over anhydrous sodium sulfate, it was filtered and concentrated. To a dioxane (20 mL) solution of the solid obtained was added methanesulfonic acid (2.28 g, 24 mmol), and this was heated to reflux for 18 hours. After the reaction solution was cooled, water was added, and the precipitated crystals were filtered, and after being washed with water were dried to yield the title compound (0.70 g, 54% yield) as yellowish-brown crystals.
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[C:9]([O:16][CH3:17])[CH:8]=1.[Cl:19][C:20]1[C:21]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:22][CH:23]=[C:24]([Cl:26])[CH:25]=1>>[Cl:19][C:20]1[C:21]([N:27]2[CH2:32][CH2:31][N:30]([C:11]([C:10]3[CH:14]=[CH:15][C:7]([N:3]4[CH2:4][CH2:5][CH2:6][S:2]4(=[O:1])=[O:18])=[CH:8][C:9]=3[O:16][CH3:17])=[O:13])[CH2:29][CH2:28]2)=[N:22][CH:23]=[C:24]([Cl:26])[CH:25]=1
Reactant: COc1cc(N2CCCS2(=O)=O)ccc1C(=O)O
Reactant: Clc1cnc(N2CCNCC2)c(Cl)c1
Product: COc1cc(N2CCCS2(=O)=O)ccc1C(=O)N1CCN(c2ncc(Cl)cc2Cl)CC1
Yield: 106.8 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-methoxybenzoic acid (266 mg) described in Preparation Example 19 and 1-(3,5-dichloropyridin-2-yl)piperazine (227 mg) and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (507 mg) was obtained.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[C:8]([C:24](O)=[O:25])[C:9]2[CH2:10][CH2:11][N:12]([CH:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[C:13](=[O:16])[C:14]=2[CH:15]=1.[ClH:27].[NH2:28][C@@H:29]([CH2:47][C:48]1[CH:53]=[C:52]([F:54])[CH:51]=[C:50]([F:55])[CH:49]=1)[C@H:30]([OH:46])[CH2:31][NH:32][C:33]1([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=2)[CH2:35][CH2:34]1.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl>CN(C)C=O.C(OCC)C.O1CCOCC1.C(OCC)(=O)C.O.C(N(CC)CC)C>[ClH:27].[F:54][C:52]1[CH:53]=[C:48]([CH:49]=[C:50]([F:55])[CH:51]=1)[CH2:47][C@H:29]([NH:28][C:24]([C:8]1[C:9]2[CH2:10][CH2:11][N:12]([CH:17]([CH2:18][CH2:19][CH3:20])[CH2:21][CH2:22][CH3:23])[C:13](=[O:16])[C:14]=2[CH:15]=[C:6]([C:2]2[O:1][CH:5]=[CH:4][N:3]=2)[CH:7]=1)=[O:25])[C@H:30]([OH:46])[CH2:31][NH:32][C:33]1([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:43])[F:44])[CH:37]=2)[CH2:35][CH2:34]1
Reactant: CCCC(CCC)N1CCc2c(C(=O)O)cc(-c3ncco3)cc2C1=O
Reactant: N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNC1(c2cccc(C(F)(F)F)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(CCC)N1CCc2c(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNC3(c4cccc(C(F)(F)F)c4)CC3)cc(-c3ncco3)cc2C1=O
Reaction time: 15 h
Yield: 72.3 %

Procedure:
Added to a solution of 150 mg of 7-(2-oxazolyl)-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid in 4 cm3 of anhydrous dimethylformamide and under an argon atmosphere are 0.19 cm3 of triethylamine and 201 mg of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)butan-2-ol hydrochloride then 69 mg of 1-hydroxy-7-azabenzotriazole and 97 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The solution is kept stirring for 15 h at a temperature close to 20° C. 50 cm3 of water and 50 cm3 of ethyl acetate are added to the reaction medium. After decanting, the organic phase is washed with 50 cm3 of a saturated aqueous solution of ammonium chloride, two lots of 20 cm3 of water and 20 cm3 of a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (5 kPa). The residual solution (around 3 cm3) is filtered through a pellet of 15 g of 40-63 μm silica. The silica pellet is washed with 40 cm3 of ethyl acetate. The filtrate is concentrated to dryness under reduced pressure (5 kPa). 255 mg is obtained of a white powder which is dissolved in 10 cm3 of ethyl ether. Added thereto, while stirring, is 0.2 cm3 of a 4N solution of hydrochloric acid in dioxane at a temperature of 20° C. The reaction mixture precipitates. The precipitate is filtered, washed with two lots of 5 cm3 of isopropyl ether and dried under vacuum at a temperature of 35° C. 236 mg of N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)propyl]-7-(2-oxazolyl)-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide hydrochloride are obtained in the form of white crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[C:5]([N:7](C(=O)C1C=CC=C(C)C=1)[C:8]1[C:17]([C:18]#[N:19])=[C:16]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1)=[O:6].[OH-].[K+].C(O)(=O)C.C(=O)([O-])O.[Na+]>C(#N)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[C:5]([NH:7][C:8]1[C:17]([C:18]#[N:19])=[C:16]([NH:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1)=[O:6]
Reactant: Cc1cccc(C(=O)N(C(=O)c2cccc(C)c2)c2nc3ccccc3c(NCc3ccccc3)c2C#N)c1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: Cc1cccc(C(=O)Nc2nc3ccccc3c(NCc3ccccc3)c2C#N)c1
Yield: 80.7 %

Procedure:
To the solution of 5 g of 3-methyl-N-(3-methylbenzoyl)-N-(4-benzylamino-3-cyanoquinolin-2-yl)benzamide in 80 ml of acetonitrile 20 ml of 1N methanolic potassium hydroxide solution are added. The reaction mixture is refluxed for 3 minutes, then 3 ml of glacial acetic acid is added to it, then it is neutralized with 50 ml of 1M sodium hydrogen carbonate solution and the resulting crystals are filtered off. The white crystalline material is recrystallized from 130 ml of acetonitrile to give 3.1 g of the title compound of general formula (I). Mp.: 230° C.
Reaction SMILES: [Br-].[C:2]([NH:10][C:11]1[CH:16]=[CH:15][N+:14]([CH2:17][CH2:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)=[CH:13][CH:12]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[BH4-].[Na+]>C(O)(C)C.O>[C:2]([NH:10][CH:11]1[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:16]1)(=[O:9])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Nc1cc[n+](CCc2c[nH]c3ccccc23)cc1)c1ccccc1
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: O=C(NC1CCN(CCc2c[nH]c3ccccc23)CC1)c1ccccc1
Yield: 82 %

Procedure:
A suspension of 4-benzamido-1-[2-(3-indolyl)ethyl] pyridinium bromide (4.2 g.) and sodium borohydride (1.14 g.) in isopropanol (50 ml.) was refluxed for 31/2 hours. After cooling, the reaction mixture was diluted with water (50 ml.). The product was separated by filtration, washed with water then with acetone and dried to give the title compound in 82% yield, m.p. 203°- 5° C.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2]1.[N:12]1([C:17]2[CH:33]=[CH:32][C:20]([O:21][CH2:22][CH2:23][NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:19][CH:18]=2)[CH:16]=[CH:15][N:14]=[CH:13]1>CO>[N:12]1([C:17]2[CH:18]=[CH:19][C:20]([O:21][CH2:22][CH2:23][N:24]([CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:2][CH:3]([OH:1])[CH2:4][O:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:32][CH:33]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: c1ccc(OCC2CO2)cc1
Reactant: c1ccc(CNCCOc2ccc(-n3ccnc3)cc2)cc1
Solvent: CO
Product: OC(COc1ccccc1)CN(CCOc1ccc(-n2ccnc2)cc1)Cc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 3.2 mL (23.9 mmol) 1,2-epoxy-3-phenoxypropane in 20 mL MeOH, add 6.99 g (23.9 mmol) 2-[4-(1H-imidazol-1-yl)phenoxy]-N-(phenylmethyl)ethanamine as the free base described above. Stir at room temperature under a nitrogen atmosphere. Follow the progress of the reaction by thin-layer chromatography on silica gel (methylene chloride:methanol, 9:1). At the completion of the reaction, evaporate the solvents. The resulting oil is chromatographed on a silica gel column using (petroleum ether :acetone, 8:2). Collect the appropriate fractions and remove the solvents to give the title compound.