Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@H:5]([CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12](Cl)=[N:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[O:19][CH3:20])(=[O:3])[CH3:2].[F:27][C:28]1[C:36]([OH:37])=[CH:35][CH:34]=[C:33]2[C:29]=1[CH:30]=[C:31]([CH3:38])[NH:32]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([O:4][C@H:5]([CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([O:37][C:36]3[C:28]([F:27])=[C:29]4[C:33](=[CH:34][CH:35]=3)[NH:32][C:31]([CH3:38])=[CH:30]4)=[N:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[O:19][CH3:20])(=[O:3])[CH3:2]
Reactant: COc1cc2c(Cl)ncnc2cc1OC[C@@H](CN1CCCC1)OC(C)=O
Reactant: Cc1cc2c(F)c(O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OC[C@@H](CN1CCCC1)OC(C)=O
Temperature: 90 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
A suspension of (2R)-7-(2-acetoxy-3-(pyrrolidin-1-yl)propoxy)-4-chloro-6-methoxyquinazoline (530 mg, 1.4 mmol) and 4-fluoro-5-hydroxy-2-methylindole (277 mg, 1.68 mmol), (prepared as described for the starting material in Example 237), in DMF (8 ml) containing potassium carbonate (290 mg, 2.1 mmol) was stirred at 90° C. for 2 hours. After cooling, the volatiles were removed under vacuum and the residue was purified by column chromatography eluting with methylene chloride/methanol (95/5) to give (2R)-7-(2-acetoxy-3-(pyrrolidin-1-yl)propoxy)-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxyquinazoline (580 mg, 81%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[C:4]([CH2:12]Br)[CH:3]=1.[CH3:14][O:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[CH2:24][NH2:25].C(N(CC)CC)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:10][CH:11]=1)[C:6](=[O:8])[N:25]([CH2:24][C:17]1[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:16]=1[O:15][CH3:14])[CH2:12]2
Reactant: COc1ccc(CN)c(OC)c1
Reactant: COC(=O)c1ccc(Br)cc1CBr
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(CN2Cc3cc(Br)ccc3C2=O)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.2 %

Procedure:
To a solution of methyl 4-bromo-2-(bromomethyl)benzoate (1.0 g, 3.25 mmol) and (2,4-dimethoxyphenyl)methanamine (0.65 g, 3.90 mmol) in THF (16 mL) was added triethylamine (0.91 mL, 6.5 mmol), and the resulting mixture was stirred at room temperature for 16 h. The resulting solid was filtered off, and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography on silica gel using 1:4 EtOAc:hexanes as the eluent to give the title compound as a colorless solid (0.52 g, 44%).
Reaction SMILES: [S:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:15].[C:16]1(=O)[CH2:20][CH2:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:16]1([NH:15][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:8]=2[NH:7][C:6]([C:2]2[S:1][CH2:5][CH2:4][N:3]=2)=[CH:14]3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C1CCCC1
Reactant: Nc1cccc2cc(C3=NCCS3)[nH]c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: c1cc(NC2CCCC2)c2[nH]c(C3=NCCS3)cc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.5 %

Procedure:
[2-(4,5-Dihydro-1,3-thiazol-2-yl)-1H-indol-7-yl]-amine (15 mg, 0.07 mmol) prepared in Step A was dissolved in 1,2-dichloroethane (10 mL). Cyclopentanone (12 mg, 0.14 mmol) and sodium triacetoxyborohydride (29 mg, 0.14 mmol) were added thereto, and the mixture was stirred for 3 h at room temperature. The reaction was quenched by water, and the reaction mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed under reduced pressure, and the residue was purified by column chromatography to give the title compound (6.7 mg, Yield 34%).
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)([O-:3])=[O:2].[C:9]([O-])([O-])=O.[K+].[K+].IC>C(#N)C>[CH3:9][N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]=[CH:6]1
Reactant: O=[N+]([O-])c1c[nH]cn1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: Cn1cnc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 80 %

Procedure:
To a mixture of 4-nitro-1H-imidazole (2.0 g, 17.7 mmol) and K2CO3 (3.67 g, 26.5 mmol) in acetonitrile (20 mL) was added iodomethane (1.3 mL, 3.0 g, 21.2 mmol) dropwise while stirring at room temperature. The resulting mixture was stirred at 60° C. overnight. It was then evaporated under reduced pressure and the residue was diluted with water (20 mL). The mixture was extracted with dichloromethane (2×20 mL). The combined extract was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 100:1 dichloromethane/methanol to afford 268a as a yellow solid (1.8 g, 82%). MS-ESI: [M+H]+ 128.1. 1H NMR (500 MHz, DMSO-d6) δ 8.37 (s, 1H), 7.82 (s, 1H), 3.76 (s, 3H).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[N:15](C(OC(C)(C)C)=O)[C:9]2=[N:10][C:11]([Br:14])=[CH:12][CH:13]=[C:8]2[CH:7]=1)=[O:5].FC(F)(F)C(O)=O>ClCCl>[CH2:2]([O:3][C:4]([C:6]1[NH:15][C:9]2=[N:10][C:11]([Br:14])=[CH:12][CH:13]=[C:8]2[CH:7]=1)=[O:5])[CH3:1]
Reactant: CCOC(=O)c1cc2ccc(Br)nc2n1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc2ccc(Br)nc2[nH]1
Yield: 89.2 %

Procedure:
A stirred solution of 18.4 g (0.05 mol) 6-bromo-pyrrolo[2,3-b]pyridine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester in 165 mL dichloromethane was cooled to 0 deg C. and then 38.0 mL trifluoroacetic acid was added over 5 min. The cooling bath was removed and after 2 h at room temperature the reaction mixture was poured into 500 mL saturated aqueous sodium bicarbonate solution. The organic layer was extracted three times with 150 mL portions of dichloromethane; the combined organic phases were washed with 200 mL brine, dried over magnesium sulfate and filtered. The solvent was evaporated and the residue was dried under high vacuum to give 12.0 g (95.5%) of the desired product as a colourless solid.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]([NH:14][NH:15]C(OC(C)(C)C)=O)=[O:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]1([C:7]2[O:11][C:10]([C:12]([NH:14][NH2:15])=[O:13])=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NNC(=O)c1ccc(-c2ccccc2)o1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NNC(=O)c1ccc(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.2 %

Procedure:
To a solution of tert-butyl 2-(5-phenylfuran-2-carbonyl)hydrazinecarboxylate (300 mg, 1 mmol) in DCM (10 mL), TFA (4.85 g, 50 mmol) was added dropwise. The mixture was stirred at RT overnight, then concentrated under reduced pressure and purified by silica gel column chromatography (EtOAc:Petroleum ether:TEA=50:50:1) to afford 5-phenylfuran-2-carbohydrazide as a light yellow solid (150 mg, 74%). MS (ES+) C11H10N2O2 requires: 202. found: 203 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C-]#N.[K+].[C:15](#[N:17])[CH3:16]>C1OCCOCCOCCOCCOCCOC1>[C:15]([CH2:16][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])#[N:17]
Reactant: COC(=O)c1cccc(Br)c1
Reactant: CC#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [C-]#N
Agent: [K+]
Product: COC(=O)c1cccc(CC#N)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 91 %

Procedure:
To a solution of methyl 3-bromobenzoate (10.0 g, 44 mmol) in acetonitrile (100 mL) were added potassium cyanide (5.7 g, 87 mmol) and 18-crown-6 (1.0 g), and the mixture was stirred at room temperature for 3 days. The reaction mixture was filtrated, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=5/95→30/70). The combined solution was concentrated under reduced pressure to give the title compound (7.0 g, 91%) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:10]([CH2:11][C:12](=[O:24])[CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:27][O:28][C:29](=O)[O:30]C>C1COCC1.CCOC(C)=O>[CH3:27][O:28][C:29]([CH:11]1[C:12](=[O:24])[CH2:13][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:10]1[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:15]2)=[O:30]
Reactant: CC(C)(C)OC(=O)N1CC2CC(=O)CC(C1)N2C(=O)OC(C)(C)C
Reactant: COC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C1C(=O)CC2CN(C(=O)OC(C)(C)C)CC1N2C(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 58.9 %

Procedure:
Compound W (15.91 g, 46.7 mmol) was dissolved in THF (100 mL). NaH (55% in oil, 4.71 g, 98 mmol) was added portionwise, followed by dimethylcarbonate (8.86 mL, 105 mmol). The reaction mixture was heated to reflux for 1 h. The mixture was cooled to 0° C. with an ice bath, and treated cautiously with ice-water (50 mL). The org. layer was diluted with EtOAc (200 mL), and washed with aq. 1M HCl (100 mL), and with brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 1:3→1:2→1:1→2:1) yielded the title compound (Rf=0.7, EtOAc/heptane 1:1) as a yellow oil (10.96 g, 58%). LC-MS: tR=1.03, ES+: 399.25.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[F:19][C:20]([F:34])([O:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](O)=[O:29])[CH:21]([F:23])[F:22]>>[O:15]=[C:13]1[NH:12][C:8]2=[N:9][CH:10]=[CH:11][C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:28](=[O:29])[C:27]4[CH:31]=[CH:32][CH:33]=[C:25]([O:24][C:20]([F:19])([F:34])[CH:21]([F:22])[F:23])[CH:26]=4)[CH:18]=[CH:17][CH:16]=3)=[C:7]2[NH:14]1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Reactant: O=C(O)c1cccc(OC(F)(F)C(F)F)c1
Product: O=C(Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1)c1cccc(OC(F)(F)C(F)F)c1
Yield: 36 %

Procedure:
Method H2 was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and 3-(1,1,2,2-tetrafluoroethoxy)benzoic acid to afford the title compound as a light pink solid (69 mg, 36%). 1H-NMR (δ, ppm, DMSO-d6): 6.49 (d, 1H, HPy,5, J=5.8 Hz), 6.86 (t, 1H, CF2H, J=51.7 Hz), 6.94 (d, 1H, Harom, J=7.2 Hz), 7.44 (t, 1H, Harom, J=8.2 Hz), 7.54 (d, 1H, Harom, J=7.6 Hz), 7.62-7.67 (m, 3H, Harom), 7.80-7.82 (m, 2H, Harom), 7.95 (d, 1H, Harom, J=7.8 Hz) 10.49 (s, 1H, NHamide), 11.25 (s, 1H, NHurea), 11.44 (s, 1H, NHurea). 13C-NMR (δ, ppm, DMSO-d6): 105.81 (CF2), 106.61, 107.79 (CF2) 110.90, 113.78, 114.68, 116.38, 120.76, 124.77, 126.26, 130.2, 130.40, 136.62, 140.51, 141.35, 144.60, 147.17, 148.04, 154.22, 154.75, 164.17. HRMS (EI): m/z [M+H] calcd for C21H14F4N4O4: 463.1024, found: 463.1022.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH:6]([C:7]#[CH:8])[O:5][C:4](=[O:9])[NH:3]1.[Cl:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19](I)[CH:20]=2)[N:15]=[CH:14][N:13]=1.C(NC(C)C)(C)C>C1COCC1.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.[Cu](I)I>[Cl:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=[C:14]([C:8]#[C:7][CH:6]2[O:5][C:4](=[O:9])[NH:3][C:2]2([CH3:10])[CH3:1])[N:13]=1
Reactant: C#CC1OC(=O)NC1(C)C
Reactant: Clc1ncnc2ccc(I)cc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC1(C)NC(=O)OC1C#Cc1nc(Cl)c2ccccc2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.2 %

Procedure:
A mixture of 4,4-Dimethyl-5-ethynyl-2-oxazolidinone (1.10 g, 7.90 mmol), 4chloro-6-iodoquinazoline (1.63 g, 5.60 mmol), dichlorobis(triphenylphosphine)palladium(II) (200 mg, 0.28 mmol), copper iodide (53 mg, 0.28 mmol), and diisopropylamine (0.57 g, 5.60 mmol) in anhydrous THF (30 mL) was stirred at room temperature under nitrogen for 4 hours. After concentration, the residue was dissolved in CH2Cl2 (80 mL), washed with aqueous NH4Cl and brine, dried over sodium sulfate, and concentrated to give the crude product as brown oil. Purification by silica gel column using 50-70% EtOAc in hexane afforded 1.22 g (72%) of yellow solid: 1H NMR (CDCl3) δ 1.49 (s, 3H), 1.53 (s, 3H), 5.14 (s, 1H), 5.57 (brs, 1H), 7.95 (dd, 1H), 8.04 (d, 1H, J=8.8 Hz), 8.38 (d, 1H, J=2.0 Hz), 9.05 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[C:5]#[C:6][C:7](O)([CH3:9])[CH3:8])[CH3:2].CCN(S(F)(F)[F:18])CC>ClCCl>[CH2:1]([O:3][C:4](=[O:11])[C:5]#[C:6][C:7]([F:18])([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C#CC(C)(C)O
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C#CC(C)(C)F
Temperature: -78 °C
Reaction time: 2 h
Yield: 20.4 %

Procedure:
A solution of 4-hydroxy-4-methyl-pent-2-ynoic acid ethyl ester (4.9 g, 155 mmol) in dichloromethane (30 mL) was cooled to −78° C. and treated with DAST (5.3 g, 161.2 mmol) the reaction mixture was stirred for 2 h at −78° C. then warmed to room temperature and poured over ice. After the ice had melted, the phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried (sodium sulfate) and concentrated on a rotary evaporator to provide 5.0 g (100%) of 4-fluoro-4-methyl-pent-2-ynoic acid ethyl ester as a brown oil.
Reaction SMILES: O1CCCC1.[Cl:6][C:7]1[C:8]([CH:19]([C:33]2[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=2[F:40])[S:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:9][C:10]([CH2:13][CH2:14][C:15]([O:17]C)=[O:16])=[N:11][CH:12]=1.[OH-].[Na+].Cl>CO>[Cl:6][C:7]1[C:8]([CH:19]([C:33]2[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=2[F:40])[S:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:30])[F:32])=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:9][C:10]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[N:11][CH:12]=1
Reactant: COC(=O)CCc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(C(F)(F)F)cc2)c(Cl)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(C(F)(F)F)cc2)c(Cl)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.6 %

Procedure:
To a tetrahydrofuran (2 ml) solution of methyl 3-[5-chloro-4-[(2,5-difluorophenyl)(4-trifluoromethylphenylsulfonyl)methyl]pyridin-2-yl]propionate (92 mg, 0.17 mmol) were added methanol (2 ml) and a 1N aqueous solution of sodium hydroxide (2 ml) at 0° C. The resulting mixture was stirred at room temperature for 2 hours. To the reaction mixture was added 1N hydrochloric acid and the product thus obtained was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was washed with ethanol and collected by filtration to give the title compound (61 mg, 0.12 mmol, 68%) as a white solid.
Reaction SMILES: [OH-].[Mg+2:2].[OH-].C(=O)([O-])[O-].[C:8]([CH2:11][S:12][CH2:13][C:14]([OH:16])=[O:15])([OH:10])=[O:9]>>[C:8]([CH2:11][S:12][CH2:13][C:14]([O-:16])=[O:15])([OH:10])=[O:9].[Mg+2:2].[C:8]([CH2:11][S:12][CH2:13][C:14]([O-:16])=[O:15])([OH:10])=[O:9]
Reactant: O=C(O)CSCC(=O)O
Agent: O=C([O-])[O-]
Agent: [Mg+2]
Agent: [OH-]
Product: O=C([O-])CSCC(=O)O

Procedure:
Magnesium (carboxymethylthio)acetate is prepared by reacting magnesium hydroxide or carbonate with (carboxymethylthio) acetic acid, this salt being a mucolytic agent of the invention. It is called compound LJ 1165 hereinafter.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[C:27]5[CH:28]=[CH:29][CH:30]=[C:21]([C:22]=45)[S:20]3(=[O:32])=[O:31])[CH2:14][CH:15]=2)=[CH:2]1.[H-].[Na+].[CH3:35]I>O1CCOCC1.O>[CH3:35][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[C:27]5[CH:28]=[CH:29][CH:30]=[C:21]([C:22]=45)[S:20]3(=[O:32])=[O:31])[CH2:12][CH:11]=2)=[CH:2]1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CC=C(c2c[nH]c3ccccc23)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(C2=CCN(CCCN3c4cccc5cccc(c45)S3(=O)=O)CC2)c2ccccc21
Temperature: 20 °C
Reaction time: 2 h
Yield: 29.1 %

Procedure:
A mixture of 2-{3-[4-(3-indolyl)-1,2,3,6-tetrahydro-1-pyridyl]propyl}naphtho [1,8-cd]isothiazole 1,1-dioxide (11 g) in dmethylformamide (150 cc) is added over 30 minutes to sodium hydride (1.3 g) in a 50% dispersion in vaseline oil, under a current of argon, maintaining the temperature at about 20° C. The reaction medium is stirred for 2 hours at a temperature of about 20° C. then a solution of methyl iodide (3.9 g) in dioxane (50 cc) is added over 15 minutes. Stirring is maintained for 15 hours at a temperature of about 20° C. The reaction mixture is redissolved in distilled water (250 cc) and the organic phase is extracted with dichloromethane (4×100 cc) and then washed with distilled water (400 cc), dried over anhydrous magnesium sulphate, filtered and concentrated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). The residue obtained is purified by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with dichloromethane as eluant, and recrystallized from boiling methyl ethyl ketone (70 cc). 2-{3-[4-(1-Methyl-3-indolyl)1,2,3,6-tetrahydro-1-pyridyl]propyl }naphtho[1,8-cd]isothiazole 1,1-dioxide (3.3 g) is obtained, m.p. 161° C.
Reaction SMILES: C[NH:2]C(C1N(CC2N3C=C(C)C=CC3=NC=2C2C=CC(C)=CC=2)N=CN=1)=O.[F:28][C:29]1[CH:30]=[CH:31][C:32]2[N:33]([C:35]([CH2:45][N:46]3[CH:50]=[N:49][C:48]([C:51]([O:53]C)=O)=[N:47]3)=[C:36]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[N:37]=2)[CH:34]=1.N>>[F:28][C:29]1[CH:30]=[CH:31][C:32]2[N:33]([C:35]([CH2:45][N:46]3[CH:50]=[N:49][C:48]([C:51]([NH2:2])=[O:53])=[N:47]3)=[C:36]([C:38]3[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=3)[N:37]=2)[CH:34]=1
Reactant: COC(=O)c1ncn(Cc2c(-c3ccc(F)cc3)nc3ccc(F)cn23)n1
Reactant: CNC(=O)c1ncnn1Cc1c(-c2ccc(C)cc2)nc2ccc(C)cn12
Agent: N
Product: NC(=O)c1ncn(Cc2c(-c3ccc(F)cc3)nc3ccc(F)cn23)n1

Procedure:
The title compound was prepared according to the procedure described for compound 68 from methyl 1-((6-fluoro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-1H-1,2,4-triazole-3-carboxylate and ammonia. m/e+ 355 for C17H13F2N6O (M+H)+.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH2:9]([C:13]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[N:16]2[N:27]=[CH:28][CH:29]=[C:15]2[N:14]=1)[CH2:10][CH2:11][CH3:12].O>COCCOC.O>[Br:8][C:29]1[CH:28]=[N:27][N:16]2[C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[CH:18][C:13]([CH2:9][CH2:10][CH2:11][CH3:12])=[N:14][C:15]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCc1cc(OCc2ccncc2)n2nccc2n1
Solvent: O
Solvent: COCCOC
Product: CCCCc1cc(OCc2ccncc2)n2ncc(Br)c2n1
Reaction time: 1 h
Yield: 93.8 %

Procedure:
NBS (0.38 g) was added to a solution of 0.5 g of 5-n-butyl-7-(4-pyridylmethoxy)pyrazolo[1,5-a]pyrimidine in 10 ml of DME-water (3:1) at 0° C. and stirred for 1 hour. The mixture was stirred at room temperature for another 2 hours to allow the reaction to proceed. Some water was added to the reaction mixture, and the crystals precipitated were collected by filtration to provide 0.6 g of the title compound as colorless crystals. The structure and melting point of the compound obtained are shown in Table 1.
Reaction SMILES: [Br:1][CH:2]([P:6](=[O:9])([OH:8])[OH:7])[CH:3]([OH:5])[CH3:4].[Na].[C:11](Br)(=[O:13])[CH3:12]>>[Br:1][CH:2]([P:6](=[O:8])([OH:7])[OH:9])[CH:3]([O:5][C:11](=[O:13])[CH3:12])[CH3:4]
Reactant: CC(O)C(Br)P(=O)(O)O
Reactant: CC(=O)Br
Agent: [Na]
Product: CC(=O)OC(C)C(Br)P(=O)(O)O
Temperature: 25 °C

Procedure:
One and one-half grams of (1-bromo-2-hydroxypropyl)phosphonic acid prepared from the sodium salt obtained in Example 22 is heated with 5 ml. of acetyl bromide for one hour. The excess acetyl bromide is distilled off under reduced pressure and ice-cold water is added to the residue. The solution is stirred at room temperature and lyophilized to give (1bromo-2-acetoxypropyl)phosphonic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Br[CH2:16][CH2:17][O:18][CH3:19].[H-].[Na+]>C1COCC1>[CH3:19][O:18][CH2:17][CH2:16][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 25 °C

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (200 mg, 1.03 mmol), 1-bromo-2-methoxyethane (280 mg, 2.01 mmol), and NaH (200 mg, 4 mmol) in THF (15 mL) was stirred at reflux for 24 hours, cooled to the ambient temperature, and concentrated in vacuo. The residue was treated with HCl(aq) and extracted with EtOAc. The insoluble solid was removed by filtration, and the organic solution was concentrated to give the title compound. MS (m/z): 253 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([NH2:15])=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1.[F:17][C:18]([F:26])([F:25])[C:19]([F:24])([F:23])[C:20](O)=O>>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=2)=[CH:6][C:5]2[NH:15][C:20]([C:19]([F:24])([F:23])[C:18]([F:26])([F:25])[F:17])=[N:16][C:4]=2[CH:3]=1
Reactant: O=C(O)C(F)(F)C(F)(F)F
Reactant: Nc1cc(Cl)c(-c2ccc(F)cc2)cc1N
Product: Fc1ccc(-c2cc3[nH]c(C(F)(F)C(F)(F)F)nc3cc2Cl)cc1
Yield: 43 %

Procedure:
A solution of 4-chloro-5-(4-fluorophenyl)benzene-1,2-diamine (200 mg, 0.85 mmol) in pentafluoropropanoic acid (2 ml) was stirred for 10 h at 80° C. The reaction was then quenched by the addition of water (100 ml), pH adjusted to 7 with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3×100 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue, which was purified by Pre-TLC with 10% ethyl acetate in petroleum ether to produce 5-chloro-6-(4-fluorophenyl)-2-(pentafluoroethyl)-1H-1,3-benzodiazole as a white solid (132.4 mg, 43%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O-:7])=[O:6].[Na+].[C:12]([C:16]([CH2:18][N:19]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]([CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:22][C@@H:21]([NH:36][C:37](OC2C=CC=CC=2)=[O:38])[C:20]1=[O:46])=[O:17])([CH3:15])([CH3:14])[CH3:13]>CN(C)C1C=CN=CC=1.CS(C)=O>[C:12]([C:16]([CH2:18][N:19]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]([CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:22][C@@H:21]([NH:36][C:37](=[O:38])[NH:1][C:2]2[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=2)[C:5]([OH:7])=[O:6])[C:20]1=[O:46])=[O:17])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)C(=O)CN1C(=O)[C@H](NC(=O)Oc2ccccc2)CN(C2CCCCC2)c2ccccc21
Reactant: Nc1cccc(C(=O)[O-])c1
Agent: CN(C)c1ccncc1
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)C(=O)CN1C(=O)[C@H](NC(=O)Nc2cccc(C(=O)O)c2)CN(C2CCCCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 70.9 %

Procedure:
Under an argon atmosphere, 2.0 g of sodium 3-aminobenzoate, 77 mg of 4-dimethylaminopyridine and 3.0 g of Molecular Sieves 3A were added to a solution of 3.0 g of (R)-(−)-1-tert-butylcarbonylmethyl-2-oxo-3-phenoxycarbonylamino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine in 30 ml of anhydrous dimethylsulfoxide. The mixture was stirred at room temperature for 15 hours. After filtration of the reaction mixture, ice water and a 1N aqueous solution of sodium hydroxide were added to the filtrate. The mixture was extracted with ethyl acetate. The organic layer was washed successively with a 1N aqueous solution of sodium hydroxide, 1N hydrochloric acid and brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. To the residue was added a mixed solvent of ethanol and water (2:1). Crystals so precipitated were collected by filtration, whereby 2.32 g of the title compound was obtained.