Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]=[CH:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[B-](F)(F)F.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N+]#N)=[CH:21][C:20]=1[CH3:27].[CH3:28][OH:29]>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH:11]2[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:9]([O:29][CH3:28])[CH2:10]2)=[CH:21][C:20]=1[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CC=CC1
Reactant: CO
Reactant: Cc1cc([N+]#N)ccc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Product: COC1CC(c2ccc(Cl)c(C)c2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
Synthesized according to General Procedure 2. To a stirred solution of tert-butyl-2,5-dihydro-1H-pyrrole-1-carboxylate (2.5 g, 14.8 mmol) in methanol (75 mL) under N2 at RT was added 4-chloro-3-methylbenzenediazonium tetrafluoroborate (5.3 g, 22.2 mmol), followed by the addition of palladium(II) acetate (336 mg, 1.50 mmol). The resulting solution was stirred at RT for 1 hour, diluted with ethyl acetate (375 mL) and partitioned with saturated aqueous NaHCO3 solution (150 mL). The organic layer was removed and washed with saturated aqueous NaHCO3 solution (150 mL), brine (150 mL), dried over MgSO4 and concentrated under reduced pressure. The residue was dried under vacuum to afford tert-butyl 4-(4-chloro-3-methylphenyl)-2-methoxypyrrolidine-1-carboxylate (4.25 g, 13.0 mmol, 88% yield) as a brown oil. The crude product was used without any further purification in the next reaction step. 1H-NMR (400 MHz, DMSO-d6) δ 7.35-7.26 (m, 2H), 7.16 (dd, J=1.9, 8.2 Hz, 1H), 5.20-5.05 (m, 1H), 3.70-3.63 (m, 1H), 3.54-3.45 (m, 1H), 3.28 (s, 3H), 3.21-3.10 (m, 1H), 2.30 (s, 3H), 2.10-1.98 (m, 2H) and 1.47 (s, 9H) ppm.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:8]=1[N:14]([CH2:19][CH:20]([OH:22])[CH3:21])[S:15]([CH3:18])(=[O:17])=[O:16].C(N(CC)CC)C>ClCCCl>[CH3:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:8]=1[N:14]([CH2:19][CH:20]([O:22][S:2]([CH3:1])(=[O:4])=[O:3])[CH3:21])[S:15]([CH3:18])(=[O:17])=[O:16]
Reactant: Cc1cccc(C)c1N(CC(C)O)S(C)(=O)=O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cc1cccc(C)c1N(CC(C)OS(C)(=O)=O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.5 %

Procedure:
31.4 ml (46.6 g, 0.4 moles) of methanesulfonyl chloride are added dropwise, within one hour, to a solution of 94.5 g (0.368 moles) of 1-[N-(2,6-dimethylphenyl)-methane-sulfonamido]-2-propanol and 55.3 ml (40.5 g, 0.4 moles) of trietyl amine in 600 ml of 1,2-dichloroethane. During the addition the mixture is cooled with ice to maintain its temperature at 10°-12° C. The mixture is stirred at room temperature for additional 4 hours and then washed thrice with 100 ml of water, each. The dichloroethane solution is dried over anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure, and the thick, oily residue is triturated with 120 ml of isopropanol. The resulting crystals are filtered off, washed with ice-cold isopropanol and dried. 93.2 g (75.8%) of 1-[N-(2,6-dimethylphenyl)-methane-sulfonamido]-2-methanesulfonyloxy-propane are obtained as a white, crystalline substance melting at 111°-114° C.
Reaction SMILES: [C:1]([CH2:4][PH:5](=[O:7])[O-:6])(=O)C.[Na+:8].[NH2:9][CH2:10][CH2:11][CH2:12][NH2:13].[CH2:14](O)C>>[CH3:14][P:5]([C:4]1([CH3:1])[NH:13][CH2:12][CH2:11][CH2:10][NH:9]1)(=[O:7])[O-:6].[Na+:8]
Reactant: CCO
Reactant: NCCCN
Reactant: CC(=O)C[PH](=O)[O-]
Agent: [Na+]
Product: CC1(P(C)(=O)[O-])NCCCN1

Procedure:
Sodium acetylmethylphosphinate (2.9 g, 0.02 mol) and 1,3-diaminopropane (1.7 ml, 1.5 g, 0.02 mol) were stirred together in ethanol (60 ml) for 21/2 days and then evaporated under reduced pressure. The white solid was dried in vacuo, removing most of the ethanol. No unreacted starting material remained by N.m.r. The purity was estimated as approximately 95% from n.m.r, 4.1 g product was obtained.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([OH:24])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][C:12]1[N:13]=[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:15][C:16]=1[CH3:17])[CH3:2].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:30]([O:29][C:27](=[O:28])[CH2:26][O:24][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][CH2:11][C:12]2[N:13]=[C:14]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[O:15][C:16]=2[CH3:17])=[C:3]([CH2:1][CH3:2])[CH:4]=1)[CH3:31]
Reactant: CCOC(=O)CBr
Reactant: CCc1cc(O)ccc1OCCc1nc(-c2ccccc2)oc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(OCCc2nc(-c3ccccc3)oc2C)c(CC)c1
Temperature: 55 °C
Yield: 67.8 %

Procedure:
A mixture of 3-ethyl-4-[2-(5-methyl-2-phenyloxazole-4-yl)ethoxy]phenol (0.29 g. 0.90 mmol), ethyl bromoacetate (0.25 mL, 2.25 mmol) and cesium carbonate (0.45 g, (1.38 mmol) in anhydrous DMF (4 mL) was heated for 24 h at 55° C. The mixture was concentrated in vacuo, and the residue was partitioned between EtOAc (50 mL) and water (40 mL), washed with brine, dried (Na2SO4), and removed in vacuo to give a crude oil which was purified using radial chromatography eluting with 2% EtOAc/MeCl2 to give a white solid (0.25 g, 68%): 1H NMR (400 MHz, CDCl3) δ 7.97 dd, J=8.3, 2.4 Hz, 2H), 7.45-7.39 (m, 3H), 6.75 (dd, J=8.3, 2.0 Hz, 2H), 2H), 6.64 (dd, J=8.8, 3.4 Hz, 1H), 4.55 (s, 2H), 4.24 (q, J=6.5 Hz, 2H), 4.10 (t, J=6.4 Hz, 2H), 2.97 (t, J=6.6 Hz, 2H), 2.57 (t, J=7.3 Hz, 2H), 2.37 (s, 3H), 1.29 (t, J=7.3 Hz, 3H), 1.12 (t, J=6.5 Hz, 3H); MS (ES) m/e 410 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:17][CH2:18][CH2:19][CH2:20][CH:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])[CH2:25][CH2:24]2)[CH3:22])[C:9]([N+:37]([O-:39])=[O:38])=[C:8]([CH3:40])[NH:7][C:6]=1[NH2:41])=[O:4].ClC1C=CC=C(C(OO)=[O:50])C=1>>[CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:17]([CH2:18][CH2:19][CH2:20][CH:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])[CH2:25][CH2:24]2)[CH3:22])=[O:50])[C:9]([N+:37]([O-:39])=[O:38])=[C:8]([CH3:40])[NH:7][C:6]=1[NH2:41])=[O:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)C1=C(N)NC(C)=C([N+](=O)[O-])C1c1ccccc1SCCCC(C)N1CCN(c2ccccc2OC)CC1
Product: COC(=O)C1=C(N)NC(C)=C([N+](=O)[O-])C1c1ccccc1S(=O)CCCC(C)N1CCN(c2ccccc2OC)CC1

Procedure:
This compound was prepared from 2-amino-1,4-dihydro-4-(2-{4-[4-(2-methoxyphenyl)-1-piperazinyl]-pentylthio}phenyl)-6-methyl-5-nitro-3-pyridinecarboxylic acid methyl ester and m-chloroperbenzoic acid in the same manner as described for Example 2. 1H-NMR (CDCl3) ∂ 1.65(br s,4H); 2.02(m,2H); 2.42(s,3H); 2.49(m,2H); 2.71(s,4H); 2.98(m,2H); 3.12(s,4H); 3.61(s,3H); 3.86(s,3H); 5.76(s,1H); 6.68(s,2H); 6.84-7.01(m,4H); 7.27(m,4H); 7.81-7.86(m,1H). Mass spectrum: 598 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@:8]23[CH2:13][C@H:12]2[CH2:11][O:10][C:9]3=[O:14])[CH:5]=[CH:6][CH:7]=1.[BH4-].[Li+].C1COCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCOC(C)=O.CCCCCCC>[F:1][C:2]1[CH:3]=[C:4]([C@:8]2([CH2:9][OH:14])[CH2:13][C@H:12]2[CH2:11][OH:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1OC[C@@H]2C[C@]12c1cccc(F)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: OC[C@@H]1C[C@@]1(CO)c1cccc(F)c1
Temperature: -7.5 °C
Reaction time: 15 h

Procedure:
(1S,5R)-1-(3-fluorophenyl)-3-oxabicyclo[3.1.0]hexan-2-one (4, 10.08 g, 0.052 mol, 1.0 equiv.) was dissolved in 2-methyl-THF (75.60 mL) under nitrogen. The solution was cooled to −5 to −10° C., and 2.0 M Lithium tetrahydroborate in THF (39.34 mL, 0.079 mol, 1.5 equiv.) was added to the reaction mixture while maintaining the internal temperature below 0° C. The reaction was stirred at 20-25° C. for 14-16 hours and monitored by HPLC and TLC (EtOAc/Heptane=1/1). Once the reaction was completed, the reaction mixture was cooled to 0-5° C. and reverse quenched into a pre-cooled (0-5° C.) 20% aqueous citric acid solution (50.40 mL, 1.67 equiv.) at such a rate as to maintain the internal temperature below 5° C. Once the quench was complete, the reaction mixture was warmed to 20-25° C. and stirred for at least 20 min. The aqueous layer was back extracted once with 2-methyl-THF (50.40 mL). The organic layers were combined and washed once with saturated aqueous sodium bicarbonate solution (20.16 mL) and once with 20% aqueous NaCl (20.16 mL). The solvent was removed under reduced pressure then azeotroped with 2-methyl-THF until KF is less than 1500 ppm to afford the title compound, ((1S,2R)-1-(3-fluorophenyl)cyclopropane-1,2-diyl)dimethanol; 5 (10.29 g).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:24][O:25][CH2:26][CH3:27])[N:14]([CH2:15][C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[C:7]([O:28]CC3C=CC=CC=3)[CH:6]=[CH:5][C:4]=2[N:3]=1.[H][H].ClCCl.[OH-].[NH4+]>C(O)C.[Pd].CO>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:24][O:25][CH2:26][CH3:27])[N:14]([CH2:15][C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[C:7]([OH:28])[CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCOCc1nc2c(N)nc3ccc(OCc4ccccc4)cc3c2n1CC(C)(C)NS(C)(=O)=O
Reactant: [H][H]
Agent: [Pd]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3ccc(O)cc3c2n1CC(C)(C)NS(C)(=O)=O
Yield: 60 %

Procedure:
N-[2-(4-Amino-8-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulfonamide (1.16 g, 2.33 mmol) was dissolved in 50 mL of ethanol and 10% palladium on carbon (0.46 g) was added. The mixture was shaken overnight under 50 psi (3.4×105 Pa) of hydrogen. Dichloromethane (100 mL) and methanol (100 mL) were added and reaction was filtered through CELITE filter agent. The filter cake was washed with 200 mL of 1:1 dichloromethane:methanol. The filtrate was concentrated under reduced pressure to give a white solid. The solid was precipitated from a minimum amount of ethanol and then redissolved in dichloromethane containing a minimum amount of methanol. Aqueous ammonium hydroxide was added. The two phases were mixed by shaking and then separated. The organic fraction was discarded and the aqueous fraction was extracted with four portions of dichloromethane followed by two portions of ethyl acetate. The combined organic fractions were concentrated. The volume of the aqueous fraction was reduced, and a precipitate formed. The aqueous fraction was made basic by the addition of aqueous ammonium hydroxide and the resulting precipitate was recovered by filtration. The solid precipitate was combined with the residue from the organic fraction to give 0.75 g of crude product. This material was purified by column chromatography on a HORIZON HPFC system. A silica gel cartridge was used with the eluent being a gradient of 30-50% CMA in chloroform to provide 0.57 g of N-[2-(4-amino-2-ethoxymethyl-8-hydroxy-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulfonamide as a white powder, m.p. 252-254° C.
Reaction SMILES: [K].[NH2:2][C:3]1[C:8]([C:9]([O-:11])=O)=[CH:7][N:6]=[C:5]([S:12]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:56][C:57]1[CH:63]=[CH:62][C:60]([NH2:61])=[CH:59][CH:58]=1.CN1CCOCC1>CN1C(=O)CCC1.O>[F:56][C:57]1[CH:63]=[CH:62][C:60]([NH:61][C:9]([C:8]2[C:3]([NH2:2])=[N:4][C:5]([SH:12])=[N:6][CH:7]=2)=[O:11])=[CH:59][CH:58]=1
Reactant: Nc1ccc(F)cc1
Reactant: Nc1nc(SC(c2ccccc2)(c2ccccc2)c2ccccc2)ncc1C(=O)[O-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [K]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CN1CCOCC1
Product: Nc1nc(S)ncc1C(=O)Nc1ccc(F)cc1
Reaction time: 12 h
Yield: 490 %

Procedure:
Solid portions of potassium-4-amino-2-tritylsulfanylpyrimidine-5-carboxylate (46 g, 10 mmol) followed by HATU (39 g, 0.10 mol) were added, at ambient temperature, to a solution of 4-fluoroaniline (11 g, 0.10 mol) and NMM (31 g, 0.30 mol) in NMP (500 mL). After stirring for 12 hours, the resulting orange solution was poured into water (1000 mL) and the oily, solid precipitant was collected, dissolved in dichloromethane (500 mL), and diluted with acetic acid (50 mL). The resulting solution was stirred (ambient temperature, 3 h), then concentrated in vacuo (to about 150 mL total volume) and diluted with diethyl ether (100 mL). The resulting yellow solid was collected, washed with dichloromethane and dried in vacuo to afford the titled compound (13 g, 49 mmol, 49% yield). 1H NMR (300 MHz, CD3OD) δ 8.20 (s, 1H), 7.58 (dd, J=9.3, 4.8 Hz, 2H), 7.07 (app. t, J=9.0 Hz, 2H); MS (+APCI) m/z 265 (MH+, 100).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[C:18]1([OH:24])C=CC=CC=1.C(Cl)(Cl)Cl>C(O)C.O.S(=O)(=O)(O)O>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([CH:18]=[O:24])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: Oc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1cc(C=O)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
2,4-di-t-butylphenol (75 g, 0.36 mole) was dissolved in 200 ml absolute ethanol in a 1 L round bottom flask equipped with a water-cooled condenser. Sodium hydroxide (82 g, 2.0 moles) was dissolved in 80 ml water and added while still hot to the solution of phenol. Chloroform (156 g, 1.31 mole) was added in 2 ml portions over a 45-minute period. The resulting yellow-brown mixture was stirred 1 hour while cooling to ambient temperature. The mixture was diluted with 500 ml of 1M sulfuric acid and extracted with 200 ml of dichloromethane. The organic layer was isolated in a separatory funnel and dried over anhydrous magnesium sulfate. The mixture was filtered and rotoevaporated to a thick syrup. The yield was 33%. The IR spectrum of the crude product showed the characteristic aldehyde carbonyl (C=O) stretching frequency at 1648 cm-1. The product was used without further purification.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].O.[F:6][C:7]([F:20])([F:19])[C:8]1[CH:9]=[C:10]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[NH2:11]>C(Cl)(Cl)Cl>[F:6][C:7]([F:19])([F:20])[C:8]1[CH:9]=[C:10]([N:11]=[C:1]=[S:2])[CH:12]=[C:13]([C:15]([F:16])([F:18])[F:17])[CH:14]=1
Reactant: S=C(Cl)Cl
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClC(Cl)Cl
Solvent: O
Product: FC(F)(F)c1cc(N=C=S)cc(C(F)(F)F)c1
Reaction time: 0.25 h

Procedure:
0.052 Mol of thiophosgene were mixed with 60 ml of water and were stirred for 15 minutes. 0.040 Mol of 3,5-bistrifluoromethylaniline were dropped with 30 ml chloroform, and the mixture was stirred for 2 hours at 15° C. The organic solution was washed with HCl 2M, dried and the solvent was removed under vacuum to obtain 3,5-bistrifluoromethylphenylisothiocyanate as a yellow-red oil, that was used as crude product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][CH2:24]I)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.Cl.[F:27][C@H:28]1[CH2:32][CH2:31][NH:30][CH2:29]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][CH2:24][N:30]3[CH2:31][CH2:32][C@H:28]([F:27])[CH2:29]3)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12
Reactant: F[C@H]1CCNC1
Reactant: Clc1c(-c2ccccc2)nnc2c1c(-c1ccccc1)nn2CCI
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: F[C@H]1CCN(CCn2nc(-c3ccccc3)c3c(Cl)c(-c4ccccc4)nnc32)C1
Reaction time: 48 h
Yield: 29.6 %

Procedure:
A solution of 4-chloro-1-(2-iodoethyl)-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine (90 mg, 0.2 mmol) in dry CH2Cl2 (2 mL) was added to (S)-3-fluoropyrrolidine hydrochloride (126 mg, 1 mmol), DIPEA (0.21 mL, 1.2 mmol) was added and the reaction stirred for 2 days. Further CH2Cl2 (3 mL), (S)-3-fluoropyrrolidine hydrochloride (126 mg, 1 mmol) and DIPEA (0.21 mL, 1.2 mmol) was added and the reaction stirred for an additional 7 days. The resultant residue was purified using chromatography (silica gel, gradient 20 to 100% ethyl acetate/isohexane), followed by preparative HPLC to provide Compound IIt as a white solid (25 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([CH:21]=1)[C:7]([NH:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][OH:20])=[CH:14][CH:13]=1)=[O:8].C(N(CC)CC)C.C(Cl)[Cl:32]>>[NH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][OH:20])=[CH:14][CH:13]=1.[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([CH:21]=1)[C:7]([Cl:32])=[O:8]
Reactant: COc1ccc(Cl)cc1C(=O)NCCc1ccc(CCO)cc1
Reactant: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Cl)cc1C(=O)Cl
Product: NCCc1ccc(CCO)cc1

Procedure:
The 2-{4-[2-(5-chloro-2-methoxybenzamido)-ethyl]-phenyl}-ethanol (oil) used as starting material is obtained by the acylation of 2-[4-(2-aminoethyl)-phenyl]-ethanol (oil) with 5-chloro-2-methoxybenzoyl chloride in anhydrous methylene chloride in the presence of triethylamine as acid acceptor.
Reaction SMILES: CO[C:3]1([CH3:11])[CH:7]=[CH:6][C:5]([O:9]C)([CH3:8])[O:4]1.CC(=O)/C=C\C(=O)C.[C:20](O)(=[S:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)(=O)C.O>[C:20]([CH:6]([CH2:7][C:3](=[O:4])[CH3:11])[C:5](=[O:9])[CH3:8])(=[S:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC1(C)C=CC(C)(OC)O1
Reactant: OC(=S)c1ccccc1
Agent: CC(=O)/C=C\C(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)CC(C(C)=O)C(=S)c1ccccc1
Yield: 69.8 %

Procedure:
In a 50 ml three-necked flask equipped with thermometer, 10 ml addition funnel and magnetic stirrer is placed 6 g of 2,5-dimethoxy-2,5-dimethyl-2,5-dihydrofuran, 24 ml H2O and 1 drop of glacial acetic acid. The mixture (which is crude cis-3-hexene-2,5-dione) is stirred for one hour until homogeneous. Then 5.25 g thiobenzoic acid is added over a five-minute period. The mixture is allowed to stand for eighteen more minutes and is then extracted with 35 ml of methylene chloride. After drying over anhydrous sodium sulfate and subsequent solvent removal, 7.55 g of crude 3-thiobenzoyl-2,5-hexanedione is recovered. The crude material is purified by column chromatography on 108 g silicic acid packed in ether:hexane (1:9) mixture. Elution with 630 ml ether:hexane (1:9) solvent mixture; followed by elution with 500 ml ether:hexane (1:4) solvent mixture; followed by elution with 850 ml ether:hexane (1:3) solvent mixture gives 6.2 g of 3-thiobenzoyl-2,5-hexanedione, having the following analyses:
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[CH3:13][S:14](Cl)(=[O:16])=[O:15].O>C(Cl)Cl>[CH3:13][S:14]([O:5][CH2:4][CH2:3][CH2:2][F:1])(=[O:16])=[O:15]
Reactant: OCCCF
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OCCCF
Temperature: 25 °C
Reaction time: 18 h
Yield: 108.4 %

Procedure:
To an ice cold, stirred solution of 19.0 g (0.244 mole) of 3-fluoropropanol and 39.5 g (0.300 mole) of triethylamine in 300 mL of methylene chloride was added dropwise 34.4 g (0.300 mole) of methanesulfonyl chloride. The resultant mixture was allowed to warm to room temperature and was stirred for approximately 18 hours. The mixture was poured into water and was washed with an aqueous, saturated sodium bicarbonate solution. The organic phase was dried over anhydrous magnesium sulfate and was filtered. The filtrate was distilled under reduced pressure to yield 41.3 g of 3-fluoropropyl methanesulfonate as a liquid, bp 116° C./15 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N+:10]([O-:11])=[N:9][C:8](=[O:12])[N:7]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([NH:21]C(=O)OC(C)(C)C)[CH2:17][CH2:16]3)[C:6]=2[CH:29]=1.C(O)(C(F)(F)F)=O.NC1CCN(CCN2C3C(=CC(C#N)=CC=3)N=CC2=O)CC1>>[NH2:21][CH:18]1[CH2:17][CH2:16][N:15]([CH2:14][CH2:13][N:7]2[C:6]3[CH:29]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[N+:10]([O-:11])=[N:9][C:8]2=[O:12])[CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)n[n+]([O-])c3ccc(Cl)cc32)CC1
Agent: N#Cc1ccc2c(c1)ncc(=O)n2CCN1CCC(N)CC1
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(CCn2c(=O)n[n+]([O-])c3ccc(Cl)cc32)CC1

Procedure:
tert-Butyl {1-[2-(6-chloro-1-oxido-3-oxo-1,2,4-benzotriazin-4(3H)-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 206, 0.65 g) was deprotected with TFA as described for Intermediate 197 to give the crude free base of the product, 0.517 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15]Br.FC(F)(F)C1C=CC(C2(C#N)CCCC2)=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([C:9]#[N:10])[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: BrCCCCBr
Reactant: N#CCc1cccc(Cl)c1
Agent: N#CC1(c2ccc(C(F)(F)F)cc2)CCCC1
Product: N#CC1(c2cccc(Cl)c2)CCCC1

Procedure:
1-(3-Chlorophenyl)cyclopentanecarbonitrile (494) was synthesized from 2-(3-chlorophenyl)acetonitrile (493) and 1,4-dibromobutane following the procedure described for 1-(4-trifluoromethyl-phenyl)-cyclopentanecarbonitrile (237).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11]3([C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14](=[O:21])[O:13]3)[O:10][N:9]=2)=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH3:27]O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:14]([O:13][CH3:27])=[O:21])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C1OC2(CC(c3ccc(Cl)cc3)=NO2)c2ccccc21
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccccc1-c1cc(-c2ccc(Cl)cc2)no1
Temperature: 0 °C

Procedure:
A solution of 6.3 g. (0.020 mole) of 3'-(p-chlorophenyl)-spiro[isobenzofuran-1(3H),5'(4'H)-isoxazol]-3-one, 2 ml. of concentrated H2SO4 and 300 ml. of methanol was stirred at reflux for 20 hours. The cooled solution was poured into ice water (3 liters) and extracted with ether. The combined organic extracts were washed twice with water, dried over CaSO4 and concentrated under vacuum to yield 5.8 g. of colorless crystals (88%) of product. Recrystallization from hexane afforded 5.4 g. of an analytically pure sample; m.p. 89.5°-91° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[CH:2]1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C.[CH2:25]([O:27][CH2:28][CH2:29][N:30]1[C:34]2=[N:35][CH:36]=[CH:37][CH:38]=[C:33]2[N:32]=[C:31]1[CH2:39][N:40]1[CH2:45][CH2:44][N:43]([CH2:46][CH2:47][NH2:48])[CH2:42][CH2:41]1)[CH3:26].[OH2:49]>ClCCl>[C:6]([OH:8])(=[O:7])[C:3]([OH:27])=[O:49].[CH2:25]([O:27][CH2:28][CH2:29][N:30]1[C:34]2=[N:35][CH:36]=[CH:37][CH:38]=[C:33]2[N:32]=[C:31]1[CH2:39][N:40]1[CH2:41][CH2:42][N:43]([CH2:46][CH2:47][NH:48][C:6]([C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)=[O:8])[CH2:44][CH2:45]1)[CH3:26]
Reactant: O
Reactant: CCOCCn1c(CN2CCN(CCN)CC2)nc2cccnc21
Reactant: O=C(O)c1ccoc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCCn1c(CN2CCN(CCNC(=O)c3ccoc3)CC2)nc2cccnc21
Product: O=C(O)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.6 %

Procedure:
To a stirred mixture of 1.12 parts of 3-furancarboxylic acid, 2 parts of N,N-diethylethanamine and 195 parts of dichloromethane were added 2.6 parts of 2-chloro-1-methylpyridinium iodide. After stirring for 1 hour at room temperature, 3.6 parts of 4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl]-1-piperazine-ethanamine and the mixture was stirred for 6 hours at room temperature. The reaction mixture was poured into water and the layers were separated. The organic layer was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol, saturated with ammonia (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the ethanedioate salt in 2-propanol. The salt was filtered off and crystallized from acetonitrile. The product was filtered off and dried, yielding 2.4 parts (39.6%) of N-[2-[4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl]-1-piperazinyl]ethyl]-3-furancarboxamide ethanedioate(1:2); 132.2° C. (compound 110).