Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[NH:11][C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[CH3:20])[N:4]=1)[CH3:2].[H-].[Na+].Br[CH2:24][CH2:25][CH2:26][CH3:27]>C(OCC)(=O)C>[CH2:24]([N:4]1[C:3]([CH2:1][CH3:2])=[N:11][C:10]2[C:5]1=[N:6][CH:7]=[N:8][C:9]=2[C:12]1[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=1[CH3:20])[CH2:25][CH2:26][CH3:27]
Reactant: CCc1nc2ncnc(-c3c(C)cc(C)cc3C)c2[nH]1
Reactant: CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCCCn1c(CC)nc2c(-c3c(C)cc(C)cc3C)ncnc21
Reaction time: 1 h
Yield: 26.7 %

Procedure:
A solution of 8-ethyl-6-(2,4,6-trimethylphenyl)purine (200 mg, 0.75 mmol) in anhydrous dimethylfomamide (5 mL) was cooled to 0° C., and treated with sodium hydride dispersion in mineral oil (72 mg 50% w/w, 1.50 mmol). After 1 hour, bromobutane (0.10 mL, 0.90 mmol) was added by syringe, and the mixture was allowed to stir for 12 hours. It was poured into ethyl acetate (120 mL), and was washed with water (3×120 mL) and brine (100 mL). The aqueous layers were back-extracted in sequence with ethyl acetate (120 mL), and the extracts were combined, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was separated by column chromatography (silica gel, 20:80 ethyl acetate-hexane) to afford the title product as a viscous oil (64.2 mg, 0.20 mmol, 27%). TLC RF 0.20 (30:70 ethyl acetate-hexane). 1H NMR (300 MHz, CDCl3): d 8.96 (1H, s), 6.95 (2H, s), 4.25 (2H, t, J=7.5 Hz), 2.93 (2H, q, J=7.7 Hz), 2.32 (3H, s), 2.04 (6H, s), 1.91-1.86 (2H, m), 1.50-1.38 (2H, m), 1.39 (3H, t, J=7.7 Hz), 1.01 (3H, t, J=7.5 Hz). MS (NH3-CI): m/e 325 (3), 324 (23), 323 (100).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][CH2:22][CH3:23]>FC(F)(F)C(O)=O.[Pt](=O)=O>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Agent: O=[Pt]=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2c(N)nc3c(c2n1CCCCN)CCCC3
Reaction time: 144 h

Procedure:
A catalytic amount of platinum (IV) oxide was added to a solution of 1-(4-aminobutyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (2.2 g, 7.06 mmol) in trifluoroacetic acid (200 mL). The reaction mixture was hydrogenated at 50 psi (3.44×105 Pa) on a Parr apparatus for 6 days The reaction mixture was filtered to remove the catalyst and the filtrate was concentrated under vacuum. The residue was combined with 1 N hydrochloric acid (100 mL) and heated on a steam bath for 2 hours. The mixture was cooled, made basic with ammonium hydroxide and then extracted with dichloromethane. The extract was concentrated under vacuum to provide of 1-(4-aminobutyl)-2-butyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin4-amine as a solid, m.p. 63-67° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[Br:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC.O>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[CH:14][CH:13]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: O=[N+]([O-])c1ccccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: O=[N+]([O-])c1ccccc1-c1ccc(Br)cc1

Procedure:
o-iodonitrobenzene (9.42 g, 37.84 mmol), 4-bromobenzeneboronic acid (7.6 g, 37.84 mmol), potassium carbonate (21 g, 151.36 mmol) was added to 190 mL DME/water (3:2) solution and degassed for 30 minutes. Pd(PPh3)4 (437 mg, 0.38 mmol) was added to the slurry under nitrogen and the slurry was degassed for another 5 minutes. The reaction was refluxed under nitrogen for 6 h. Content of the flask was filtered through a pad of celite and partitioned in ethyl acetate and brine. Organic phase was dried over anhydrous Na2SO4 and evaporated under vacuum. Crude yellow oil was flashed over silica gel using 5% ethylacetate/hexane. Final compound was isolated as colorless oil (9.8 g, 35.4 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.[C:23]([NH:26][C:27]1[S:28][CH:29]=[C:30]([CH2:32]Cl)[N:31]=1)(=[O:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[ClH:1].[C:23]([NH:26][C:27]1[S:28][CH:29]=[C:30]([CH2:32][O:19][C:13]2[CH:12]=[C:11]3[C:16]([C:7]([NH:6][C:5]4[CH:20]=[CH:21][C:2]([Cl:1])=[CH:3][C:4]=4[F:22])=[N:8][CH:9]=[N:10]3)=[CH:15][C:14]=2[O:17][CH3:18])[N:31]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)Nc1nc(CCl)cs1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCc1csc(NC(C)=O)n1
Product: Cl
Temperature: 40 °C
Reaction time: 7 h
Yield: 48.2 %

Procedure:
A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (250 mg, 0.78 mmol), (prepared as described for the starting material in Example 24), 2-acetamido-4-chloromethylthiazole (164 mg, 0.86 mmol) and potassium carbonate (216 mg, 1.5 mmol) in DMF (5 ml) was stirred at 40° C. for 7 hours. The mixture was partitioned between ethyl acetate and water and the aqueous layer was adjusted to pH7 with 2M hydrochloric acid. The organic phase was washed with water, brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (95/5). The purified solid was dissolved in a mixture of methylene chloride and methanol and a 5M solution of hydrogen chloride in isopropanol (1.0 ml) was added. The volatiles were removed by evaporation to give a solid, which was triturated with ether, collected by filtration and dried under vacuum to give 7-((2-acetamidothiazol-4-yl)methoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline hydrochloride (96 mg, 24%). m.p. 194-202° C.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=[O:19])=[CH:13][CH:12]=1>>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:18](=[O:19])[NH:17][C:14]1[CH:15]=[CH:16][C:11]([Br:10])=[CH:12][CH:13]=1)[CH2:2]2
Reactant: O=C=Nc1ccc(Br)cc1
Reactant: OC1CN2CCC1CC2
Product: O=C(Nc1ccc(Br)cc1)OC1CN2CCC1CC2
Yield: 60 %

Procedure:
3-Quinuclidinol and 4-bromophenyl isocyanate were used. Filtration of the precipitated solid from the cooled reaction mixture afforded the title compound (60%) as a white solid: mp 217.5-219.5° C.; FAB LRMS m /z (relative intensity, %) 328 (16), 327 ([MH+ with Br81 ], 100), 326 (16), 325 ([MH+ with Br79 ], 100).
Reaction SMILES: Br[C:2]1[C:3]([C:9]2([CH3:14])[O:13]CCO2)=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.[Mg].C1(C#N)[S:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[NH4+].[O:25]1CC[CH2:27][CH2:26]1>>[CH3:8][C:4]1[C:3]([C:9](=[O:13])[C:14]2[S:20][CH:19]=[CH:18][CH:17]=2)=[CH:2][CH:7]=[CH:6][C:5]=1[C:26](=[O:25])[CH3:27]
Reactant: N#Cc1cccs1
Reactant: Cc1cccc(Br)c1C1(C)OCCO1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Product: CC(=O)c1cccc(C(=O)c2cccs2)c1C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred and refluxing Grignard-complex, previously prepared starting from 72 parts of 2-(3-bromo-o-tolyl)-2-methyl-1,3-dioxolane, 6.8 parts of magnesium and 180 parts of dry tetrahydrofuran, is added dropwise a solution of 30.6 parts of 2-thenonitrile in 90 parts of dry tetrahydrofuran. Upon completion, stirring at reflux is continued for 2 hours. The reaction mixture is allowed to stirr overnight at room temperature. After cooling to 0° C, the mixture is decomposed by the addition of 200 parts of a saturated ammonium chloride solution while keeping the temperature below 20° C. The product is extracted with 1200 parts of ether. The extract is washed three times with 300 parts of water and upon saturation of the ether-phase with gaseous hydrogen chloride, the ketimine-compound is separated as an oil. The ether is decanted and the oil is stirred and refluxed for 3 hours in 500 parts of a 6N hydrochloric acid solution. After cooling, the product is extracted with chloroform (2 × 225 parts). The extract is dried and evaporated. The residue is distilled twice, yielding 2'-methyl-3'-(2-thenoyl)acetophenone; bp. 185°-190° C at 0.4 mm. pressure.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)(=O)=O.[Br-:14].[Li+]>CC(C)=O>[Br:14][CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: [Br-]
Reactant: CS(=O)(=O)OCCC1CCOCC1
Agent: [Li+]
Solvent: CC(C)=O
Product: BrCCC1CCOCC1
Yield: 73.4 %

Procedure:
To a stirring solution of 2-(4-oxanyl)ethyl methanesulfonate (11.9 g, 56.9 mmol) in dry acetone (300 mL) was added lithium bromide (29.7 g, 56.9 mmol). The reaction was refluxed under an N2 atmosphere for 5 h. The acetone was removed by rotary evaporation, water (150 mL) was added and the mixture was extracted with dichloromethane (2×100 mL). The combined extracts were dried (K2CO3), filtered and concentrated by rotary evaporation to yield a light brown oil. The crude compound was then distilled (65° C., 0.2 mm) to yield 8.06 g of a colorless oil (73.3% yield).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([NH:30][C@@H:31]([CH2:34][CH3:35])[CH2:32][OH:33])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[C:11]([NH:30][C@@H:31]([CH2:34][CH3:35])[CH:32]=[O:33])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC[C@@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC[C@@H](C=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a stirred solution of dry dimethylsulfoxide (2.4 ml, 2.8 eq, 33.82 mmol) in dry dichloromethane (30 ml) under an argon atmosphere at −78° C., was added oxalyl chloride (2M solution in DCM, 8.45 ml, 1.40 eq, 16.9 mmol), dropwise. The reaction mixture was stirred at −78° C. for 1 h, after which time a solution of (S)-2-(trityl-amino)-butan-1-ol (4 g, 1 eq, 12.07 mmol) in DCM (30 ml) was added dropwise with stirring. The reaction mixture was stirred at this temperature for 2 h after which was added a solution of triethylamine (TEA, 8.4 ml, 5 eq, 60.27 mmol) in DCM (30 ml), and the solution allowed to warm to room temperature over 1 h. The reaction mixture was diluted with more DCM (100 ml) and washed with water (250 ml). The aqueous phase was extracted with DCM (3×50 ml), and the combined organic phase washed with brine (50 ml), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash silica chromatography (ethyl acetate:Hexane 1:4) to afford (S)-2-(trityl-amino)-butyraldehyde as a light yellow oil; Yield: 3.64 g (91%). 1H-NMR (CDCl3, 250 MHz): δ 0.95 (3 H, t, J=7.5 Hz, —NHCH(CH2CH3)CHO), 1.72-1.52 [2 H, m, NHCH(CH2CH3)CHO], 2.76 (1 H, s, br, —NH), 3.41-3.36 [1 H, m, NHCH(CH2CH3)CHO], 7.35-7.17 (12 H, m, ArH), 7.67-7.51 (3 H, m, ArH), 9.05 (1 H, s, NHCH(CH2CH3)CHO). δC (250 MHz, CDCl3) 202.95 (CO), 146.23 (C), 129.23 (6×CH), 127.96 (6×CH), 126.85 (3×CH), 71.13 (C), 62.62 (CH), 24.78 (CH2), 10.48 (CH3)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.[Br:10][C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(O)C.COCCOC>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:13][CH:12]=1
Reactant: OB(O)c1cccnc1
Reactant: Brc1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: Brc1ccc(-c2cccnc2)cc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
In a 100 mL three-necked flask were placed 2.4 g (20 mmol) of 3-pyridineboronic acid, 5.6 g (19 mmol) of para-bromoiodobenzene, and 4.5 g (42 mmol) of sodium carbonate. The atmosphere in the flask was replaced with nitrogen, and to the flask were added 15 mL of water, 25 mL of DME, and 10 mL of ethanol. The mixture was degassed by being stirred under reduced pressure, to which 0.22 g (0.19 mmol) of tetrakis(triphenylphosphine)palladium(0) was added. The mixture was stirred under nitrogen stream at 80° C. for 12 hours. After a predetermined time, water was added to the mixture, and an organic substance was extracted with chloroform from the aqueous layer. The obtained extract was washed with a saturated aqueous sodium chloride solution together with the organic layer and then dried over magnesium sulfate. The mixture was subjected to suction filtration through Celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855), and the filtrate was condensed to obtain an oily substance. The obtained substance was purified by silica gel column chromatography (hexane:ethyl acetate=3:1); thus, 1.8 g of the target yellow oily substance was obtained with a yield of 38%.
Reaction SMILES: Br[CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)=O.[Br:19][C:20]1[CH:21]=[N:22][C:23]([NH2:26])=[N:24][CH:25]=1.O>CN(C=O)C>[Br:19][C:20]1[CH:21]=[N:22][C:23]2[N:24]([C:2]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:3]([C:5]3[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=3)[N:26]=2)[CH:25]=1
Reactant: O=Cc1ccc(C(=O)C(Br)c2ccccc2)cc1
Reactant: Nc1ncc(Br)cn1
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(-c2nc3ncc(Br)cn3c2-c2ccccc2)cc1
Temperature: 90 °C

Procedure:
0.15 g (0.5 mM) of 4-[bromo(phenyl)acetyl]benzaldehyde and 2.0 equivalents of 5-bromopyrimidin-2-amine are dissolved in 6 ml DMF. The reaction mixture is heated at 90° C. overnight. The reaction mixture is cooled and water is added. It is then extracted with ethyl acetate. The organic layer is dried and concentrated. The crude product is purified by column chromatography to obtain the desired compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:32])[CH2:16][N:17]2[CH:20]([S:21][CH2:22][CH2:23][CH2:24][C:25]([O:27]CC=C)=[O:26])[CH2:19][C:18]2=[O:31])=[CH:4][CH:3]=1.N1CCCC1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:32])[CH2:16][N:17]2[CH:20]([S:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])[CH2:19][C:18]2=[O:31])=[CH:4][CH:3]=1
Reactant: C=CCOC(=O)CCCSC1CC(=O)N1CC(=O)NCCCCCCc1ccc(F)cc1
Solvent: C1CCNC1
Solvent: ClCCl
Product: O=C(O)CCCSC1CC(=O)N1CC(=O)NCCCCCCc1ccc(F)cc1
Yield: 52 %

Procedure:
N-[6-(4-Fluorophenyl)hexyl]-[4-(3-allyloxycarbonylpropyl)thio-2-oxo-azetidin-1-yl]-acetamide (1.4 g) was dissolved in dry dichloromethane (30 ml) and the resulting solution treated with pyrrolidine (0.3 g) and (tetrakistriphenylphosphino)palladium (0.2 g) at room temperature until TLC analysis showed absence of starting material. The mixture was washed with dilute HCl, brine, dried (MgSO4) and evaporated. The residue was purified by chromatography on silica gel (dichloromethane:methanol:acetic acid, 90:9:1) to give the title compound as an oil, 0.7 g, 52% yield.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH3:15])=[CH:7][CH:6]=1)=[O:4].[Br:16]NC(=O)CCC(N)=O.CCOC(C)=O>C(Cl)(Cl)(Cl)Cl.CCCCCC.CC(N=NC(C#N)(C)C)(C#N)C>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:15][Br:16])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(C)c2ccccc12
Reactant: NC(=O)CCC(=O)NBr
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CBr)c2ccccc12
Yield: 69.4 %

Procedure:
To a stirred solution of 4-methyl-naphthalene-1-carboxylic acid methyl ester (Preparation 50, 10.85 g, 54.18 mmol) in CCl4 (500 mL) was added N-bromosuccinamide (9.93 gm, 55.81 mmol) followed by AIBN (0.1 g, 0.612 mmol) at room temperature. Resulting reaction mixture was refluxed for 3 hours. Progress of reaction was monitored by TLC using 5% EtOAc in hexane. Rf of new spot and starting material was 0.8 and 0.7 respectively. After consumption of starting material, reaction mixture was concentrated in vacuo to residue. Residue was dissolved in EtOAc (300 mL) and washed with water (2×300 mL), brine (300 mL), dried over sodium sulphate and evaporated in vacuo to get pale yellow semisolid. Crude was purified by column chromatography using 100-200 mesh silica gel. Desired product was eluted in 4% EtOAc in hexane to afford white solid (10.5 g, 69.39%). 1H NMR (400 MHz, CDCl3) δ: 4.00 (s, 3H), 4.93 (s, 2H), 7.56 (d, J=7.48 Hz, 1H), 7.62-7.68 (m, 2H), 8.06 (d, J=7.4 Hz, 1H), 8.17-8.20 (m, 1H), 8.90-8.93 (m, 1H).
Reaction SMILES: [CH3:1][N:2](C)[CH2:3][CH2:4][CH2:5][CH:6]1[C:12]2[CH:13]=[C:14]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:15]=[CH:16][C:11]=2[CH:10]=[CH:9][C:8]2[CH:21]=[CH:22][CH:23]=[CH:24][C:7]1=2.CN(C)CCC=C1C2C=CC=CC=2C=CC2C=CC=CC1=2>>[CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH:6]1[C:12]2[CH:13]=[C:14]([S:17]([CH3:20])(=[O:18])=[O:19])[CH:15]=[CH:16][C:11]=2[CH:10]=[CH:9][C:8]2[CH:21]=[CH:22][CH:23]=[CH:24][C:7]1=2
Reactant: CN(C)CCCC1c2ccccc2C=Cc2ccc(S(C)(=O)=O)cc21
Agent: CN(C)CCC=C1c2ccccc2C=Cc2ccccc21
Product: CNCCCC1c2ccccc2C=Cc2ccc(S(C)(=O)=O)cc21

Procedure:
By substituting 5-(3-dimethylaminopropyl)-3-methylsulfonyl-5H-dibenzo[a,d]cycloheptene for the 5-(3-dimethylaminopropylidene)-5H-dibenzo[a,d]cycloheptene of Example 6, Step A., and following substantially the same procedure described in Example 6, Steps A and B., there is obtained 5-(3-methylaminopropyl)-3-methylsulfonyl-5H-dibenzo[a,d]cycloheptene as an oily residue. The base is converted to the hydrogen oxalate salt by treating an ethanolic solution of the base with a 10% excess of oxalic acid in ethanol. Dilution with absolute ether precipitates 5-(3-methylaminopropyl)-3-methylsulfonyl-5H-dibenzo[a,d]cycloheptene hydrogen oxalate as a white cyrstalline solid, m.p. 114°-119°C. dec. An analytical sample melts at 114°-115°C. dec. after two recrystallizations from mixtures of absolute ethanol and absolute ether.
Reaction SMILES: FC(F)(F)C(O)=O.C([S:11][CH2:12][CH:13]([CH2:24][CH2:25][CH2:26][NH2:27])[C:14]([N:16]1[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18]([OH:20])=[O:19])=[O:15])(=O)C>O.N>[NH2:27][CH2:26][CH2:25][CH2:24][CH:13]([CH2:12][SH:11])[C:14]([N:16]1[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18]([OH:20])=[O:19])=[O:15]
Reactant: CC(=O)SCC(CCCN)C(=O)N1CCC[C@H]1C(=O)O
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: NCCCC(CS)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
1-(2-Acetylthiomethyl-5-aminopentanoyl)-L-proline trifluoroacetate (1 g) is dissolved in a mixture of water (12 ml) and concentrated ammonia (12 ml) under a blanket of argon. The solution is stored twenty minutes at room temperature concentrated to 5 ml and applied to a column of Dowex 50 ion exchange resin in the hydrogen cycle. The column is washed with water and 1-(5-amino-2-mercaptomethylpentanoyl)-L-proline is eluted with a buffer of pyridine-acetic acid at pH 6.5.
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH2+:4].CC([O-])(C)C.[K+].C([O:14][C:15](=O)[CH2:16][CH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:26]([F:29])([F:28])[F:27])[CH:24]=2)[C:19](=[O:30])[N:18]1[CH2:31][C:32]([F:35])([F:34])[F:33])C.Cl>O>[O:30]=[C:19]1[C:20]2[C:25](=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][CH:21]=2)[CH:17]([CH2:16][C:15]([NH:4][C:3]([NH2:5])=[NH:2])=[O:14])[N:18]1[CH2:31][C:32]([F:34])([F:33])[F:35]
Reactant: CCOC(=O)CC1c2cc(C(F)(F)F)ccc2C(=O)N1CC(F)(F)F
Reactant: NC(N)=[NH2+]
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: N=C(N)NC(=O)CC1c2cc(C(F)(F)F)ccc2C(=O)N1CC(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
1.24 g guanidinium hydrochloride and 1.21 g of KOtBu were suspended using 30 ml of DMF(anhydrous) and stirred for 30 minutes at ambient temperature. Then, a solution of 0.8 g of [3-oxo-2-(2,2,2-trifluoro-ethyl)-6-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl]-acetic acid ethyl ester in 5 ml of DMF(anhydrous) were added and the mixture was stirred for 17 h at ambient temperature. The mixture was then poured into 100 ml of water and the pH was adjusted to pH=8 using aqueous HCl-solution. The aqueous layer was extracted three times using 100 ml of EA each. The organic layer was dried over MgSO4 and the solvent was removed in vacuo. Chromatography on silica gel using EA/MeOH 3:1 yielded 0.56 g of an amorphous solid (Rf(EA/MeOH 3:1)=0.45, MS (ES+): 383 (M+1)+).
Reaction SMILES: [BH4-].[Na+].CO.[Cl:5][C:6]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:7]=1[O:8][C:9]([C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1>C(OCC)(=O)C>[Cl:5][C:6]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:7]=1[O:8][C:9]([CH:17]([OH:22])[C:18]([CH3:20])([CH3:21])[CH3:19])=[CH:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)C(=O)C(=Cc1cccnc1)Oc1ccc(Cl)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)C(O)C(=Cc1cccnc1)Oc1ccc(Cl)cc1Cl

Procedure:
In this example, 0.49 g (0.0129 mole) of sodium borohydride was added portion-wise to a mixture containing 20 ml of methanol and 4.5 g (0.0129 mole) of 3-[2-(2,4-dichlorophenoxy)-3-oxo-4,4-dimethylpent-1-enyl]pyridine at 0° C. with stirring. The mixture was stirred at 0° C. for 15 minutes, then quenched by the addition of water. The mixture was then diluted with more water and then extracted twice with methylene chloride. The methylene chloride extracts were washed with water twice, dried over magnesium sulfate, filtered, then concentrated under vacuum affording a foam. The foam was dissolved in ethyl acetate, then chromatographed by flash column chromatography (silica gel) eluting with hexane and ethyl acetate mixtures. The product fractions were combined, concentrated and the residue recrystallized from methanol and water affording white crystals of the title compound mp 79.0°-81.5° C.
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][C:6]([CH2:7][NH:8][C:9]([CH:11]([O:23][CH3:24])[C:12]2[C:13]([F:22])=[C:14]([CH:18]=[CH:19][C:20]=2[F:21])[C:15](O)=[O:16])=[O:10])=[CH:5][CH:4]=1)#[N:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.Cl.[NH2:46][OH:47]>CN(C=O)C.CCN(CC)CC>[F:22][C:13]1[C:14]([C:15]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[O:16])=[CH:18][CH:19]=[C:20]([F:21])[C:12]=1[CH:11]([O:23][CH3:24])[C:9]([NH:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([C:1](=[NH:2])[NH:46][OH:47])=[CH:26][CH:25]=1)=[O:10]
Reactant: C1COCCN1
Reactant: NO
Reactant: COC(C(=O)NCc1ccc(C#N)cc1)c1c(F)ccc(C(=O)O)c1F
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(C(=O)NCc1ccc(C(=N)NO)cc1)c1c(F)ccc(C(=O)N2CCOCC2)c1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 58 %

Procedure:
To a solution under Ar of (RS)-3-[(4-cyano-benzylcarbamoyl)-methoxy-methyl]-2,4-difluoro-benzoic acid (150 mg) in DMF (2 ml) was added 1,1′-carbonyldiimidazole (74 mg). The reaction mixture was stirred 15 min at rt before addition of morpholine. After stirring 2 h at rt hydroxylamine hydrochloride (289 mg) and Et3N (0.3 ml) were added. The reaction mixture was stirred 20 h at rt, then it was poured on H2O (20 ml) and extracted with AcOEt (2×20 ml). The organic layers were washed with brine and dried (Na2SO4) and the solvent was evaporated. CC (AcOEt/MeOH 99:1 to 9:1) yielded 111 mg (58%) of (RS)-2-[2,6-difluoro-3-(morpholine-4-carbonyl)-phenyl]-N-[4-(N-hydroxycarbamimidoyl)-benzyl]-2-methoxy-acetamide. White solid. MS 463.5 ([M+H]+).