Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[Cl:14])[N:6]=1.[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:14][C:8]1[CH:9]=[C:10]([Cl:13])[CH:11]=[CH:12][C:7]=1[C:5]1[N:6]=[C:2]([N:18]2[CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19]2)[S:3][CH:4]=1
Reactant: Clc1ccc(-c2csc(Br)n2)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-c3ccc(Cl)cc3Cl)cs2)CC1
Yield: 25 %

Procedure:
A solution of 2-bromo-4-(2,4-dichlorophenyl)-1,3-thiazole (6.89 g, 22.3 mmol), tert-butyl piperazine-1-carboxylate (8.31 g, 44.6 mmol) and potassium carbonate (3.08 g, 22.3 mmol) in dimethylformamide (70 ml) was stirred at 120° C. for 13 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 2.31 g (25.0%) of the desired product as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([Br:12])=[C:7]([CH:11]=1)[C:8](O)=[O:9].O>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([Br:12])=[C:7]([CH:11]=1)[CH2:8][OH:9]
Reactant: COc1ccc(Br)c(C(=O)O)c1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Br)c(CO)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
5-Methoxy-2-bromobenzoic acid (85 g, 0.37 mol) is dissolved in anhydrous THF (100 mL) and cooled in an ice-salt bath until the temperature reaches −5° C. Borane-THF complex is added dropwise as a 1.0 M solution in THF (736 mL, 0.74 mol) at −5° C. After addition is complete, the reaction mixture is slowly warmed to room temperature and stirred for 12 hours. Water (40 mL) is slowly added dropwise and the reaction mixture stirred for 30 minutes. Additional water (350 mL) is added and the mixture is concentrated by rotary evaporator to remove most of the THF. The remaining material is extracted with EtOAc (800 mL). The organic layer is washed with saturated NaHCO3 (500 mL), brine (250 mL) and then dried (Na2SO4). Upon removal of the solvent by rotary evaporator, 5-methoxy-2-bromobenzyl alcohol is obtained as a white solid.
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[C:7]([NH2:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:5]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26]>C(Cl)Cl>[CH:1]([C:4]1[CH:8]=[C:7]([NH:9][C:25](=[O:26])[O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:6]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[N:5]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(-n2nc(C(C)C)cc2N)cc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1ccc(-n2nc(C(C)C)cc2NC(=O)Oc2ccccc2)cc1
Yield: 98.1 %

Procedure:
Using the procedure described in Example 306A, to a solution of 3-isopropyl-1-(4-methoxyphenyl)-1H-pyrazol-5-amine (333 mg, 1.45 mmol) and potassium carbonate (261 mg, 1.89 mmol) in anhydrous DCM (5.3 ml) was added dropwise phenyl chloroformate (0.55 ml, 4.34 mmol) as a solution in DCM (3.5 ml). The crude was purified by silica gel chromatography (DCM/MeOH 0-10%) to afford phenyl 3-isopropyl-1-(4-methoxyphenyl)-1H-pyrazol-5-ylcarbamate (500 mg, 98%). 1H NMR (300 MHz, CDCl3) δ 1.30 (d, J=7 Hz, 6H), 2.99 (m, 1H), 3.87 (s, 3H), 6.41 (s, 1H), 7.03 (d, J=9 Hz, 2H), 7.11-7.14 (m, 2H), 7.23-7.26 (m, 2H), 7.35-7.42 (m, 4H); LC-MS (ESI) m/z 352 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13](O)=[O:14])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1.[NH2:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[C:26]#[N:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:17])[CH3:18])[C:13]([NH:22][C:23]3[CH:30]=[CH:29][CH:28]=[C:25]([C:26]#[N:27])[CH:24]=3)=[O:14])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1
Reactant: N#Cc1cccc(N)c1
Reactant: CC(C)[C@H](C(=O)O)N1Cc2c(Cl)cnc3[nH]cc(c23)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: CC(C)[C@H](C(=O)Nc1cccc(C#N)c1)N1Cc2c(Cl)cnc3[nH]cc(c23)C1=O
Yield: 13.8 %

Procedure:
To an 8 mL scintillation vial equipped for stirring was added (R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoic acid (10 mg, 0.032 mmol). THF (0.5 mL), 3-aminobenzonitrile (7.68 mg, 0.065 mmol) and HATU (14.83 mg, 0.039 mmol) were added and the solution was stirred at 25° C. for 1 h. The reaction mixture was purified via preparative mass trigger LC-MS (AcCN/H2O, 5-50%). The fractions were collected, concentrated, and dried in vacuo to afford the title compound as a yellow oil (1.8 mg, 13.58%). 1H NMR (400 MHz, CD3OD) δ 1.00 (d, J=6.60 Hz, 3 H) 1.12 (d, J=6.57 Hz, 3 H) 2.60 (s, 1 H) 5.02 (d, J=19.71 Hz, 1 H) 5.20 (d, J=11.12 Hz, 1 H) 5.43 (d, J=19.71 Hz, 1 H) 7.43 (dt, J=7.77, 1.42 Hz, 1 H) 7.48 (t, J=7.96 Hz, 1 H) 7.81-7.85 (m, 1 H) 7.86 (s, 1 H) 8.08 (t, J=1.64 Hz, 1 H) 8.25 (s, 1 H). [M+H] calc'd for C21H18ClN5O2, 408; found, 408.4.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[I:10].[C:11](OC(=O)C)(=[O:13])[CH3:12]>S(=O)(=O)(O)O.O>[C:11]([NH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[I:10])(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1ccc(N)c(I)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)Nc1ccc(C#N)cc1I
Yield: 94.7 %

Procedure:
A mixture of 8.54 g (0.035 mole) of 4-amino-3-iodobenzonitrile (31), 16 mL (16.32 g, 0.16 mole) of acetic anhydride and five drops of concentrated sulfuric acid was heated at 70° under reflux for 10 minutes (the mixture became thick when the temperature reached 40° and some manual stirring was required). The reaction mixture was poured over 400 mL of cold water and stirred for 5 minutes to give a white solid which was filtered and dried, yielding 9.48 g (95%) of 32 as white powder, mp 176-181°. Infrared (IR) and NMR analysis gave the following results:
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2F)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:15][NH2:16]>>[CH:1]1([C:6]2[C:8]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:16][N:15]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NN
Reactant: O=C(c1ccccc1F)C1CCCC1
Product: c1ccc2c(C3CCCC3)n[nH]c2c1
Temperature: 130 °C
Yield: 89 %

Procedure:
Dissolve Cyclopentyl-(2-fluoro-phenyl)-methanone (2.5 g 13.005 mmoles) in hydrazine (20 ml) heat to 130° C. for 72 hrs. Cool mixture to 0° C. Filter the precipitate and wash with cold water to give the title compound: 2.171 g (yield=89%) MS ES+ 187.12:MSES− 185.22.
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:10](=O)[C:11]([O:13]CC)=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2].[NH2:17][C:18]([NH2:20])=[O:19].Cl.CC(O)=O>>[CH2:8]([O:7][C:5](=[O:6])[C:4](=[C:10]1[C:11](=[O:13])[NH:20][C:18](=[O:19])[NH:17]1)[O:3][CH2:1][CH3:2])[CH3:9]
Reactant: NC(N)=O
Reactant: CCOC(=O)C(=O)C(OCC)C(=O)OCC
Agent: Cl
Solvent: CC(=O)O
Product: CCOC(=O)C(OCC)=C1NC(=O)NC1=O

Procedure:
A mixture of diethyl 2-ethoxy-3-oxo-succinate (55.86 g, 1 eq) and urea (14.41 g, 1 eq.) was refluxed for 2.5 h in 1 M HCl—AcOH (1200 ml, 5 eq.) and allowed to become cool. The cooled mixture was evaporated to dryness. The residues were dissolved in MeOH, heated aside for crystallization. After crystallization, the precipitates were filtered to give a product which was an off-white solid (15.11 g, 27.5%).
Reaction SMILES: [C:1]([CH2:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:8])[C:2]1C=CC=CC=1.[C:18]1(C(=O)CC(=O)C)C=CC=CC=1>>[C:11]1([C:10](=[O:17])[CH:9]([CH3:18])[C:1](=[O:8])[CH3:2])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(=O)CC(=O)c1ccccc1
Reactant: O=C(CC(=O)c1ccccc1)c1ccccc1
Product: CC(=O)C(C)C(=O)c1ccccc1

Procedure:
Synthetic procedure was identical with that described in synthetic example 42(1), except that raw material dibenzoyl methane was replaced by 1-phenyl-1,3-butandione.
Reaction SMILES: CO.[CH3:3][C:4]1[CH:13]=[C:12]([C:14]([O:16]C)=[O:15])[C:11]([CH3:18])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7].[OH-].[Li+]>O1CCCC1>[CH3:9][O:8][C:6]([C:5]1[C:4]([CH3:3])=[CH:13][C:12]([C:14]([OH:16])=[O:15])=[C:11]([CH3:18])[CH:10]=1)=[O:7]
Reactant: COC(=O)c1cc(C)c(C(=O)OC)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc(C)c(C(=O)O)cc1C
Reaction time: 3 h
Yield: 74.7 %

Procedure:
Methanol (20 ml) was added to a solution of dimethyl 2,5-dimethylterephthalate (3.95 g, 17.8 mmol) in tetrahydrofuran (40 ml) and the resulting mixture was cooled on a water bath. A 2N-aqueous lithium hydroxide solution (9.8 ml, 19.6 mmol) was slowly added thereto and stirred for 3 hours. The solvent was distilled off under reduced pressure and the residue was adjusted to pH 1 to 2 with a 1N-hydrochloric acid and extracted with ethyl acetate (×3). The extract solution was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by a silica gel chromatography (eluent: chloroform/methanol=30/1) to obtain 4-(methoxycarbonyl)-2,5-dimethylbenzoic acid (2.77 g, 75%).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:10])[CH2:4][CH:5]=[CH:6][C:7](O)=[O:8].CCN(CC)CC.C(OC(Cl)=O)C(C)C.[I:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[C:33](=[O:37])[NH:32][C:31](=[O:38])[C:30]2=[CH:39][NH:40][C:41]1[CH:46]=[CH:45][C:44]([CH:47]2[CH2:51][CH2:50][CH2:49][NH:48]2)=[CH:43][CH:42]=1>CN(C)C=O>[CH3:2][N:3]([CH3:10])[CH2:4][CH:5]=[CH:6][C:7]([N:48]1[CH2:49][CH2:50][CH2:51][CH:47]1[C:44]1[CH:45]=[CH:46][C:41]([NH:40][CH:39]=[C:30]2[C:29]3[C:34](=[CH:35][CH:36]=[C:27]([I:26])[CH:28]=3)[C:33](=[O:37])[NH:32][C:31]2=[O:38])=[CH:42][CH:43]=1)=[O:8]
Reactant: CN(C)CC=CC(=O)O
Reactant: O=C1NC(=O)c2ccc(I)cc2C1=CNc1ccc(C2CCCN2)cc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)CC=CC(=O)N1CCCC1c1ccc(NC=C2C(=O)NC(=O)c3ccc(I)cc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.6 %

Procedure:
4-Dimethylamino-but-2-enoic acid hydrochloride salt (66 mg, 0.40 mmol) in N,N-dimethylformamide (1 mL) is treated with Et3N (0.06 mL) at 0° C. To the mixture is then added isobutylchloroformate (0.05 mL). The mixture is then stirred at this temperature for 30 min before addition of 6-Iodo-4-[(4-pyrrolidin-2-yl-phenylamino)-methylene]-4H-isoquinoline-1,3-dione (80 mg, 0.17 mmol) in N,N-dimethylformamide (3 mL) dropwisely and the reaction is allowed to stir at room temperature overnight. After an aqueous workup, the final residue is purified with prep-TLC to afford the title compound (20 mg, 21%). 1H NMR (400 MHz, DMSO) δ12.52 (1H, d, J=12.4 Hz), 11.39-11.41 (1H, m), 8.90-8.94 (1H, m), 8.59 (1H, m), 7.21-7.75 (6H, m), 6.48-6.59 (1.4H, m), 6.01-6.05 (0.6H, m), 5.1-5.24 (1H, m), 3.57-3.91 (2H, m), 3.06-3.07 (1H, m), 2.82-2.84 (1H, m), 2.1-2.39 (2H, m), 2.18 (3H, s), 1.96 (3H, s), 1.77-1.95 (2H, m). MS (ESI): 571.0 (M+1)+1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[C:13]([CH3:19])[CH:14]=[C:15]([CH3:18])[CH:16]=2)[N:11]=[CH:10][C:9]=1[C:20]([O:22]C)=[O:21].[OH-].[K+].C(O)C.Cl>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[C:13]([CH3:19])[CH:14]=[C:15]([CH3:18])[CH:16]=2)[N:11]=[CH:10][C:9]=1[C:20]([OH:22])=[O:21]
Reactant: COC(=O)c1cnc2c(C)cc(C)cc2c1-c1ccccc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(C)c2ncc(C(=O)O)c(-c3ccccc3Cl)c2c1
Yield: 96 %

Procedure:
A mixture of methyl 4-(2-chlorophenyl)-6,8-dimehtyl-3-quinolinecarboxylate (0.98 g), potassium hydroxide (0.5 g) and 80% ethanol (10 ml) was refluxed for 15 mins. The mixture was diluted with water and acidified with hydrochloric acid to give 4-(2-chlorophenyl)-6,8-dimethyl-3-quinolinecarboxylic acid as crystals (0.90 g, 96.8%), which was recrystallized from ethanol as colorless prisms. m.p. 234°-235° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=S)=[CH:4][CH:3]=1.Cl.[NH2:19][OH:20].C(=O)(O)[O-].[Na+]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[N:19][OH:20])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[CH:4][CH:3]=1
Reactant: Fc1ccccc1C(=S)Nc1ccc(Br)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: ON=C(Nc1ccc(Br)cc1)c1ccccc1F
Temperature: 25 °C
Yield: 77.6 %

Procedure:
A mixture of N1-(4-bromophenyl)-2-fluoro-1-benzenecarbothioamide (1.56 g, 0.00505 mol), hydroxylamine hydrochloride (0.44 g, 0.00631 mol) and sodium bicarbonate (0.53 g, 0.00631 mol) was heated in absolute ethanol (25 mL) at reflux under nitrogen atmosphere for 14 hours. The reaction mixture was cooled to ambient temperature, the solvent was removed under reduced pressure and the residue partitioned between saturated solution of sodium bicarbonate in water (50 mL) and ethyl acetate (50 mL). The organic phase was washed with brine, dried with magnesium sulfate and concentrated. The residue was suspended in cold diethyl ether and the precipitate was collected by filtration and dried to yield N1-(4-bromophenyl)-2-fluoro-1-benzeneamidoxime (1.21 g, 0.00392 mol) as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([CH:12]=[C:13]([C:17](=O)[CH3:18])[C:14](=[O:16])[CH3:15])=[C:8]2[C:3]=1[C:4](=[O:21])[CH:5]=[C:6]([CH3:20])[O:7]2.[NH2:22]/[C:23](/[CH3:32])=[CH:24]\[C:25]([O:27][CH:28]1[CH2:31][CH2:30][CH2:29]1)=[O:26]>CC(O)C>[C:14]([C:13]1[CH:12]([C:9]2[CH:10]=[CH:11][C:2]([F:1])=[C:3]3[C:8]=2[O:7][C:6]([CH3:20])=[CH:5][C:4]3=[O:21])[C:24]([C:25]([O:27][CH:28]2[CH2:31][CH2:30][CH2:29]2)=[O:26])=[C:23]([CH3:32])[NH:22][C:17]=1[CH3:18])(=[O:16])[CH3:15]
Reactant: CC(=O)C(=Cc1ccc(F)c2c(=O)cc(C)oc12)C(C)=O
Reactant: C/C(N)=C/C(=O)OC1CCC1
Solvent: CC(C)O
Product: CC(=O)C1=C(C)NC(C)=C(C(=O)OC2CCC2)C1c1ccc(F)c2c(=O)cc(C)oc12

Procedure:
150 mg (0.52 mmol) of 3-[(5-fluoro-2-methyl-4-oxo-4H-chromen-8-yl)methylene]pentane-2,4-dione are dissolved with 40.4 mg (0.26 mmol) of cyclobutyl 3-aminocrotonate in 5 ml of 2-propanol and heated under reflux under argon for 3 h. The solvent is removed in vacuo, and the residue is purified by column chromatography (mobile phase: ethyl acetate/cyclohexane 2:1). 54.8 mg (50% of theory) of the title compound are obtained as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Sn](CCCC)(CCCC)CCCC)[N:8]=2)[O:6][CH2:5][CH2:4][O:3]1.Br[C:27]1[N:31]2[N:32]=[C:33]([N:36]3[CH2:40][CH2:39][CH2:38][CH:37]3[C:41]3[CH:46]=[C:45]([F:47])[CH:44]=[CH:43][C:42]=3F)[CH:34]=[CH:35][C:30]2=[N:29][CH:28]=1>C1(C)C=CC=CC=1>[F:47][C:45]1[CH:46]=[C:41]([C@H:37]2[CH2:38][CH2:39][CH2:40][N:36]2[C:33]2[CH:34]=[CH:35][C:30]3[N:31]([C:27]([C:9]4[CH:10]=[CH:11][CH:12]=[C:7]([C:2]5([CH3:1])[O:3][CH2:4][CH2:5][O:6]5)[N:8]=4)=[CH:28][N:29]=3)[N:32]=2)[CH:42]=[CH:43][CH:44]=1
Reactant: Fc1ccc(F)c(C2CCCN2c2ccc3ncc(Br)n3n2)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(C2(C)OCCO2)n1
Solvent: Cc1ccccc1
Product: CC1(c2cccc(-c3cnc4ccc(N5CCC[C@@H]5c5cccc(F)c5)nn34)n2)OCCO1
Temperature: 110 °C

Procedure:
In step 15-1, 2-(2-methyl-1,3-dioxolan-2-yl)-6-(tributylstannyl)pyridine (57 g, 124 mmol) in 100 mL of toluene was cannula transferred under the argon atmosphere to a suspension of 3-bromo-6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine (15-1) (30 g, 83 mmol) and tetrakis(triphenylphospine)palladium (4.8 mg, 4.15 mmol) in 500 mL of toluene. The resulting reaction mixture was heated to 110° C. for overnight. The reaction progress was monitored by LC/Mass. After the reaction was complete, the reaction vessel was cooled to room temperature and the solvent reduced to ⅓ of the original volume. The purification was performed by flash chromatography using pure ethyl acetate to afford (R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-(2-methyl-1,3-dioxolan-2-yl)pyridine-2-yl)imidazo[1,2-b]pyridazine (15-2). 1H NMR (400 MHz, DMSO-d6) δ 8.10 (s, 1H), 8.09 (s br, 1H), 7.93 (d, 1H, J=9.6 Hz), 7.72 (m, 1H), 7.39 (m, 2H), 7.18 (m, 2H), 7.04 (m, 1H), 6.89 (br s, 1H), 5.16 (d, 1H, J=8.0 Hz), 4.02 (m, 3H), 3.91 (m, 2H), 3.68 (m, 2H), 2.48 (m, 1H), 2.05 (m, 2H), 1.88 (m, 1H), 1.69 (s, 3H). LCMS: m/z 446.2 (M+1).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][C@H:4]([O:7][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[C@@:3]1([CH3:26])[OH:25].[Cl:27][C:28]1[C:35]([CH3:36])=[C:34](F)[CH:33]=[CH:32][C:29]=1[C:30]#[N:31].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[Cl:27][C:28]1[C:35]([CH3:36])=[C:34]([NH:1][C@@H:2]2[CH2:6][CH2:5][C@H:4]([OH:7])[C@:3]2([OH:25])[CH3:26])[CH:33]=[CH:32][C:29]=1[C:30]#[N:31]
Reactant: Cc1c(F)ccc(C#N)c1Cl
Reactant: CC(C)(C)[Si](O[C@H]1CC[C@@H](N)[C@]1(C)O)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(N[C@@H]2CC[C@H](O)[C@@]2(C)O)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 6.4 %

Procedure:
The title compound is prepared by essentially following the procedure described in Example 1, using rel-(1S,2R,5 S)-2-amino-5-(tert-butyl(diphenyl)silyl)oxy-1-methyl-cyclopentanol (409 mg, 1.1 mmol, Preparation 43) and 2-chloro-4-fluoro-3-methyl-benzonitrile (142 mg, 0.84 mmol). A 0.2 M solution of the crude product in THF is treated with tetrabutylammonium fluoride (1.3 mL, 1.3 mmol, 1.0 M in THF) and stirred at room temperature for 16 h. The mixture is treated with water, concentrated in vacuo and extracted with EtOAc. The organic extracts are dried over magnesium sulfate, filtered, and concentrated. The resulting material is purified on silica gel (25-100% EtOAc/hexanes) to give the title compound as a pale yellow oil (15 mg, 6%). The relative stereochemistry is determined by NMR studies. 1H-NMR (400 MHz, DMSO-d6) δ 7.47 (d, J=8.8 Hz, 1H), 6.78 (d, J=8.8 Hz, 1H), 5.60-5.57 (m, 1H), 4.98 (d, J=4.2 Hz, 1H), 4.68 (s, 1H), 3.73-3.70 (m, 2H), 2.12 (s, 3H), 2.09-2.09 (m, 2H), 1.69-1.67 (m, 1H), 1.52-1.49 (m, 1H), 1.07 (s, 3H). LC-ES/MS m/z 281 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[C:11]([O:15][C:16](=[O:19])[CH2:17]Br)([CH3:14])([CH3:13])[CH3:12]>CN(C)C=O>[C:11]([O:15][C:16](=[O:19])[CH2:17][O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: Oc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccc(Br)cc1
Temperature: 75 °C
Yield: 82.9 %

Procedure:
4-Bromophenol (20.4 g, 118 mmol) dissolved in dry N,N-dimethylformamide was carefully treated with sodium hydride (4 g, 167 mmol). t-Butylbromoacetate (23 g, 118 mmol) was added and the mixture heated to 75° C. for 90 minutes. The reaction was concentrated in vacuo and the residue partitioned between ethyl acetate and water. The organic phase was washed with saturated ammonium acetate and concentrated in vacuo to yield 28.1 g of tert-butyl(4-bromophenoxy)acetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([O:16]C(C)(C)C)=O)[C:11]([CH3:27])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:10]=1.F[C:29](F)(F)C(O)=O.CCN(CC)CC.C(OC(=O)C)(=O)C>>[C:14]([N:12]1[CH2:13][C:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])=[CH:10][C:11]1([CH3:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:16])[CH3:29]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC(c2cc(F)ccc2F)=CC1(C)c1ccccc1
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)N1CC(c2cc(F)ccc2F)=CC1(C)c1ccccc1
Reaction time: 1 h

Procedure:
To a flame-dried flask equipped with stir bar under nitrogen was charged 20-9 (14 mg, 38 μmol) and anhydrous CH2CL2 (1 mL). The resulting solution was treated with trifluoroacetic acid (0.2 mL) and stirred 1 hour at 25° C. Upon completion, the reaction was concentrated, diluted with toluene (5 mL) and again concentrated. The TFA salt was then suspended in CH2CL2 at 25° C., and treated successively with Et3N (50 μL, 380 μmol) and acetic anhydride (25 μL, 20 μmol). After 1 hour, the reaction was complete. The reaction was concentrated and flash column chromatography (SiO2, 0-50% EtOAc/hex gradient) provided 20-10 as a clear oil: 1H NMR (300 MHz, CDCl3) δ 7.36 (m, 5H), 7.03 (m, 3H), 6.22 (m, 1H), 4.82 (m, 2H), 2.15 and 2.05 (s, 3H, rotamers), 1.98 and 1.74 (s, 3H, rotamers); LRMS m/z (M+H) 314.0 found, 314.2 required.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl.[F:19][C:20]1([F:25])[CH2:24][CH2:23][NH:22][CH2:21]1>CN(C=O)C.C(OCC)(=O)C>[F:19][C:20]1([F:25])[CH2:24][CH2:23][N:22]([C:2]2[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=2)[CH2:21]1
Reactant: Cc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: FC1(F)CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc(N2CCC(F)(F)C2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 47.3 %

Procedure:
To a solution of 6-chloro-2-methyl-3-nitropyridine (0.3 g, 1.74 mmol) in DMF (2 mL) was added K2CO3 (0.72 g, 5.23 mmol) followed by 3,3-difluoropyrrolidine hydrochloride (0.74 g, 5.23 mmol) and the reaction mixture was heated for 4 h at 80° C. The reaction mixture was then diluted with ethyl acetate and the organic layer was washed with saturated aqueous sodium bicarbonate solution. The organic layer was then dried over sodium sulphate and concentrated. The crude material obtained was purified by column chromatography (silica: 100-200 mesh, MeOH:DCM 2-3%) to afford the title compound (0.2 g, 47%). LCMS (ES+) 244.05 (M+H)+, RT 3.028 minutes (method 1).
Reaction SMILES: CN(C)[CH:3]=[C:4]1[CH2:9][CH2:8][CH2:7][CH:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]1=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([NH:39][C:40]([NH2:42])=[NH:41])[CH:30]=[CH:31][C:32]=1[N:33]1[CH:37]=[C:36]([CH3:38])[N:35]=[CH:34]1>>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([NH:39][C:40]2[N:42]=[CH:3][C:4]3[CH2:9][CH2:8][CH2:7][CH:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]=3[N:41]=2)[CH:30]=[CH:31][C:32]=1[N:33]1[CH:37]=[C:36]([CH3:38])[N:35]=[CH:34]1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: CCOC(=O)C1CCCC(=CN(C)C)C1=O
Solvent: O=[N+]([O-])O
Product: CCOC(=O)C1CCCc2cnc(Nc3ccc(-n4cnc(C)c4)c(OC)c3)nc21

Procedure:
The title compound was prepared from ethyl 3-[1-dimethylamino-methylidene]-2-oxo-cyclohexanecarboxylate (49 mg, 0.22 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (55 mg, 0.15 mmol) using in analogous manner the procedure described in example 45b). Obtained as a pale-yellow solid (8 mg, 10%). MS ISP (m/e): 408.4 [(M+H)+]. mp 162-164° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:4][C@@H:5]1[O:8][C:7](=[O:9])[CH2:6]1.[OH-:19].[Na+]>C1COCC1.O>[OH:8][C@@H:5]([CH2:4][CH:3]([O:2][CH3:1])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:6][C:7]([OH:19])=[O:9]
Reactant: CCCCCCCCCC(C[C@H]1CC(=O)O1)OC
Reactant: [OH-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCC(C[C@H](O)CC(=O)O)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 7 (187 mg, 0.729 mmol, 1.0 equiv) in THF (2.5 mL) was added a solution of NaOH (32.) mg, 0.802 mmol, 1.1 equiv) in water (1 L). The reaction mixture was stirred at rt for 2 h, transferred to a separatory funnel, diluted with water (5 mL) and extracted with ether. The aqueous layer was acidified with 2 N HCl (3 mL) and extracted with ether (2×15 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo to afford (3S)-1 (187 mg, 93%) as a colorless oil that was used without further purification: ATR/IR 2920, 2851, 1709, 1412, 1189, 1079, 738 cm−1; 1H NMR (CDCl3) 4.85-4.7 (m, 1H), 3.55-3.45 (m, 1H), 3.39, 3.38 (2s, 3H), 2.56-2.52 (m, 2H), 1.80-1.35 (m, 3H), 1.35-1.25 (m, 14H), 0.90 (t, 3H, J=6.9 Hz); 13C NMR (CDCl3) 176.5, 175.8, 81.5, 78.7, 68.0, 65.3, 56.7, 55.9, 41.5, 39.6, 39.0, 32.8, 32.6, 31.8, 29.7, 29.5, 29.2, 25.1, 24.4, 22.6, 14.1; MS (EI) m/z 274 (M+, 0.5), 256 (0.5), 171, 25, 129 (100), 97 (15).