Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][CH:5]=1.CCN(CC)CC.[O:23]=[C:24]1[NH:33][C:32]2[N:31]=[C:30]([O:34][CH2:35][CH2:36][CH2:37][CH:38]=O)[CH:29]=[CH:28][C:27]=2[CH2:26][CH2:25]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.CCOC(C)=O>[CH3:3][C:4]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:38][CH2:37][CH2:36][CH2:35][O:34][C:30]3[N:31]=[C:32]4[C:27]([CH2:26][CH2:25][C:24](=[O:23])[NH:33]4)=[CH:28][CH:29]=3)[CH2:12][CH2:11]2)[CH:7]=[CH:6][CH:5]=1
Reactant: O=CCCCOc1ccc2c(n1)NC(=O)CC2
Reactant: Cc1cccc(N2CCNCC2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1cccc(N2CCN(CCCCOc3ccc4c(n3)NC(=O)CC4)CC2)n1
Reaction time: 0.5 h
Yield: 63.2 %

Procedure:
To a suspension of 1-(6-methyl-pyridin-2-yl)-piperazine bishydrochloride (0.77 g, 3.08 mmol) in dichloroethane (10 mL) was added Et3N (1.0 mL, 7.17 mmol) and the mixture was stirred for 30 min. 4-(7-Oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde (0.85 g, 3.63 mmol) was added as a solution in dichloroethane (3 mL) and the mixture was stirred at room temperature for 15 min. NaBH(OAc)3 (1.1 g, 5.2 mmol) was added as a solid and the mixture was stirred at room temperature for 3 h. The reaction was poured into EtOAc and washed with saturated NaHCO3 and brine, dried over MgSO4 and concentrated. The residue was partitioned between EtOAc and pH 4.5 aqueous citric acid. The product went into the aqueous layer selectively over the impurities. The aqueous layer was neutralized with solid NaHCO3 to pH 8 and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4 and concentrated to give the title compound as a sticky foam (0.77 g). The foam was dissolved in Et2O and treated with anhydrous HCl gas to give a white precipitate. The mixture was filtered, washed with Et2O and hexanes, and dried to give a white solid (616 mg). MS: APCI: M+1: 396.1 (Exact Mass: 395.23).
Reaction SMILES: [N:1]1([C:5]2[CH:10]=[C:9]([NH:11][C:12]3[NH:13][N:14]=[C:15]([CH3:17])[CH:16]=3)[N:8]=[C:7]([S:18][C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[CH:28]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29]1.F[B-](F)(F)F.CN(C)C(O)=[N+](C)C.C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C>[N:1]1([C:5]2[CH:10]=[C:9]([NH:11][C:12]3[NH:13][N:14]=[C:15]([CH3:17])[CH:16]=3)[N:8]=[C:7]([S:18][C:19]3[CH:27]=[CH:26][C:22]([C:23]([NH:33][CH:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:24])=[CH:21][CH:20]=3)[N:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: Cc1cc(Nc2cc(N3CCC3)nc(Sc3ccc(C(=O)O)cc3)n2)[nH]n1
Reactant: NC1CCCC1
Agent: CN(C)C(O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2cc(N3CCC3)nc(Sc3ccc(C(=O)NC4CCCC4)cc3)n2)[nH]n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A 25 ml round bottom flask was charged with 4-[4-azetidin-1-yl-6-(5-methyl-2H-pyrazol-3-ylamino)-pyrimidin-2-ylsulfanyl]-benzoic acid (200 mg, 0.48 mmol), cyclopentyl amine (85 mg, 1 mmol), 2-(1H-benzotriazol-1-yl)-1,1,3,3, -tetramethyluroniumtetrafluoroborate (321 mg, 1 mmol), diisopropylethylamine (0.34 ml, 2 mmol) in dimethylformamide (5 ml), under nitrogen. The reaction mixture was stirred at room temperature for 18 hours and then was diluted with ethyl acetate (40 ml), washed with a saturated sodium hydrogen carbonate aqueous solution (40 ml) and brine (40 ml). The organic was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was triturated in dichloromethane to afford the title compound. 1H NMR (DMSO-d6): 1.60-1.65 (4H, m), 1.70-1.80 (2H, m), 1.95-2.10 (5H, m), 2.20-2.30 (2H, m), 3.90-4.00 (4H, s), 4.30-4.35 (1H, m), 5.35-5.40 (1H, s), 7.70-7.75 (2H, d), 8.00-8.05 (2H, d), 8.45-8.50 (1H, d), 9.3 (1H, s). MS (ES+): 450.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][CH2:22]I.[C-:24]#[N:25].[K+].O>CN(C=O)C.[Cl-].[Na+].O>[C:24]([CH2:22][CH2:21][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)/[C:7](=[CH:11]\[C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)/[C:6]=1[CH3:20])#[N:25]
Reactant: [C-]#N
Reactant: CSc1ccc(/C=C2/C(C)=C(CCI)c3cc(F)ccc32)cc1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ccc(/C=C2/C(C)=C(CCC#N)c3cc(F)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of the iodide from Step 1 (3.7g, 8.5 mmol) and potassium cyanide (5.5 g, 85 mmol) in DMF (40 mL) was stirred at room temperature for 45 minutes. There was added water (50 mL) and brine (100 mL) and the mixture was extracted with 1:1 ethyl acetate-hexane (4×100 mL); the combined extracts were washed with water (2×50 mL) and brine (1×50 mL), dried and evaporated. The crude residue was chromatographed on silica gel eluting with a 1:2 mixture of ether-ethyl acetate to afford the title compound as a yellow oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5]O[CH2:3][CH2:2]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:21]([C:23]1[CH:24]=[CH:25][C:26]2[C:38](=[O:39])[C:37]3[C:36]4[C:31](=[CH:32][C:33]([C:40]#[N:41])=[CH:34][CH:35]=4)[NH:30][C:29]=3[C:28]([CH3:43])([CH3:42])[C:27]=2[CH:44]=1)=O.[O:45]1[CH2:48][C:47](=O)[CH2:46]1>C1COCC1>[CH3:42][C:28]1([CH3:43])[C:29]2[NH:30][C:31]3[C:36](=[CH:35][CH:34]=[C:33]([C:40]#[N:41])[CH:32]=3)[C:37]=2[C:38](=[O:39])[C:26]2[CH:25]=[CH:24][C:23]([CH:21]3[CH2:3][CH2:2][N:1]([CH:47]4[CH2:46][O:45][CH2:48]4)[CH2:6][CH2:5]3)=[CH:44][C:27]1=2
Reactant: C1COCCN1
Reactant: O=C1COC1
Reactant: CC1(C)c2cc(C=O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)c2cc(C3CCN(C4COC4)CC3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
With the same condition as the method for synthesizing the Compound B3-32 (morpholine (6 μl, 1.5 eq.) and sodium triacetoxy borohydride (81 mg, 2.0 eq.) were added to THF (1 ml) solution of the Compound B2-29: 8-formyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (30 mg, 0.095 mmol), and stirred at room temperature for 1 hour. The reaction solution was filtered to remove insoluble matters. The residues obtained after concentration under reduced pressure were purified by high performance liquid chromatography to obtain the Compound B3-32 (6,6-dimethyl-8-morpholin-4-yl methyl-11-oxo-6,11-dihydro-5H-benzo carbazole-3-carbonitrile) (19 mg, 50%)), the title compound was synthesized from the Compound B3-13-2 and oxetan-3-one.
Reaction SMILES: [F:1][C:2]1([F:12])[C:6]([F:8])([F:7])[C:5]([F:10])([F:9])[CH2:4][CH:3]1[OH:11].C([Li])CCC.[P:18](Cl)([S:23][CH2:24][CH2:25][CH3:26])([O:20][CH2:21][CH3:22])=[O:19].O>O1CCCC1.CCCCCC>[P:18]([S:23][CH2:24][CH2:25][CH3:26])([O:11][CH:3]1[CH2:4][C:5]([F:9])([F:10])[C:6]([F:7])([F:8])[C:2]1([F:12])[F:1])([O:20][CH2:21][CH3:22])=[O:19]
Reactant: OC1CC(F)(F)C(F)(F)C1(F)F
Reactant: CCCSP(=O)(Cl)OCC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCSP(=O)(OCC)OC1CC(F)(F)C(F)(F)C1(F)F
Temperature: -20 °C
Reaction time: 24 h
Yield: 22.2 %

Procedure:
4 g (0.02 mol) of 2,2,3,3,4,4-hexafluorocyclopentan-1-ol, dissolved in 50 ml of tetrahydrofuran, are treated, at -70° C., with 8 ml of a 2.5-molar butyllithium solution in hexane. The mixture is heated to -20° C. and 5 g (0.02 mol) of O-ethyl S-propyl chlorothiophosphate are then added dropwise. To complete the reaction, the mixture is stirred for 24 hours at 20° C., a little water is added to the reaction mixture, and the mixture is filtered through silica gel. After the solvent has been distilled off and the residue has been distilled, 1.6 g (22% of theory) of O-ethyl O-(2,2,3,3,4,4-hexafluorocyclopentyl) S-propyl thiophosphate of a boiling point of b.p.0.15 90°-92° C. are obtained.
Reaction SMILES: [F:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[C:18](=O)([O-])[O-].[K+].[K+].IC>C(#N)C>[F:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1
Reactant: O=C([O-])[O-]
Reactant: CS(=O)(=O)c1cccc(C2CCNCC2)c1F
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CN1CCC(c2cccc(S(C)(=O)=O)c2F)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-[2-fluoro-3-(methylsulfonyl)-phenyl]-piperidine (0.02 g, 0.078 mmol) in acetonitrile (2 ml) was added potassium carbonate (0.02 g, 0.14 mmol) and iodomethane (0.0047 ml, 0.078 mmol). The mixture was stirred at ambient temperature for 1 h. MS m/z (relative intensity, 70 eV) 271 (M+, 66), 270 (bp), 192 (9), 133 (13) 97 (32).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1[C:8]([O:10]CC)=[O:9].[OH-].[Na+]>C1COCC1.O.CO.O>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1[C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)c1[nH]c(C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1cc(C)c(C(=O)O)[nH]1
Temperature: 75 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
To a solution of ethyl 3,5-dimethyl-2-pyrrolecarboxylate (Aldrich) (504 mg, 3 mmol) in THF/H2O/MeOH (5:1:1, 30 ml ) was added NaOH (480 mg, 12 mmol) in H2O (12 ml). The mixture was stirred at 75° C. overnight. The homogeneous mixture was washed with ether. To the aqueous layer was added a saturated aqueos KHSO4 solution until the pH was about 3. The solution was then extracted with dichloromethane. The extracts were dried over MgSO4 and evaporated. The residue was purified on silica (ethylacetate/methanol, 90/10) to give the title compound (375 mg, 90%).
Reaction SMILES: N[C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([OH:17])=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:8]=2)[O:4][N:3]=1.C=O.[C:24]([BH3-])#[N:25].[Na+].[C:28](=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[CH3:28][N:25]([CH3:24])[C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([OH:17])=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:8]=2)[O:4][N:3]=1
Reactant: CC(C)(C)c1cc(-c2nc(N)no2)cc(C(C)(C)C)c1O
Reactant: O=C([O-])[O-]
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CN(C)c1noc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 45 %

Procedure:
To a stirred mixture of 2.0 g (0.0069 mole) of 4-(3-amino-1,2,4-oxadiazol-5-yl)-2,6-bis(1,1-dimethylethyl)phenol and 2.0 g (0.0067 mole) of paraformaldehyde in 45 ml of glacial acetic acid (under a nitrogen atmosphere) is added 2.0 g (0.032 mole) of sodium cyanoborohydride, in portions over ten minutes. The mixture is stirred at room temperature for 24 hours, then cooled in ice and treated cautiously with 250 ml of ice water. Solid sodium carbonate is added until the reaction mixture becomes slightly basic. The mixture is extracted with ethyl acetate (4×100 ml), and the combined organic layers are washed with brine (2×200 ml), dried (anhydrous sodium sulfate), and evaporated. Recrystallization of the residue from aqueous methanol yields 1.0 g (45% yield) of the analytically pure product, mp 135°-138°.
Reaction SMILES: [CH2:1]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C@@H:18]1[CH2:27][CH2:26][C:25]2[C:20](=[C:21]([N:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)[CH:22]=[CH:23][CH:24]=2)[CH2:19]1.C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:34][N:31]1[CH2:32][CH2:33][N:28]([C:21]2[CH:22]=[CH:23][CH:24]=[C:25]3[C:20]=2[CH2:19][C@H:18]([NH:17][C:12](=[O:14])[C:11]2[CH:10]=[CH:9][C:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:16][CH:15]=2)[CH2:27][CH2:26]3)[CH2:29][CH2:30]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Reactant: O=C(O)c1ccc(Cc2ccccc2)cc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(Cc4ccccc4)cc2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-Benzylbenzoic acid (0.50 g, 2.4 mmol) was dissolved in thionyl chloride (10 mL) and heated at reflux for 20 min. The excess of thionyl chloride was evaporated in vacuo, the residue was treated with toluene and again the solvent was removed in vacuo. Crude acid chloride (100 mg, 0.46 mmol) was dissolved in methylene chloride (5 mL) and added dropwise to an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (110 mg, 0.44 mmol) and triethylamine (90 μL, 0.65 mmol) in methylene chloride (25 mL). After the addition, the reaction was allowed to stir at ambient temperature for 15 min and was then washed with dilute aqueous sodium hydrogen carbonate. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroformnethanol saturated with NH3 (100:3) as the eluent. Yield: 130 mg (62%) of the title compound as white crystals: mp 191-192° C.; [α]21D −39° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 439 (28, M+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](C(Cl)=O)=[CH:3][CH:2]=1.N1C=CC([C:16](O)=[O:17])=CC=1.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[CH:27]=[C:28]([NH:33][C:34](=[O:43])[C:35]2[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][CH:36]=2)[CH:29]=[CH:30][C:31]=1[Cl:32]>O.N1C=CC=CC=1>[Cl:32][C:31]1[CH:30]=[CH:29][C:28]([NH:33][C:34](=[O:43])[C:35]2[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][CH:36]=2)=[CH:27][C:26]=1[NH:25][C:16]([C:5]1[CH:6]=[N:1][CH:2]=[CH:3][CH:4]=1)=[O:17]
Reactant: O=C(O)c1ccncc1
Reactant: N#Cc1ccc(C(=O)Nc2ccc(Cl)c(N)c2)cc1
Reactant: O=C(Cl)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: N#Cc1ccc(C(=O)Nc2ccc(Cl)c(NC(=O)c3cccnc3)c2)cc1
Temperature: 110 °C

Procedure:
A mixture of pyrid-4-ylcarbonyl chloride (prepared by the reaction of pyridine-4-carboxylic acid and oxalyl chloride; 0.213 g), N-(3-amino-4-chlorophenyl)-4-cyanobenzamide (0.27 g) and pyridine (4 ml) was stirred and heated to 110° C. for 16 hours. After cooling, the mixture was poured into water (25 ml). The resultant precipitate was collected, washed with water and dried to give the title compound as a solid (0.32 g); NMR Spectrum: (DMSOd6) 7.58 (d, 1H), 7.75 (m, 1H), 7.85 (d, 2H), 8.01 (d, 2H), 8.10 (m, 3H), 8.80(d, 2H); Mass Spectrum: M+H+ 377.
Reaction SMILES: Cl[CH2:2][C:3](=O)[C:4](=[N:10][O:11][CH2:12][C:13]#[CH:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:16][C:17]([NH2:19])=[S:18].O>C(O)C>[NH2:19][C:17]1[S:18][CH:2]=[C:3]([C:4](=[N:10][O:11][CH2:12][C:13]#[CH:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:16]=1
Reactant: C#CCON=C(C(=O)CCl)C(=O)OCC
Reactant: NC(N)=S
Solvent: CCO
Solvent: O
Product: C#CCON=C(C(=O)OCC)c1csc(N)n1
Yield: 53.5 %

Procedure:
Ethyl 4-chloro-3-oxo-2-propargyloxyiminobutyrate (syn isomer, 61 g.), thiourea (20 g.), sodium acetate 3-hydrate (35.8 g.), water (150 ml.) and ethanol (180 ml.) were treated in a similar manner to that of Example F-(3) to give ethyl 2-(2-aminothiazol-4-yl)-2-propargyloxyiminoacetate (syn isomer, 35.6 g.).
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])=[CH:12][CH:11]=1)([OH:9])[CH3:8])(=O)C.[OH-].[Na+].C(O)C>O>[F:23][C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[C:13]1[CH:14]=[CH:15][C:10]([C:7]([OH:9])([CH3:8])[CH2:6][CH2:5][OH:4])=[CH:11][CH:12]=1
Reactant: CC(=O)OCCC(C)(O)c1ccc(-c2ccc(F)cc2F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(O)(CCO)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
A solution of 3.2 g. of 1 -acetoxy-3-(2',4'-difluoro-4-biphenylyl)-3-butanol and 2 g. of NaOH in 30 ml. of 80% aqueous ethanol is heated under reflux for 3 hours. Water is added; the product is extracted with chloroform, and the extract is evaporated to give 3-(2',4'-difluoro-4-biphenylyl)butane-1,3-diol, m.p. 82°-84°.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH:13][C:14]2[C:15]([O:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:27][Li]>O1CCCC1>[OH:3][C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]([NH:13][C:14]2[C:15]([O:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:12])=[CH:8][CH:9]=1)([CH3:27])[CH3:2]
Reactant: CC(=O)c1ccc(CC(=O)Nc2cccnc2Oc2cccnc2)cc1
Reactant: [Li]C
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(CC(=O)Nc2cccnc2Oc2cccnc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(4-Acetyl-phenyl)-N-[2-(pyridin-3-yloxy)-pyridin-3-yl]-acetamide (0.130 grams, 0.374 mmole) in tetrahydrofuran (10 ml) at −78° C. 1.0 M methyl lithium in tetrahydrofuran (1.123 ml, 1.123 mmole) was added and stirred at −78° C. for 30 minutes, allowed to warm to room temperature for 30 minutes and cooled to −78° C. The mixture was quenched with water and extracted with ethyl acetate. The combined organics were washed with water and brine, dried over MgSO4, filtered and concentrated to a product which was purified by chromatography on silica eluting with 3% methanol/methylene chloride. Recrystalization from ethyl acetate/hexane gave a solid (0.045 g). M.P. 122-124° C.; Anal. calcd. for C21H21N3O3: C, 69.41; H, 5.82; N, 11.50. Found: C, 69.02; H, 6.12; N, 11.30.
Reaction SMILES: [C:1](O)(=[O:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:26][C:27]1[CH:44]=[CH:43][C:42]([C@H:45]2[C@H:50]([O:51][CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[C@@H:49]([O:59][CH2:60][C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)[C@H:48]([O:67][CH2:68][C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)[C@@H:47]([CH2:75][O:76][CH2:77][C:78]3[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=3)[O:46]2)=[CH:41][C:28]=1[CH2:29][C:30]1[CH:40]=[CH:39][C:33]([CH2:34][NH:35][CH:36]2[CH2:38][CH2:37]2)=[CH:32][CH:31]=1>C(Cl)Cl.CCN(CC)CC>[Cl:26][C:27]1[CH:44]=[CH:43][C:42]([C@H:45]2[C@H:50]([O:51][CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[C@@H:49]([O:59][CH2:60][C:61]3[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=3)[C@H:48]([O:67][CH2:68][C:69]3[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=3)[C@@H:47]([CH2:75][O:76][CH2:77][C:78]3[CH:79]=[CH:80][CH:81]=[CH:82][CH:83]=3)[O:46]2)=[CH:41][C:28]=1[CH2:29][C:30]1[CH:40]=[CH:39][C:33]([CH2:34][N:35]([CH:36]2[CH2:37][CH2:38]2)[C:1](=[O:3])[CH3:2])=[CH:32][CH:31]=1
Reactant: Clc1ccc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(CNC2CC2)cc1
Reactant: CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N(Cc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of acetic acid (0.11 g) and Et3N (0.14 mL) in CH2Cl2 (1 mL) at room temperature, EDCI (96 mg) and HOBt (68 mg) was added. The mixture was stirred 30 min at room temperature. A solution of N-(4-(2-chloro-5-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)benzyl)benzyl)cyclopropanamine (intermediate AQ) (40 mg) in CH2Cl2 (0.2 mL) was added dropwise. The reaction was monitored by LC-MS. After the starting material was consumed. CH2Cl2 was added to dilute the solution. The resulting mixture was then washed with H2O, 1N HCl, aqueous NaHCO3 and brine, CH2Cl2 was removed under reduced pressure, and the crude product was purified by preparative TLC to give intermediate AR (20 mg). MS ESI (m/z): 836 (M+H)+, 853 (M+NH4)+.
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].[N+:7]([CH2:10][S:11]([C:13]1[C:18]2[O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:17]=2[CH:16]=[CH:15][CH:14]=1)=[O:12])([O-:9])=[O:8].S(S([O-])=O)([O-])(=O)=[O:27].[Na+].[Na+]>C(O)(=O)C.O>[N+:7]([CH2:10][S:11]([C:13]1[C:18]2[O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:17]=2[CH:16]=[CH:15][CH:14]=1)(=[O:27])=[O:12])([O-:9])=[O:8]
Reactant: O=S([O-])S(=O)(=O)[O-]
Reactant: O=[N+]([O-])CS(=O)c1cccc2c1oc1ccccc12
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])CS(=O)(=O)c1cccc2c1oc1ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 3% aqueous solution of potassium permanganate (83 ml, 16.2 mmol) was added to a stirred solution of 4-(nitromethylsulphinyl)dibenzofuran (3.72 g, 13.5 mmol) at 50° C. in acetic acid (100 ml). The reaction mixture was stirred for 1 hour at ambient temperature and then treated with a saturated aqueous solution of sodium metabisulphite until colourless. The reaction mixture was then diluted with water (200 ml). The solid material was removed by filtration, air dried and recrystallised from toluene/cyclohexane to give 4-(nitromethylsulphonyl)dibenzofuran as a white crystalline solid (2.95 g), m.p. 162°-165° C.; NMR (DMSOd6): 6.80 (s,2H) 7.48-8.79 (m,7H); m/e (electron impact): 291 (M+); microanalysis, found: C,53.6; H,3.0; N,4.7%; C13H9NO5S requires: C,53.6; H,3.1; N,4.8%.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[NH:3].Br[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[C:12]([NH:16][C:17]([CH:19]1[CH2:21][C:20]1([CH3:23])[CH3:22])=[O:18])[C:13]([OH:15])=[O:14]>O>[CH3:22][C:20]1([CH3:23])[CH2:21][CH:19]1[C:17]([NH:16]/[C:12](=[CH:11]\[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][NH:3][C:2]([NH2:4])=[NH:1])/[C:13]([OH:15])=[O:14])=[O:18]
Reactant: CC1(C)CC1C(=O)NC(=CCCCCCBr)C(=O)O
Reactant: N=C(N)N
Solvent: O
Product: CC1(C)CC1C(=O)N/C(=C\CCCCCNC(=N)N)C(=O)O
Temperature: 70 °C
Yield: 34.5 %

Procedure:
To a solution of 2 mmoles of guanidine (prepared from 432 mg of guanidine sulfate and 630 mg of barium hydroxide octahydrate) in 7 ml of water was added 332 mg (1 mmole) of 8-bromo-2-(2,2-dimethylcyclopropanecarboxamido)-2-octenoic acid, and the solution was heated at 70° C. in a nitrogen atmosphere for 1 hr. The reaction mixture was applied to a 2×25 cm column of Dowex 50W-X8 (H+, 100-200 mesh) After elution with water the fractions containing the product were pooled and evaporated under reduced pressure. The residue was dissolved in several ml of warm ethanol and added dropwise to 100 ml of ether with rapid stirring. Filtration and washing with ether gave 107 mg of Z-2-(2,2-dimethylcyclopropanecarboxamido)-8-guanidino-2-octenoic acid as an amorphous electrostatic powder. Homogeneous by TLC (n-BuOH, HOAc, H2O; 4:1:1). ##STR72##
Reaction SMILES: [CH3:1][C@@H:2]([OH:7])[CH2:3][C@H:4]([OH:6])[CH3:5].[F:8][C:9]([F:39])([F:38])[C:10]1[CH:11]=[C:12]([C:16]2[CH:37]=[CH:36][C:19]3[NH:20][C:21]([NH:23][C:24]([C:26]4[N:27]=[C:28]5[CH:33]=[CH:32][C:31](Cl)=[N:30][N:29]5[CH:35]=4)=[O:25])=[N:22][C:18]=3[CH:17]=2)[CH:13]=[CH:14][CH:15]=1.O>CN(C=O)C>[F:39][C:9]([F:8])([F:38])[C:10]1[CH:11]=[C:12]([C:16]2[CH:37]=[CH:36][C:19]3[NH:20][C:21]([NH:23][C:24]([C:26]4[N:27]=[C:28]5[CH:33]=[CH:32][C:31]([O:6][C@H:4]([CH3:5])[CH2:3][C@H:2]([OH:7])[CH3:1])=[N:30][N:29]5[CH:35]=4)=[O:25])=[N:22][C:18]=3[CH:17]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: O=C(Nc1nc2cc(-c3cccc(C(F)(F)F)c3)ccc2[nH]1)c1cn2nc(Cl)ccc2n1
Reactant: C[C@@H](O)C[C@@H](C)O
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](C[C@@H](C)O)Oc1ccc2nc(C(=O)Nc3nc4cc(-c5cccc(C(F)(F)F)c5)ccc4[nH]3)cn2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 48.1 %

Procedure:
To a solution of (2R,4R)-(−)-pentanediol (31.2 mg) in dry DMF (1 mL) NaH (12 mg, 60% dispersion in mineral oil) was added, and the mixture was stirred at room temperature for 20 minutes under nitrogen. To this mixture 6-chloro-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-trifluoromethyl-phenyl)-1H-benzoimidazol-2-yl]-amide (45.6 mg) was added. The reaction was monitored by LCMS until substantially complete. Then, 10 mL of water was added and the reaction mixture was stirred for 10 minutes. The reaction was then filtered through a fine fritted funnel and the crude product was washed with water. After air drying, purified by column chromatography to obtain 6-((1R,3R)-3-hydroxy-1-methyl-butoxy)-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-trifluoromethyl-phenyl)-1H-benzoimidazol-2-yl]-amide (25.2 mg). LCMS (m/z): 526.1. 1H NMR (400 MHz, CDCl3) δ 8.39 (1H, s) 7.89 (1H, s) 7.45-7.85 (7H, m) 6.79 (1H, d) 5.42 (1H, ddd) 3.95 (1H, d) 2.18 (1H, brs) 1.91 (1H, ddd) 1.69-1.79 (1H, m) 1.44 (3H, d) 1.26 (3H, d)