Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(N(C)C)=C(C)C.[Si:9]([O:16][C@@H:17]([CH2:21][O:22][CH:23]1[CH2:26][CH2:25][CH2:24]1)[C:18]([OH:20])=O)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].N1C=CC=CC=1.[CH3:33][C:34]1[CH:35]=[CH:36][C:37]([NH2:40])=[N:38][CH:39]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[Si:9]([O:16][C@@H:17]([CH2:21][O:22][CH:23]1[CH2:26][CH2:25][CH2:24]1)[C:18]([NH:40][C:37]1[CH:36]=[CH:35][C:34]([CH3:33])=[CH:39][N:38]=1)=[O:20])([C:12]([CH3:13])([CH3:14])[CH3:15])([CH3:10])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](COC1CCC1)C(=O)O
Reactant: Cc1ccc(N)nc1
Agent: CC(C)=C(Cl)N(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)[C@H](COC2CCC2)O[Si](C)(C)C(C)(C)C)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.8 %

Procedure:
1-Chloro-N,N,2-trimethylprop-1-en-1-amine (0.133 mL, 1.00 mmol) was added to a stirred solution of (S)-2-(tert-butyldimethylsilyloxy)-3-cyclobutoxypropanoic acid (Intermediate R4) (250 mg, 0.91 mmol) in DCM (5 mL) at room temperature under nitrogen. The resulting solution was stirred at room temperature for 30 minutes. Pyridine (0.147 mL, 1.82 mmol) was added followed by a solution of 5-methylpyridin-2-amine (108 mg, 1.00 mmol) in DCM (5 mL) and the resulting solution was stirred at ambient temperature for 1 hour. 1M citric acid (10 mL) and DCM (50 mL) were added and the phases were separated. The organic phase washed with water (10 mL) and brine (10 mL), dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with 0 to 30% ethyl acetate in isohexane to afford the product (195 mg, 58.7%). 1H NMR (400 MHz, DMSO) δ 0.01 (d, 6H), 0.80 (s, 9H), 1.24-1.37 (m, 1H), 1.43-1.53 (m, 1H), 1.59-1.72 (m, 2H), 1.94-2.06 (m, 2H), 2.13 (s, 3H), 3.33-3.44 (m, 2H), 3.77-3.87 (m, 1H), 4.29-4.34 (m, 1H), 7.49-7.54 (m, 1H), 7.86 (d, 1H), 8.02-8.06 (m, 1H), 9.25 (s, 1H); m/z (ESI+) (M+H)+=365.47; HPLC tR=3.60 min.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][C@H:17]([CH3:19])[NH:16][C@@H:15]([CH3:20])[C:14]3=[O:21])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[Cl:51][C:52]1[S:56][C:55]([CH:57]=[CH:58][C:59](O)=[O:60])=[CH:54][CH:53]=1>CN(C=O)C>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][C@H:17]([CH3:19])[N:16]([C:59](=[O:60])[CH:58]=[CH:57][C:55]4[S:56][C:52]([Cl:51])=[CH:53][CH:54]=4)[C@@H:15]([CH3:20])[C:14]3=[O:21])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: O=C(O)C=Cc1ccc(Cl)s1
Reactant: C[C@@H]1N[C@@H](C)CN(Cc2ccc3c(N)ncnc3c2)C1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H]1CN(Cc2ccc3c(N)ncnc3c2)C(=O)[C@H](C)N1C(=O)C=Cc1ccc(Cl)s1
Reaction time: 2 h
Yield: 53 %

Procedure:
To a solution of (3S,5S)-1-(4-amino-quinazolin-7-ylmethyl)-3,5-dimethyl-piperazin-2-one (42 mg, 0.147 mmol), major epimer from EXAMPLE 88, Part D, in 2 mL of DMF is added TBTU (52 mg, 0.162 mmol), triethylamine (0.02 mL, 0.162 mmol) and 3-(5-chloro-thiophen-2-yl)-acrylic acid (28 mg, 0.15 mmol), EXAMPLE 25. After stirring for two hours, the reaction mixture is directly purified by reverse phase HPLC (10-70% ACN/H2O). The product (35.5 mg, 36%) is isolated as a yellow solid with a melting point of 116-120° C. C22H22ClN5O2S: MS m/z: 456, 458. Anal. calcd. for C22H22ClN5O2S.C2HF3O2: C, 50.57; H, 4.07; N, 12.29. Found: C, 46.48; H, 3.64; N, 11.04.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][CH2:12][CH2:13][N:14]2C(=O)C3C(=CC=CC=3)C2=O)[CH:4]=[CH:3][N:2]=1.O.NN>C(O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][CH2:12][CH2:13][NH2:14])[CH:4]=[CH:3][N:2]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccc2ccncc12
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCc1cccc2ccncc12
Yield: 100.5 %

Procedure:
To a refluxing solution of 0.174 g of [3-(8-isoquinolinyl)propyl]-1H-isoindole-1,3-(2H)-dione in 8 mL of ethanol was added 0.12 mL of hydrazine hydrate and the reaction was stirred at reflux for 5.5 hours. The solvent was removed under reduced pressure and the residue was triturated with chloroform. The chloroform extract was concentrated to an oil which was passed through a short column of silica gel (chloroform-methanol-triethylamine; 1:4:15) to yield 0.103 g of 8-isoquinolinepropanamine as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:14][CH3:15])[C:10]=1[CH:11]([CH3:13])[CH3:12])[CH2:6]O.P(Br)(Br)[Br:17].O>CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:14][CH3:15])[C:10]=1[CH:11]([CH3:13])[CH3:12])[CH2:6][Br:17]
Reactant: BrP(Br)Br
Reactant: COc1cc(CO)cc(OC)c1C(C)C
Solvent: CCOCC
Solvent: O
Product: COc1cc(CBr)cc(OC)c1C(C)C
Yield: 175.2 %

Procedure:
To 3,5-Dimethoxy-4-i-propylbenzyl alcohol (12.57 g, 59.8 mmol) in dry ether (100 mL) at 0° C. was added PBr3 (3.0 mL, 31.2 mmol) dropwise under nitrogen. The reaction was monitored by TLC. After the reaction was completed (˜4 h), water (180 mL) was added. The organic layer was separated and the aqueous layer was extracted with ether (3×50 mL). The extract was washed with water (20 mL), sat. Na2CO3 (20 mL), water (20 mL) and brine (20 mL), and dried over anhydrous sodium sulfate. Evaporation of the solution yielded pure bromide (14.93 g, 91.4%) as a white solid. 1HNMR (CDCl3, ppm): δ 1.29 (d, J=7.1 Hz, 6H), 3.64 (hept, J=7.1 Hz, 1H), 3.84 (s, 6H), 4.50 (s, 2H), 6.60 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:13](Cl)=[N:12][CH:11]=[N:10][C:9]=3[S:15][C:4]=2[CH:3]=1.[Cl:16][C:17]1[CH:18]=[C:19]([NH2:31])[CH:20]=[CH:21][C:22]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.Cl.C([O-])(O)=O.[Na+]>O1CCOCC1.CC(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:13]([NH:31][C:19]4[CH:20]=[CH:21][C:22]([O:23][CH2:24][C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=5)=[C:17]([Cl:16])[CH:18]=4)=[N:12][CH:11]=[N:10][C:9]=3[S:15][C:4]=2[CH:3]=1
Reactant: Nc1ccc(OCc2ccccn2)c(Cl)c1
Reactant: Clc1ncnc2sc3cc(Br)ccc3c12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: C1COCCO1
Product: Clc1cc(Nc2ncnc3sc4cc(Br)ccc4c23)ccc1OCc1ccccn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 80.4 %

Procedure:
A mixture of 7-Bromo-4-chloro[1]benzothieno[2,3-d]pyrimidine (4.85 g, 16.2 mmol), 3-Chloro-4-(pyridin-2-ylmethoxy)-phenylamine (4.73 g, 18.1 mmol, 1.12 equiv), and HCl in dioxane (4.0 M, 7.25 mL) in IPA (100 mL) was heated to reflux for 3 days. The suspension was filtered and washed with IPA (3×20 mL) to collect a light tan solid. The solid was triturated with ether to give a yellow solid. The yellow solid was added to a saturated NaHCO3 solution in a few portions to adjust pH to 7. The suspension was stirred at rt for 5 min then filtered and washed with water and methanol to give a yellow solid. The solid was placed under vacuum oven at 35° C. for 60 h to yield 6.48 g (76%) of product. 1H-NMR (CD3OD) δ 8.81 (d, J=5.4 Hz, 1H), 8.59 (s, 1H), 8.45 (d, J=8.4 Hz, 1H), 8.37 (t, 1H), 8.34 (d, J=2.1 Hz, 1H), 8.04 (d, J=8.2 Hz, 1H), 7.87 (d, J=2.7 Hz, 1H), 7.81 (m, 1H), 7.80 (dd, J=2.1, 8.9 Hz, 1H), 7.63 (dd, J=2.1, 8.9 Hz, 1H), 7.31 (d, J=8.7 Hz, 1H), 5.51 (s, 2H); LCMS RT=3.43 min, [M+H]+=499.0
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:12]([O-])=O)[CH:9]=2)[CH2:4]1.[CH3:16][C:17](OC(C)=O)=[O:18]>CCO.O.[Pd]>[CH3:1][N:2]([CH3:15])[CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:12][C:17](=[O:18])[CH3:16])[CH:9]=2)[CH2:4]1
Reactant: CC(=O)OC(C)=O
Reactant: CN(C)C1Cc2ccc([N+](=O)[O-])cc2C1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: CC(=O)Nc1ccc2c(c1)CC(N(C)C)C2
Temperature: 20 °C
Reaction time: 16 h
Yield: 73.5 %

Procedure:
A solution of crude nitroindanamine 108 (19.82 g, 95.8 mmol) in EtOH (200 mL) and Pd/C (500 mg) was stirred in 2×100 mL batches under H2 (60 psi) for 16 h. The combined batches were filtered through Celite, and washed with warm EtOH (1 L) and then DMF (100 mL). The solvent was evaporated and the residue suspended in dioxane (130 mL), and Ac2O (19 mL, 190 mmol) added dropwise. The mixture was stirred at 20° C. for 16 h, diluted with water (200 mL), the pH adjusted to 10 with cNH3, and the mixture stirred for 30 min. The precipitate was filtered, washed with water (50 mL) and dried to give pure 5-acetamide 109 (15.38 g, 73%) as tan powder: mp 94-96° C.; 1H NMR δ 7.42 (br s, 1H, NH), 7.08-7.14 (m, 3H, H-4, H-6, H-7), 2.97-3.08 (m, 3H, H-2, CH2), 2.78-2.89 (m, 2H, CH2), 2.30 [s, 6H, N(CH3)2], 2.15 (s, 3H, COCH3); 13C NMR δ 168.3, 142.8, 137.9, 136.3, 124.5, 118.5, 116.6, 68.1, 43.8 (2), 37.7, 37.1, 24.5. Anal. calcd for C13H18N2O.H2O: C, 66.1; H, 8.5; N, 11.9. Found: C, 66.1; H, 8.5; N, 11.9%.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([F:7])=[C:4]([F:6])[F:5].[CH:10]([O:12][CH2:13][CH:14]1[CH2:19][CH2:18][CH:17]([CH2:20][OH:21])[CH2:16][CH2:15]1)=[CH2:11].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[F:5][C:4]([F:6])([O:21][CH2:20][CH:17]1[CH2:18][CH2:19][CH:14]([CH2:13][O:12][CH:10]=[CH2:11])[CH2:15][CH2:16]1)[CH:3]([F:7])[C:2]([F:9])([F:8])[F:1]
Reactant: FC(F)=C(F)C(F)(F)F
Reactant: C=COCC1CCC(CO)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=COCC1CCC(COC(F)(F)C(F)C(F)(F)F)CC1
Temperature: 25 °C
Yield: 75.9 %

Procedure:
Hexafluoropropene (264 g, 1.76 mol) was added dropwise to a mechanically stirred mixture of 1,4-cyclohexanedimethanol vinyl ether (300 g, 1.76 mol), acetonitrile (600 mL), and K2CO3 (121 g, 0.88 mol), at 0° C. under N2. The reaction flask was placed in an ice bath to moderate the exothermic reaction during the addition of hexafluoropropene. After complete addition of hexafluoropropene, the reaction mixture was stirred for an additional hour at room temperature and filtered. The filtrate was added to 1.5 L water and mixed well. The lower layer formed was separated, washed with water (3×300 mL), and concentrated under reduced pressure (approximately 0.05 mm Hg) to afford 1,1,2,3,3,3-hexafluoro-1-{[4(vinyloxymethyl)cyclohexyl]methoxy}propane(cis/trans mixture) as a colorless liquid (428 g, 76% yield); b.p. 55-60° C./0.05 mm Hg; Refractive Index 1.4145 at 23.7° C.; GC/MS: m/z at 320 for M+; 19F and 1H NMR spectral data are consistent with the structure.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][C:18](Cl)=[O:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[NH2:21][CH2:22][CH2:23][NH:24][CH2:25][CH2:26][NH:27][CH2:28][CH2:29][NH2:30]>C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>[C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][C:18]([NH:21][CH2:22][CH2:23][NH:24][CH2:25][CH2:26][NH:27][CH2:28][CH2:29][NH:30][C:18](=[O:19])[CH2:17][CH2:16][C:7]2[CH:8]=[C:9]([C:12]([CH3:13])([CH3:15])[CH3:14])[C:10]([OH:11])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=2)=[O:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCNCCNCCN
Reactant: CC(C)(C)c1cc(CCC(=O)Cl)cc(C(C)(C)C)c1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)c1cc(CCC(=O)NCCNCCNCCNC(=O)CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Reaction time: 2 h

Procedure:
0.02 moles β-(3,5-di-t-butyl-4-hydroxy phenyl) propionyl chloride in 25 ml methylene chloride was added to a stirred mixture containing a solution of 0.02 mol triethylene tetramine in 125 ml methylene chloride and 25 ml 10% sodium carbonate. The mixture was stirred for two hours and then separated. The methylene chloride layer was washed with 5% sodium carbonate solution and then with water, subsequently dried over anhydrous magnesium sulfate and finally evaporated to dryness. A resinous material of 1,8-bis[β-(3,5-di-t-butyl-4-hydroxy phenyl) propionamido]-3,6-diazaoctane resulted which was pulverized to give a light brown solid having a melting point of 80°-110° C.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH2:44][CH3:45])[N:38]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=O)C.[H-].[Na+]>O1CCCC1.C(O)C>[C@@H:6]1([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]3[S:33][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH2:44][CH3:45])[N:38]=4)=[CH:35][CH:36]=3)[CH:25]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CCOc1cccc(-c2ccc(Cc3cc([C@@H]4O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]4OC(C)=O)ccc3Cl)s2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1cccc(-c2ccc(Cc3cc([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)ccc3Cl)s2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chlorobenzene 71 obtained in Example 128-(4) and tri-n-butyl (6-ethoxy-2-pyridyl) tin (see WO 00/74681) were treated in a manner similar to Example 128-(5) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(6-ethoxy-2-pyridyl)-2-thienylmethyl) benzene as colorless crystals. APCI-Mass m/Z 660/662 (M+H). (2) The above 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(6-ethoxy-2-pyridyl)-2-thienylmethyl)benzene (245 mg) was dissolved in tetrahydrofuran (5 ml), added thereto was a solution of sodium hydride (oil, 9 mg) in ethanol (5 ml), and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=100:0-90:10) to give the desired 1-(β-D-glucopyranosyl)-4-chloro-3-(5-(6-ethoxy-2-pyridyl)-2-thienylmethyl)benzene (145 mg) as colorless powder. APCI-Mass m/Z 492/494 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][NH2:10].S(F)([O-])(=O)=O.[CH2:16]([O:18][C:19](=[O:29])[CH2:20][N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C:22]1=C[OH2+])[CH3:17].O.[OH-].[K+]>C(Cl)Cl>[CH2:16]([O:18][C:19](=[O:29])[CH2:20][N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C:22]1=[N:10][NH:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[CH3:17]
Reactant: CCOC(=O)CN1CCCCC1=C[OH2+]
Reactant: NNc1ccc(Cl)cc1Cl
Agent: O=S(=O)([O-])F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CN1CCCCC1=NNc1ccc(Cl)cc1Cl
Reaction time: 0.5 h

Procedure:
A solution of 17.7 parts of 2,4-dichlorophenylhydrazine in methylene chloride was added dropwise to the above reaction mixture containing [1-(2-ethoxy-2-oxoethyl)piperidin-2-ylidene]methyloxonium fluorosulfate while keeping the temperature of the reaction less than 30° C. After the addition was completed the reaction was stirred for an additional 30 minutes. The reaction mass was then poured into 1000 parts of water. The pH was raised to 12.0 with 20% potassium hydroxide solution. The crude product was extracted with three successive portions of 1000 parts of methylene chloride. The organic extracts of the product were dried over anhydrous sodium sulfate. The solution of the product was filtered to remove the drying agent. The solvent was removed at a reduced pressure of 50-300 mm with a rotary evaporator leaving the crude product which was used in the next step without further purification.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:20]([O:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1)[CH2:21][CH2:22][CH3:23]>>[CH2:20]([O:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:29][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:31][CH:32]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCOc1ccc(C=O)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: CCCCOc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-butoxybenzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(4-butoxyphenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [C:1]1([C:7]([CH3:11])=[CH:8][CH:9]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]1([S:18]([C:21]#[N:22])(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.B(OCCCC)(OCCCC)OCCCC>>[C:12]1([S:18]([C:21]2[CH:11]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:8]=[CH:9][N:22]=2)(=[O:19])=[O:20])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(=CC=O)c1ccccc1
Reactant: N#CS(=O)(=O)c1ccccc1
Agent: CCCCOB(OCCCC)OCCCC
Product: O=S(=O)(c1ccccc1)c1cc(-c2ccccc2)ccn1
Temperature: 112 °C
Yield: 68.7 %

Procedure:
First, 0.93 g (6.36 mmol) of 3-phenyl-2-butenal and 0.99 g (5.91 mmol) of benzenesulfonyl cyanide were introduced to a 3-necked flask (25 ml volume) equipped with a thermometer, a magnetic stirrer, a Dean-Stark water type distilling receiver, and a condenser tube. Toluene (5 ml) as the solvent and butanol (0.5 ml) were added, and 0.14 g (0.59 mmol) of tributyl borate was added. Then the mixture was heated under reflux for 2 hours while agitating at an internal temperature of 112° C. in a nitrogen atmosphere, separating and removing water that was produced. After this solution was cooled to room temperature, the low-boiling components, such as solvent, etc., were removed under reduced pressure to give the desired, crude product. The crude product was purified by silica gel column chromatography (eluting solvent: ethyl acetate/hexane=1/4) to give 1.20 g of 2-benzenesulfonyl-4-phenylpyridine with the following properties as colorless crystals (purity of 99%, yield of 71% based on benzenesulfonyl cyanide).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:21])[CH2:3][O:4][C:5]1[CH:20]=[CH:19][C:8]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])=[CH:7][CH:6]=1.[N+:22]([C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH:27]=O)([O-:24])=[O:23].[BH3-]C#N.[Na+]>CO.CC(O)=O>[N+:22]([C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27][NH:1][C@@H:2]([CH3:21])[CH2:3][O:4][C:5]1[CH:20]=[CH:19][C:8]([C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])=[CH:7][CH:6]=1)([O-:24])=[O:23]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: C[C@H](N)COc1ccc(C(=O)OCc2ccccc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: C[C@@H](COc1ccc(C(=O)OCc2ccccc2)cc1)NCc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.1 %

Procedure:
To a cooled (0) solution of benzyl (S)-4-(2-amino-1-propoxy)benzoate (1.50 g, 5.26 mmol) and 2-nitrobenzaldehyde (0.87 g, 5.76 mmol) in MeOH—AcOH (16 ml, 15:1, v/v) was added NaBH3CN (1.65 g, 26.3 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was quenched by sat. NaHCO3 and extracted with EtOAc. The extract was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel with CHCl3 to 5% MeOH in CHCl3 as eluent to give benzyl (S)-4-[2-(2-nitrobenzylamino)-1-propoxy]benzoate (931 mg, 42%) as a yellow oil. 1H-NMR (CDCl3) δ1.21 (d, J=6.4 Hz, 3 H), 3.13-3.18 (m, 1 H), 3.88-3.97 (m, 2 H), 4.06-4.20 (m, 2 H), 5.34 (s, 2 H), 6.89-6.94 (m, 2 H), 7.29-7.65 (m, 8 H), 7.94-8.03 (m, 3 H); FAB-MAS, m/z 421 (M++1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:13]2[CH2:25][OH:26])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36].C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH:13]2[CH2:25][O:26][S:35]([CH3:34])(=[O:37])=[O:36])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCCC2(CCN(Cc3ccccc3)C2)C1CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC2(CCN(Cc3ccccc3)C2)C1COS(C)(=O)=O
Temperature: 0 °C

Procedure:
A solution of 10 mmol of tert-butyl 2-benzyl-6-hydroxymethyl-2,7-diazaspiro[4.5]decane-7-carboxylate in 30 ml of dichloromethane is admixed at 0° C. with 15 mmol of triethylamine, followed by 11 mmol of methanesulphonyl chloride. The reaction mixture is stirred at 0° C. for an hour and then at room temperature for an hour. The reaction mixture is poured into saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane. The combined organic extracts are washed with brine, dried with sodium sulphate and evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60 F) on the basis of the Rf value.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([F:20])[CH:19]=1)[NH2:16].CC(C)([O-])C.[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH:3]=1)[NH:16][C:15]1[CH:14]=[C:13]([F:12])[CH:19]=[C:18]([F:20])[CH:17]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Reactant: Nc1cc(F)cc(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Cl)cc1Nc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-chloro-2-fluoro-1-nitrobenzene (2.500 g, 14.24 mmol) and 3,5-difluoroaniline (2.206 g, 17.09 mmol) in DMF (22.61 mL) was added potassium tert-butoxide (3.20 g, 28.5 mmol) under argon and the solution was stirred at rt overnight. The solution was poured into water and extracted with DCM, and the organic extracts were purified by column chromatography on a silica gel column using 5 to 10% gradient of EtOAc in hexane as eluent to give 5-chloro-N-(3,5-difluorophenyl)-2-nitroaniline as an orange solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 6.98 (tt, J=9.34, 2.20 Hz, 1H) 7.02-7.11 (m, 3H) 7.35 (d, J=2.15 Hz, 1H) 8.14 (d, J=9.00 Hz, 1H) 9.40 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:12](=[O:30])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[F:26])=[CH:17][C:16]([C:27]([NH2:29])=O)=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C(Cl)=NC(Cl)=NC=1Cl.CN(C)C=O>O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[N:11]([CH2:31][CH:32]([CH3:33])[CH3:34])[C:12](=[O:30])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[F:26])=[CH:17][C:16]([C:27]#[N:29])=[CH:15][CH:14]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2F)c2cc(C(N)=O)ccc2c1=O
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2F)c2cc(C#N)ccc2c1=O
Yield: 84.5 %

Procedure:
A solution of 3-[[(tert-butoxycarbonyl)amino]methyl]-4-(2-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxamide (Example 10 (4)) (0.23 g, 0.5 mmol) and cyanuric chloride (0.28 g, 1.5 mmol) in N,N-dimethylformamide (10 mmol) was stirred at 0° C. for 1 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-n-hexane to give tert-butyl[6-cyano-4-(2-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.19 g, 86.4%) as crystals.
Reaction SMILES: [C:1]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:8])[C:2]1C=C[CH:5]=[CH:4][CH:3]=1.[O:20]1C=CC=C1C(Cl)=O>>[O:20]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:1]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:8]
Reactant: CCOC(=O)CCCCCCC(=O)c1ccccc1
Reactant: O=C(Cl)c1ccco1
Product: CCOC(=O)CCCCCCC(=O)c1ccco1
Yield: 71 %

Procedure:
Following a procedure analogous to that described above for 49a, but substituting 2-furanoyl chloride, the title compound was obtained in 71% yield: 1H NMR (300 MHz, CDCl3) δ 7.59 (d, J=1.8 Hz, 1H), 7.19 (d, J=3.3 Hz, 1H), 6.54 (dd, J=3.3, 1.8 Hz), 4.12 (q, J=6.9 Hz, 2H), 2.82 (t, J=7.5 Hz, 2H), 2.30 (t, J=7.5 Hz, 2H), 1.72 (m, 2H), 1.64 (m, 2H), 1.38 (m, 4H), 1.25 (t, J=6.9 Hz, 3H); 13C NMR (75.4 MHz, CDCl3) δ 14.07, 23.87, 24.58, 28.68, 28.72, 34.05, 38.14, 59.98, 111.97, 116.68, 146.05, 152.60, 173.52, 189.39.