Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][C:11]=1[N+:19]([O-:21])=[O:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:22]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH2:26][CH2:25][CH2:24][CH2:23]1>>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([N:22]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:16])=[CH:12][C:11]=1[N+:19]([O-:21])=[O:20])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: c1ccc2c(c1)CCCCN2
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1[N+](=O)[O-]
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)N2CCCCc3ccccc32)cc1[N+](=O)[O-]

Procedure:
The carboxylic acid from Example B (0.911 g, 3.08 mmol) was reacted with 2,3,4,5-tetrahydro-1H-1-benzazepine (0.453 g, 3.08 mmol) according to the procedure in Example 1A. The product was purified by flash chromatography on silica (eluant EtOAc:pet. ether 50:50); yield 0.58 g (43%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:33]O)[CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:17]=[C:16]([N:27]3[CH2:31][CH2:30][CH2:29][CH:28]3[CH3:32])[N:15]=2)[CH2:10][CH2:9]1.C[CH2:36][N:37](CC)CC.CS(Cl)(=O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:33][C:36]#[N:37])[CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:17]=[C:16]([N:27]3[CH2:31][CH2:30][CH2:29][CH:28]3[CH3:32])[N:15]=2)[CH2:10][CH2:9]1
Reactant: CCN(CC)CC
Reactant: CC1CCCN1c1nc(-c2ccc(F)cc2)cc(N2CCN(c3ncc(CO)cc3Cl)CC2)n1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC1CCCN1c1nc(-c2ccc(F)cc2)cc(N2CCN(c3ncc(CC#N)cc3Cl)CC2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice cooled solution of (5-chloro-6-{4-[6-(4-fluoro-phenyl)-2-(2-methyl-pyrrolidin-1-yl)-pyrimidin-4-yl]-piperazin-1-yl}-pyridin-3-yl)-methanol (136 mg, 0.282 mmol) and Et3N (79 μL, 0.564 mmol) in DCM, add MsCl (33 μL, 0.422 mmol) dropwise. Remove ice bath and stir for 1 h at room temperature. Dilute with 3 volumes of DCM, wash with brine, dry the organic layer (Na2SO4) and concentrate under reduced pressure. Dissolve the crude mesylate in DMSO, add 138 mg of NaCN and heat at 60° C. until no starting material remains as indicated by TLC. Dilute with water and extract the aqueous solution with EtOAc. Wash the organic extract with water (2×) followed by brine (1×), dry (Na2SO4) and concentrate under reduced pressure to give crude product. Purify using flash chromatography to give pure title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([Sn](C)(C)C)[S:10][C:3]=12.Br[C:16]1[N:21]=[C:20]([CH:22]=[O:23])[CH:19]=[CH:18][CH:17]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:16]3[N:21]=[C:20]([CH:22]=[O:23])[CH:19]=[CH:18][CH:17]=3)[S:10][C:3]=12
Reactant: C[Sn](C)(C)c1cc2nccc(Cl)c2s1
Reactant: O=Cc1cccc(Br)n1
Product: O=Cc1cccc(-c2cc3nccc(Cl)c3s2)n1
Yield: 27 %

Procedure:
This material was prepared by coupling 7-chloro-2-(trimethylstannyl)thieno[3,2-b]pyridine 39a (0.707 g, 2.17 mmole) with 6-bromopyridine-2-carbaldehyde (0.396 g, 2.17 mmole) using tereakis(triphenylphosphine)palladium(0) (100 mg) as catalyst in a manner as previously described for example 39b to give a white solid (0.161 g, 27%). 1H NMR (300 MHz, CDCl3) δ 10.15 (1H, s), 8.61 (1H, d, J=5.1 Hz), 7.93–8.09 (4H, m) 7.31 (1H, d, J=5.1 Hz); ESIMS (MH+): 275.00.
Reaction SMILES: [O:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[CH:2]1.[NH2:9][C@H:10]([CH2:27][CH3:28])[CH2:11][N:12]1[CH:16]=[CH:15][C:14]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([Cl:25])[C:18]=2[CH3:26])=[N:13]1>>[Cl:25][C:19]1[C:18]([CH3:26])=[C:17]([C:14]2[CH:15]=[CH:16][N:12]([CH2:11][C@H:10]([NH:9][C:6]([C:4]3[N:3]=[CH:2][O:1][CH:5]=3)=[O:8])[CH2:27][CH3:28])[N:13]=2)[CH:24]=[CH:23][C:20]=1[C:21]#[N:22]
Reactant: O=C(O)c1cocn1
Reactant: CC[C@@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2C)n1
Product: CC[C@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2C)n1)NC(=O)c1cocn1
Yield: 29.9 %

Procedure:
(R)—N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)butan-2-yl)oxazole-4-carboxamide was prepared using the method of Example 34(d) starting from 4-oxazolecarboxylic acid (0.2 g, 1.769 mmol) and (R)-4-(1-(2-aminobutyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile (0.532 g, 1.474 mmol). The product was triturated using diethyl ether. Yield 29.9%. 1H-NMR (400 MHz; CDCl3): δ 1.02 (t, 3H), 1.58 (m, 2H), 2.57 (s, 3H), 4.39 (m, 3H), 6.43 (d, 1H), 7.45 (d, 1H), 7.49 (d, 3H), 7.53 (dd, 1H), 7.58 (d, 1H), 7.85 (d, 1H), 8.22 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:15][CH:14]=2)[CH:9](O)[CH3:10])=[CH:4][CH:3]=1.CS(Cl)(=O)=O.C([N:34](CC)CC)C>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:15][CH:14]=2)[CH:9]([NH2:34])[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(O)C(Cc1ccc(C#Cc2ccccc2)cc1)c1ccc(Cl)cc1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Product: CC(N)C(Cc1ccc(C#Cc2ccccc2)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
141 mg of the alcohol compound thus obtained was dissolved in 2 ml of ethyl acetate, and 62 μl of methanesulfonyl chloride and 161 μl of triethylamine were added thereto, followed by stirring at room temperature for 30 minutes. Insoluble precipitates were filtered off from the reaction solution. Then, the filtrate was concentrated under reduced pressure, and the residue was dissolved in 5 ml of dimethylformamide. Then, 255 mg of sodium azide was added thereto, followed by heating at 80° C. for 4 hours. The reaction solution was left to cool to room temperature. Then, ethyl ether and water were added thereto for extraction. The organic layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then, the solvent was distilled off under reduced pressure. The residue was heated and refluxed together with 187 mg of triphenylphosphine in 7 ml of 10%-water containing tetrahydrofuran for one hour. The reaction solution was evaporated to dryness under reduced pressure. Then, the residue was dissolved in ethanol and again evaporated to dryness under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol=50/1→10/1) to obtain 129 mg (yield: 92%) of (1RS, 2SR)-2-(4-chlorophenyl)-1-methyl-3-(4-phenylethynylphenyl)propylamine.
Reaction SMILES: [Br:1][C:2]([Br:5])(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([C@@H:29]1[CH2:34][O:33][C@@H:32]([C:35]2[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=2)[O:31][CH2:30]1)[CH2:26][CH2:27][CH3:28].CCCCCC>C(Cl)Cl>[Br:1][C:2]([Br:5])=[CH:39][C:38]1[CH:37]=[CH:36][C:35]([C@H:32]2[O:31][CH2:30][C@H:29]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:34][O:33]2)=[CH:42][CH:41]=1
Reactant: BrC(Br)(Br)Br
Reactant: CCCC[C@H]1CO[C@H](c2ccc(C=O)cc2)OC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCCC
Product: CCCC[C@H]1CO[C@H](c2ccc(C=C(Br)Br)cc2)OC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of 13.6 g of tetrabromomethane in 150 ml of methylene chloride was placed at 0° C. in a sulphonation flask under argon gasification and treated within 10 minutes with a solution of 21.51 g of triphenylphosphine in 40 ml of methylene chloride. After completion of the addition, the clear orange solution was stirred at 0° C. for a further 5 minutes and then a solution of 5.08 g of p-(trans-5-butyl-1,3-dioxan-2-yl)benzaldehyde in 30 ml of methylene chloride was added dropwise within 5 minutes. The mixture was subsequently stirred at 0° C. for a further 30 minutes, then the flask content was poured into 800 ml of hexane and the separated precipitate was filtered off (rinsing with hexane). The concentrated filtrate was digested with 400 ml of hexane, left to stand at 0° C. for 15 hours, filtered (rinsing with hexane) and the filtrate was concentrated. Low-pressure chromatography (0.5 bar) of the residue (8.2 g) on silica gel with hexane followed by petroleum ether/ethyl acetate/triethylamine (97:3:0.5) gave 3.23 g of trans-2-[p-(2,2-dibromovinyl)phenyl]-5-butyl-1,3-dioxane as colourless crystals (purity 95.1%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:19][CH2:18][NH:17][C:16]3=[O:20])[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.Cl[CH2:24][C:25]1[NH:26][C:27](=[O:35])[C:28]2[CH:33]=[N:32][N:31]([CH3:34])[C:29]=2[N:30]=1.[H-].[Na+]>C1COCC1.CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:19][CH2:18][N:17]([CH2:24][C:25]4[NH:26][C:27](=[O:35])[CH:28]5[CH:33]=[N:32][N:31]([CH3:34])[CH:29]5[N:30]=4)[C:16]3=[O:20])[CH2:11][CH2:10]2)=[O:8])=[CH:21][CH:22]=1
Reactant: Cn1ncc2c(=O)[nH]c(CCl)nc21
Reactant: COc1ccc(C(=O)C2CCN(C3CCNC3=O)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)C2CCN(C3CCN(CC4=NC5C(C=NN5C)C(=O)N4)C3=O)CC2)cc1
Temperature: 70 °C
Yield: 86.3 %

Procedure:
To a solution of 3-[4-(4-methoxy-benzoyl)-piperidin-1-yl]-pyrrolidin-2-one (0.165 mmol, 50 mg) and 6-chloromethyl-1-methyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one (0.165 mmol, 33 mg) in THF (2 mL) was added sodium hydride (60%, 0.331 mmol, 23 mg) and heated to 70° C. for 1 hour. The reaction was allowed to cool to ambient temperature, diluted with 10 mL of ether, and the resulting solid in suspension was filtered and dried under vacuum provided the title compound as an off-white solid (66.4 mg, 87% yield). HRMS calculated for C24H28N6O4 464.5286. found (ESI, [M+H]+) 465.2256. 1H NMR (400 MHz, MeOD) δ ppm 1.70-1.93 (m, 4H) 2.09-2.31 (m, 2H) 2.53-2.66 (m, 1H) 2.80-2.91 (m, 1H) 2.93-3.02 (m, 1H) 3.10-3.21 (m, 1H) 3.33-3.43 (m, 2H) 3.48-3.57 (m, 2H) 3.65-3.75 (m, 1H) 3.83-3.90 (m, 6H) 4.37-4.51 (m, 2H) 6.97 (d, J=9.03 Hz, 2H) 7.83-7.91 (m, 1H) 7.97 (d, J=9.03 Hz, 2H), analytical RP-HPLC retention time=2.77 min
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[C:42]([CH3:44])[N:41]=[C:40]([CH2:45][CH3:46])[CH:39]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[C:42]([CH3:44])[N:41]=[C:40]([CH2:45][CH3:46])[CH:39]=2)[CH:33]=1)=[O:31])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CCc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cc(C)n1
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(C)nc(CC)c3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-ethoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J8) (240 mg, 0.75 mmol) and 3-[3-(2-ethyl-6-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K34) (255 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous light yellow substance (336 mg, 77%).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]=[C:7]([NH:15][C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=3[CH3:25])[C:19]([OH:21])=O)[C:8]3[CH:9]=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1.[NH2:28][CH2:29][C@H:30]([OH:32])[CH3:31].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]=[C:7]([NH:15][C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=3[CH3:25])[C:19]([NH:28][CH2:29][C@H:30]([OH:32])[CH3:31])=[O:21])[C:8]3[CH:9]=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1
Reactant: Cc1ccc(C(=O)O)cc1Nc1nc2ccc(F)cc2c2c(=O)[nH]ccc12
Reactant: C[C@@H](O)CN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)NC[C@@H](C)O)cc1Nc1nc2ccc(F)cc2c2c(=O)[nH]ccc12
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a solution of 3-[(9-fluoro-1-oxo-1,2-dihydrobenzo[c]-2,6-naphthyridin-5-yl)amino]-4-methylbenzoic acid (Example 1, Step 5) (25 mg, 0.07 mmol) and (2R)-1-aminopropan-2-ol (8 mg, 0.1 mmol) in DMF (0.7 mL) was added BOP (91 mg, 0.21 mmol) and Hunig's base (0.4 mL, 0.21 mmol). The reaction was warmed to 60° C. and the reaction stirred for 18 hours and was then quenched by the addition of sat. aq. NaHCO3 solution. The mixture was extracted with EtOAc and the extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification by silica gel column chromatography (0-10% MeOH/CH2Cl2) afforded the title compound.
Reaction SMILES: [CH3:1][CH2:2][C:3]1[C:21]2=[N:22][C:5](=[CH:6][C:7]3[NH:11][C:10]([CH:12]=[C:13]4[CH:34]([CH3:35])[CH:33]([CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[C:15]([C:16]5[CH:27](C(OC)=O)[C:25](=[O:26])[C:24]6[C:17]=5[NH:18][C:19]([C:23]=6[CH3:32])=[CH:20]2)=[N:14]4)=[C:9]([CH3:42])[C:8]=3[CH:43]=[CH2:44])[C:4]=1[CH3:45]>N1C(C)=CC(C)=CC=1C>[CH3:1][CH2:2][C:3]1[C:21]2=[N:22][C:5](=[CH:6][C:7]3[NH:11][C:10]([CH:12]=[C:13]4[C@@H:34]([CH3:35])[C@H:33]([CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[C:15]([C:16]5[CH2:27][C:25](=[O:26])[C:24]6[C:17]=5[NH:18][C:19]([C:23]=6[CH3:32])=[CH:20]2)=[N:14]4)=[C:9]([CH3:42])[C:8]=3[CH:43]=[CH2:44])[C:4]=1[CH3:45]
Reactant: C=Cc1c(C)c2cc3nc(c4c5[nH]c(cc6nc(cc1[nH]2)C(C)=C6CC)c(C)c5C(=O)C4C(=O)OC)C(CCC(=O)OC)C3C
Solvent: Cc1cc(C)nc(C)c1
Product: C=Cc1c(C)c2cc3nc(c4c5[nH]c(cc6nc(cc1[nH]2)C(C)=C6CC)c(C)c5C(=O)C4)[C@@H](CCC(=O)OC)[C@@H]3C

Procedure:
Methyl pheophorbide-a (1, 1.0 g) was obtained from alga Spirulina destridratada by following the procedure described in K. M. Smith, D. A. Goff and D. J. Simpson, J. An. Chem. Soc., 1986, 107, 4941-4954; and R. K. Pandey, D. A. Bellnier, K. M. Smith and T. J. Dougherty, Photochem. Photobiol., 1991, 53, 65-72, both of which are incorporated herein by reference. The methyl pheophorbide-a was heated under reflux in collidine (100 ml) for 90 min during slow passage of a stream of nitrogen. See G. W. Kenner, S. W. McCombie and K. M. Smith, J. Chem. Soc. Perkin Trans. 1973, 1, 2517-2523, incorporated herein by reference. The solution is evaporated (0.1 mm Hg) and the residue was recrystallized from dichloromethane/methanol. Yield 820 mg; 91%, m.p. 217°-219° C., lit. 220°-225° C.; H. Fisher and A. Stern, Die Chemie des Pyrrole, vol II, Part 2, pp. 64 and 74, Akademische Verlag, Leipzig incorporated herein by reference. Vis: (max) 410 (112 000); 508 (11 000); 536 (9 600); 610 (8 200); 666 (45 000); NMR, ppm; 9.50, 9.38, 8.52 (each s, 3H, 3 meso H); 7.95-8.05 (m, 1H, CH═CH2); 6.30 and 6.15 (each s, 1H, CH—CH2); 5.27 to 5.12 (q, 2H, 10—CH2); 4.50 (m, 8-HO; 4.28 (m, 7-H); 3.70 (q, 2H, CH2CH3); 3.68 (s, 3H, CHCHCO2CH3); 3.62, 3.40, 3.22 (each s, 3H, 3CH3); 2.70 (7a-H); 2.31 (7a′-H); 2.56 (7b-H); 2.29 (7b′-H); 1.82 (d, 3H, 8-CH 1.70 (t, 3H, CH2CH3); 1.70 (s, 2H,2 NH)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([O:8][CH2:9][C:10]([O:12]CC)=O)=[CH:4][CH:3]=1.[CH:15]1([C:18]([N:20]2[CH2:25][CH2:24][CH:23]([NH:26][CH3:27])[CH2:22][CH2:21]2)=[O:19])[CH2:17][CH2:16]1>>[Cl:1][C:2]1[N:7]=[N:6][C:5]([O:8][CH2:9][C:10]([N:26]([CH:23]2[CH2:24][CH2:25][N:20]([C:18]([CH:15]3[CH2:17][CH2:16]3)=[O:19])[CH2:21][CH2:22]2)[CH3:27])=[O:12])=[CH:4][CH:3]=1
Reactant: CNC1CCN(C(=O)C2CC2)CC1
Reactant: CCOC(=O)COc1ccc(Cl)nn1
Product: CN(C(=O)COc1ccc(Cl)nn1)C1CCN(C(=O)C2CC2)CC1
Yield: 63 %

Procedure:
The title compound was synthesized from ethyl 2-(6-chloropyridazine-3-yloxy)acetate and cyclopropyl (4-(methylamino)piperidine-1-yl)methanone in the same manner as in Example 105 (63% yield, in 2 steps).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][N:30]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][CH:25]3[CH2:27][CH2:26]3)=[O:22])=[CH:17][CH:16]=2)[C:11]([CH3:14])=[CH:12][CH:13]=1)=[O:6].[CH3:31][CH:32]1[CH2:37][CH:36]([CH3:38])[CH2:35][NH:34][CH2:33]1>>[CH:25]1([CH2:24][NH:23][C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:10]3[C:11]([CH3:14])=[CH:12][CH:13]=[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:28]=[CH:29][N:30]=[C:2]([N:34]5[CH2:35][CH:36]([CH3:38])[CH2:37][CH:32]([CH3:31])[CH2:33]5)[CH:3]=4)[CH:9]=3)=[CH:16][CH:17]=2)=[O:22])[CH2:27][CH2:26]1
Reactant: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1
Reactant: CC1CNCC(C)C1
Product: Cc1ccc(NC(=O)c2ccnc(N3CC(C)CC(C)C3)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1

Procedure:
A solution of 2-chloro-N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)isonicotinamide (50 mg, 0.12 mmol) in 3,5-dimethylpiperidine (1 ml) was heated at 120° C. for 18 h in a sealed tube. The reaction was concentrated under vacuum, the residue purified by preparative HPLC, to give, after evaporation of the solvents under vacuum N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-2-(3,5-dimethylpiperidin-1-yl)isonicotinamide. NMR; δH [2H6] —DMSO 10.29,(1H, s), 8.62,(1H, t), 8.21,(1H, d), 7.93,(2H, d), 7.70,(1H, dd), 7.65,(1H, d), 7.44,(2H, d), 7.30,(1H, d), 7.20,(1H, s), 6.98,(1H, d), 4.35,(2H, m), 3.16,(2H, t), 2.30,(2H, t), 2.20,(3H, s), 1.78,(1H, m), 1.57,(2H, m), 1.04,(1H, m), 0.91,(6H, d), 0.80,(1 H, q), 0.43,(2H, m), 0.24,(2H, m). LCMS: retention time 3.61 min, MH+497.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH3:17][N:18]1[CH:26]=[C:25]2[C:20]([CH:21]=[CH:22][CH:23]=[C:24]2[CH:27]=O)=[N:19]1.O>O1CCCC1>[CH3:17][N:18]1[CH:26]=[C:25]2[C:20]([CH:21]=[CH:22][CH:23]=[C:24]2/[CH:27]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:19]1
Reactant: Cn1cc2c(C=O)cccc2n1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C/c1cccc2nn(C)cc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98.4 %

Procedure:
Under nitrogen atmosphere, to a suspension of sodium hydride (1.26 g, 31.5 mmol) in tetrahydrofuran (50 mL) was added a solution of ethyl diethylphosphonoacetate (7.06 g, 31.5 mmol) in tetrahydrofuran (50 mL) at 0° C., and the mixture is was stirred for 20 min. To the reaction mixture was added a solution of 2-methyl-2H-indazole-4-carbaldehyde (4.60 g, 28.7 mmol) in tetrahydrofuran (100 mL), and the mixture was warmed to room temperature over 2 hr. Water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/1) to give the title compound (6.50 g, yield 98%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[C:13]3[CH:14]=[CH:15][C:16]([OH:21])=[C:17]([CH2:18][CH2:19][CH3:20])[C:12]=3[S:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][C:9]2[C:13]3[CH:14]=[CH:15][C:16]([OH:21])=[C:17]([CH2:18][CH2:19][CH3:20])[C:12]=3[S:11](=[O:30])[CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCc1c(O)ccc2c(CCc3ccccc3)csc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCc1c(O)ccc2c1S(=O)C=C2CCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The product of Example 63, Step H (2.017 grams) in CH2Cl2 solution (40 mL) was stirred (0° C.) and treated with solid 75% m-chloroperbenzoic acid (1.567 grams) in portions. The reaction was warmed to ambient temperature after 15 minutes and stirred for 1.5 hours. Partition of the reaction between isopropyl acetate and aqueous sodium bicarbonate was followed by washing of the organic with aqueous sodium bicarbonate, then water. Drying over magnesium sulfate, filtration and evaporation afforded a solid which was chromatographed over silica gel (2 step gradient; 5:1 hex/ethyl acetate; 5:2 hex/ethyl acetate; 5:2:0.35 hex/ethyl acetate/methanol). The title compound was acquired as a white solid.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[CH2:6]([CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:15][OH:16])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[OH-].[Na+]>O>[CH2:1]([O:16][CH2:15][CH:14]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:3]1[O:5][CH2:4]1
Reactant: CCCCCCCCCCC(CO)CCCCCCCC
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCC(CCCCCCCC)COCC1CO1
Temperature: 65 °C
Reaction time: 6 h
Yield: 79.7 %

Procedure:
The 2-octyldodecyl diglycerol ether emulsifier is prepared as follows. 2-Octyldodecyl glycidyl ether is prepared using the aliphatic glycidyl ether method described above. Approximately 360 g of epichlorohydrin is added to a stirred mixture of about 1.5 kg of 2-octyldodecanol (Jarcol I-20; Jarchem Industries) and about 10 g of stannic chloride. After the resulting exotherm heats the reaction mixture to about 70° C., the mixture is stirred under nitrogen for an additional about 6 hours at about 65° C. About 190 g of sodium hydroxide prediluted in approximately 280 g of distilled water is then added and reacted for about 6 hours at about 65° C. After separating the aqueous layer, the organic layer is water washed three times, heated to about 95° C., sparged with nitrogen to dry, and distilled in the range of about 185°-210° C. and <1 mm Hg to yield approximately 1.1 kg of 2-octyldodecyl glycidyl ether. Approximately 8.1 g of sodium methoxide (25% by weight in methanol) and approximately 1400 g of anhydrous glycerine are reacted together for about 3 hours under nitrogen at about 130° C. After heating the resulting mixture to about 185° C., the 2-octyldodecyl glycidyl ether is added dropwise over a period of about 2 hours. The resultant mixture is stirred for about 4 hours at about 185° C. under nitrogen and then allowed to cool without mixing. A glycerine layer settles to the bottom and is removed by siphoning. Volatiles are distilled from the remaining material by heating to about 150° C. at about 2 mm Hg, yielding approximately 1.3 kg of product. Approximately 700 g of the product is dissolved into an excess of mixed hexanes. This hexane phase is multiply extracted with 90:10 (v:v) methanol:water. The methanol:water extracts are combined and the solvent is removed using a rotary evaporator. The resulting residue is heated to about 70° C. and filtered through a glass microfiber filter, yielding approximately 380 g of 2-octyldodecyl diglycerol ether emulsifier. The product is analyzed by gel permeation chromatography and found to be about 82% diglycerol monoaliphatic ether and about 5% triglycerol dialiphatic ether. The product has a minimum interfacial tension of about 4.8 dyne/cm