Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1([CH3:14])[CH:10]2[CH2:11][C:7]([CH3:12])([CH2:8][CH2:9]2)[CH2:6][C:5]1=[O:13])[CH:2]=[CH2:3].COCCO[AlH2-]OCCOC.[Na+]>C1(C)C=CC=CC=1>[CH2:1]([C:4]1([CH3:14])[CH:10]2[CH2:11][C:7]([CH3:12])([CH2:8][CH2:9]2)[CH2:6][CH:5]1[OH:13])[CH:2]=[CH2:3]
Reactant: C=CCC1(C)C(=O)CC2(C)CCC1C2
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=CCC1(C)C(O)CC2(C)CCC1C2
Temperature: 75 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
4-Allyl-1,4-dimethyl-bicyclo[3.2.1]octan-3-one (288 g, 1.5 mol, obtained as above in EXAMPLE IV) was added to a solution of Red-Al (65%, 506 g, 1.5 mol) in toluene at 75° C. The reaction mixture was aged for 3 hours while the temperature was maintained at 75° C., then cooled to room temperature, and subsequently quenched with a solution of sodium bicarbonate (NaHCO3). Distillation of the organic layer provided 4-allyl-1,4-dimethyl-bicyclo[3.2.1]octan-3-ol (288 g, 1.5 mol), which was then added to a MSA solution (30 g) in toluene (500 mL) and heated to reflux for 3 hours. The reaction mixture was subsequently washed with a Na2CO3 solution. Fractional distillation of the organic layer provided 2,4,8-trimethyl-5-oxa-tricyclo[6.2.1.0*2,6*]undecane (170 g) having a boiling point of 62° C. at a pressure of 0.3 mmHg
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:11]([F:27])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH3:28].C(O)(C)C>>[NH2:28][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:11]([F:27])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: N
Reactant: O=C(Nc1cc(F)c(Oc2cc(Cl)ncn2)cc1F)OCc1ccccc1
Solvent: CC(C)O
Product: Nc1cc(Oc2cc(F)c(NC(=O)OCc3ccccc3)cc2F)ncn1
Temperature: 120 °C
Yield: 15 %

Procedure:
A mixture of benzyl [4-(4-chloropyrimidin-6-yloxy)-2,5-difluorophenyl]carbamate (3.92 g) and 2M ammonia-isopropanol (50 ml) was heated at 120° C. for 2 days in a sealed tube. The reaction mixture was allowed to cool to room temperature, then concentrated under reduced pressure. The resultant residue was partitioned between ethyl acetate and a 10% aqueous solution of potassium bisulfate. The organic layer was washed with brine, dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:2). Fractions containing the target compound were concentrated under reduced pressure and the residue was dried under reduced pressure to provide the titled compound as pale yellow crystals (561 mg, 15%).
Reaction SMILES: [F:1][C:2]([F:18])([C:14]([F:17])([F:16])[F:15])[CH2:3][CH2:4][S:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])(=[O:7])=[O:6].[F:19][C:20]([S:23][CH2:24][CH2:25]OS(C(F)(F)F)(=O)=O)([F:22])[F:21].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O>[F:18][C:2]([F:1])([C:14]([F:15])([F:16])[F:17])[CH2:3][CH2:4][S:5]([CH:8]([CH2:25][CH2:24][S:23][C:20]([F:22])([F:21])[F:19])[C:9]([O:11][CH2:12][CH3:13])=[O:10])(=[O:6])=[O:7]
Reactant: O=S(=O)(OCCSC(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)CS(=O)(=O)CCC(F)(F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C(CCSC(F)(F)F)S(=O)(=O)CCC(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl (3,3,4,4,4-pentafluoro-butane-1-sulfonyl)-acetate (J. Fluorine Chem. 1985, 28(4), 425-440) (2.00 g, 6.70 mmol), trifluoro-methanesulfonic acid 2-trifluoromethylsulfanyl-ethyl ester (1.50 g, 5.36 mmol), and potassium carbonate (2.77 g, 5.36 mmol) in 1,2-dimethoxyethane (100 mL) was stirred overnight at room temperature under nitrogen. The reaction mixture was diluted with H2O (200 mL) and extracted with ethyl acetate (2×150 mL). The combined organic extracts were washed with brine (200 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, hexanes/CH2Cl2 1:1) to provide compound II-3 (0.28 g, 37%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]([C:21]#[N:22])([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)[CH2:7][C:8](OCC)=[O:9])[CH3:2].[BH4-].[Na+]>CO.O.O.O.O.O.O.[Co](Cl)Cl>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:7][C:8](=[O:9])[NH:22][CH2:21]1)[CH3:2]
Reactant: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccc(Cl)c(Cl)c1
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)CC1(c2ccc(Cl)c(Cl)c2)CNC(=O)C1
Reaction time: 1.5 h
Yield: 85.1 %

Procedure:
3-Cyano-3-(3,4-dichloro-phenyl)-pentanedioic acid diethyl ester (10 g; 27.94 mmol) was dissolved in methanol (100 mL) and cobalt(II)chloride hexahydrate (13.2 g, 55.48 mmol) was added. The solution was then cautiously treated with one gram portions of sodium borohydride (11 g, 290 mmol) over 45 minutes at 20°-30° C. The solution was allowed to stir an additional 1.5 hours and the solution was concentrated in vacuo. The residue was partitioned between dichloromethane and 1N HCl the organic phase was and washed with 1N HCl (700 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel (600 g) with a gradient of 3% to 6% methanol in dichloromethane to give 7.514 g (85%) of the title compound.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2.C(=O)([O-])[O-].[K+].[K+].[C:24](Cl)(=[O:32])[O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O.C(#N)C>[O:25]([C:24]([NH:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2)=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: NCCCOc1ccc2[nH]c(=O)ccc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C(NCCCOc1ccc2[nH]c(=O)ccc2c1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
To a mixture of water (50 ml) and acetonitrile (50 ml) are added 6-(3-aminopropoxy)carbostyril hydrochloride (5.0 g) and potassium carbonate (3.4 g) at room temperature. The mixture is stirred at room temperature for 2 hours, and cooled to -5° C. To the mixture is added dropwise phenyl chlorocarbonate (3.9 g) while the temperature of the mixture is kept below 0° C. The mixture is stirred at the same temperature for 1 hour, and thereto is added water (100 ml), and then the mixture is further stirred for 0.5 hour. The precipitated crystals are collected by filtration, and washed successively with water and acetone to give 6-(3-phenoxycarbonylaminopropoxy)carbostyril (6.0 g) as a white powder.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=O)[C:12](=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:17]1[N:22]2CN3CN(C2)C[N:18]1C3.C([O-])(=O)C.[NH4+]>C(O)(=O)C>[N:18]1[C:13]2[C:14]3[C:5]([C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:12]=2[NH:22][CH:17]=1)=[CH:4][CH:3]=[CH:2][CH:1]=3
Reactant: O=C1C(=O)c2ccccc2-c2ccccc21
Reactant: C1N2CN3CN1CN(C2)C3
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: c1ccc2c(c1)c1ccccc1c1[nH]cnc21

Procedure:
Phenanthrene-9,10-quinone or an appropriately substituted analog is reacted with hexamethylenetetramine (hexamine) and ammonium acetate in glacial acetic acid to produce the corresponding phenanthro[9,10-d]imidazole. The reaction is carried out with refluxing of the acetic acid. ##STR8## [Edgar A. Stock and A. R. Day, J. Am. Chem. Soc., 65, 452 (1943)].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH:11]=[C:10]([C:21](O)=[O:22])[CH:9]=2)=[CH:4][CH:3]=1.Cl.[Cl:25][C:26]1[N:30]([CH3:31])[N:29]=[CH:28][C:27]=1[C@H:32]([NH2:34])[CH3:33].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:25][C:26]1[N:30]([CH3:31])[N:29]=[CH:28][C:27]=1[C@H:32]([NH:34][C:21]([C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[CH:13]=[C:12]([C:14]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])[CH:11]=1)=[O:22])[CH3:33]
Reactant: C[C@@H](N)c1cnn(C)c1Cl
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)N3CCCC3)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)c3cnn(C)c3Cl)cc(C(=O)N3CCCC3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 20 mL vial was charged with 4′-methyl-5-(pyrrolidine-1-carbonyl)biphenyl-3-carboxylic acid (30 mg, 0.097 mmol), (R)-1-(5-chloro-1-methyl-1H-pyrazol-4-yl)ethanamine hydrochloride (24 mg, 0.12 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (92 mg, 0.24 mmol), N,N-diisopropylethylamine (0.068 mL, 0.39 mmol), and N,N-dimethylformamide (1.0 mL) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was purified by preparative HPLC to get the product as a light yellow solid.
Reaction SMILES: [O-:1]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:9]/[CH:10]=[CH:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15]/[CH:16]=[CH:17]/[C:18](NCC(C)C)=[O:19]>>[C:18]([OH:19])(=[O:1])[CH:17]=[CH:16][CH2:15][CH2:14][CH:13]=[CH:12][CH:11]=[CH:10][CH3:9]
Reactant: C/C=C/C=C\CC/C=C/C(=O)NCC(C)C
Reactant: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CC=CC=CCCC=CC(=O)O

Procedure:
0.05 g (10% wt) of K3PO4 and 0.05 g (10% wt) of polyethylene glycol (PEG 400) were added to 0.5 g of the spilanthol mixture (αβ unsaturated form:βγ unsaturated form=43:57) obtained in the above-mentioned (7), followed by stirring at 80° C. for 16 hours. When verified by GC, the ratio of αβ unsaturated form to βγ unsaturated form was converted to αβ unsaturated form:βγ unsaturated form=99:1. After cooling of the reaction liquid and subsequent separation of liquid by adding 5 ml of toluene and 5 ml of water, the organic layer was subjected to solvent evaporation under a reduced pressure to obtain 0.5 g of the target spilanthol (yield 99%, αβ unsaturated form:βγ unsaturated form=99:1).
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[C:4](I)=[CH:5][C:6]([O:9][CH3:10])=[N:7][CH:8]=1.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:23]#[N:24])=[C:18](B(O)O)[CH:19]=1>>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:23]#[N:24])=[C:18]([C:4]2[C:3]([CH:2]([F:12])[F:1])=[CH:8][N:7]=[C:6]([O:9][CH3:10])[CH:5]=2)[CH:19]=1
Reactant: COc1cc(I)c(C(F)F)cn1
Reactant: N#Cc1ccc(Cl)cc1B(O)O
Product: COc1cc(-c2cc(Cl)ccc2C#N)c(C(F)F)cn1

Procedure:
616 mg (purity 83%, 1.79 mmol) of 5-(difluoromethyl)-4-iodo-2-methoxypyridine and 325 mg (1.79 mmol) of 5-chloro-2-cyanophenylboronic acid in the presence of [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride/dichloromethane monoadduct were reacted according to General Method 2A. Yield: 223 mg (42% of theory)
Reaction SMILES: [N:1]1([CH2:11][CH2:12][C:13]([NH:15][CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.O=P(Cl)(Cl)Cl.CN([CH:29]=[O:30])C>>[CH3:20][N:18]([CH3:19])[CH2:17][CH2:16][NH:15][C:13](=[O:14])[CH2:12][CH2:11][N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:29]=[O:30])=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C=O
Reactant: CN(C)CCNC(=O)CCN1CCCc2ccccc21
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)CCNC(=O)CCN1CCCc2cc(C=O)ccc21

Procedure:
The procedure was carried out as described previously in step (a) of Example 5 with Compound 8 (0.74 g, 2.7 mmol), POCl3 (506 μL, 5.4 mmol), and DMF (8.6 mL). Compound 9 was obtained (0.31 g) as a viscous yellow liquid and used without any further purification. The structure of Compound 9 is given below:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1CCCCC1.Cl>N1C=CC=CC=1>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[CH:14][C:15]([OH:17])=[O:16]
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1cccc(C(F)(F)F)c1
Temperature: 0 °C
Yield: 96.4 %

Procedure:
A mixture of 3-(trifluoromethyl) benzaldehyde (25 g, 144 mmol), malonic acid (28.8 g, 277 mmol), anhydrous pyridine (100 ml) and piperidine (2 ml) was heated under reflux for 4 hours. The mixture was poured onto fresh ice (300 g) and concentrated hydrochloric acid (78 ml). The solid product was collected, dried and recrystallised (1:1 IMS/water) to give 30 g (96% of theory) of 3-(trifluoromethyl) cinnamic acid as off-white needles.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH:12]([C:21](=O)[C:22]#[C:23][CH:24]1[CH2:27][CH:26]([CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:25]1)[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.S([O-])([O-])(=O)=O.[Na+].[Na+].[Cl-].[CH3:44][O:45][NH3+:46]>N1C=CC=CC=1>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH:12]([C:21](=[N:46][O:45][CH3:44])[C:22]#[C:23][CH:24]1[CH2:27][CH:26]([CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:25]1)[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[NH3+]
Reactant: CC(C)(C)CC1CC(C#CC(=O)C(CCCOCc2ccccc2)CC(=O)OC(C)(C)C)C1
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CO
Product: CON=C(C#CC1CC(CC(C)(C)C)C1)C(CCCOCc1ccccc1)CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.4 %

Procedure:
tert-Butyl 3-(3-benzyloxypropyl)-6-[3-(2,2-dimethylpropyl)cyclobutyl]-4-oxo-5-hexynoate (3.44 g) and methanol (35 mL) were mixed. To the mixture were added sodium sulfate (2.15 g), pyridine (3.5 mL) and O-methylhydroxylammonium chloride (1.26 g). The mixture was stirred at RT overnight. The mixture was then filtered, and the filtrate was concentrated in vacuo. To the resultant residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over magnesium sulfate. The magnesium sulfate was filtered off and the filtrate was concentrated in vacuo. To the resultant residue was added silica gel (5 g), and the mixture was stirred at RT for 10 min. The silica gel was filtered off and the filtrate was concentrated in vacuo to give the title compound (3.38 g) as a crude product.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12]([C:14]#[C:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:13])[CH3:10]>>[CH2:19]([O:18][C:16]([CH:15]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:14][C:12]([O:11][CH2:9][CH3:10])=[O:13])=[O:17])[CH3:20]
Reactant: Nc1ccc(F)cc1
Reactant: CCOC(=O)C#CC(=O)OCC
Product: CCOC(=O)CC(Nc1ccc(F)cc1)C(=O)OCC

Procedure:
A solution of 10.0 g (0.09 mole) 4-fluoroaniline 7 and 8.0 g (0.047 mole) diethylacetylene dicarboxylate 8 is stirred at room temperature for 72 hours. The crude product is purified by flash chromatography using silica gel eluted initially with ethyl acetate:hexane (1:4) and finally with ethyl acetate. The fractions containing the product are combined and concentrated under reduced pressure to give 9 as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:25])=[N:4][S:5][C:6]=1[NH:7][C:8](=[O:24])[CH2:9][C:10]1[CH:11]=[CH:12][C:13]2[O:17][C:16]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[N:15][C:14]=2[CH:23]=1.CO[CH:28](OC)[N:29]([CH3:31])[CH3:30].CN(C)C=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([CH3:25])=[N:4][S:5][C:6]=1[NH:7][C:8](=[O:24])[C:9]([C:10]1[CH:11]=[CH:12][C:13]2[O:17][C:16]([CH2:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[N:15][C:14]=2[CH:23]=1)=[CH:28][N:29]([CH3:31])[CH3:30]
Reactant: COC(OC)N(C)C
Reactant: Cc1nsc(NC(=O)Cc2ccc3oc(CC(C)(C)C)nc3c2)c1Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1nsc(NC(=O)C(=CN(C)C)c2ccc3oc(CC(C)(C)C)nc3c2)c1Cl
Temperature: 110 °C
Yield: 27.3 %

Procedure:
N-(4-Choro-3-methylisothiazol-5-yl)-[2-(2,2-dimethylpropyl)benzoxazol-5-yl]acetamide (2.5 g, 0.0066 mole) [prepared as in Example 1] and N,N-dimethylformamide dimethylacetal (1.5 g, 0.013 mole) were added to a mixture of N,N-dimethylformamide (5 ml) and toluene (20 ml) and the resulting mixture was heated to 110° C. for 4 hours. The mixture as cooled to room temperature and the solvent was evaporated in vacuo. The residue was taken up in ethyl acetate and washed sequentially with brine and water, dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated in vacuo. The residue was further purified by flash column chromatography, eluting with ethyl acetate:hexane at 1:1 by volume. Further flash column chromatography, eluting with ethyl acetate:dichloromethane at 1:9 by volume gave N-(4-chloro-3-methylisothiazol-5-yl)-α-[(dimethylamino)methylene]-[2-(2,2-dimethylpropyl)benzoxazol-5-yl]acetamide (0.78 g) as a single geometrical isomer.
Reaction SMILES: [OH:1][C:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1C)[C:3]([OH:5])=[O:4].Br[CH2:20][O:21]C1C=CC=CC=1.C(C(O)=O)(=O)C1C=CC=CC=1.COC(C(C1C=CC=CC=1)=O)=O>>[OH:1][C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:21][CH3:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]([OH:5])=[O:4]
Reactant: BrCOc1ccccc1
Reactant: Cc1ccccc1C(O)(C(=O)O)c1ccccc1
Agent: COC(=O)C(=O)c1ccccc1
Agent: O=C(O)C(=O)c1ccccc1
Product: COc1ccccc1C(O)(C(=O)O)c1ccccc1

Procedure:
This compound is prepared by an analogous method to hydroxy-phenyl-o-tolyl-acetic acid (Intermediate M) by replacing bromotoluene with 2-bromomethoxy benzene and benzoyl formic acid with methyl benzoyl formate.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[CH2:17](Br)[CH2:18][CH2:19][CH3:20].Cl>>[CH2:17]([N:12]1[CH2:11][CH2:10][CH:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=2)[CH2:14][CH2:13]1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCBr
Reactant: FC(F)(F)c1cccc(C2CCNCC2)c1
Agent: Cl
Product: CCCCN1CCC(c2cccc(C(F)(F)F)c2)CC1

Procedure:
Beginning with 4-(3-Trifluoromethyl-phenyl)piperidine and n-Bu-Br: m.p. 222° C. (HCl), MS m/z (rel. intensity, 70 eV) 285 (M+, 3), 243 (12), 242 (bp), 70 (51), 56 (17).
Reaction SMILES: N[C:2]1[S:3][C:4]([CH3:10])=[C:5]([CH3:9])[C:6]=1C#N.[C:11]([NH:13][C:14]([NH2:16])=[NH:15])#[N:12].Cl.[OH-].[Na+]>O>[CH3:9][C:5]1[C:6]2[C:11]([NH2:12])=[N:13][C:14]([NH2:16])=[N:15][C:2]=2[S:3][C:4]=1[CH3:10]
Reactant: N#CNC(=N)N
Reactant: Cc1sc(N)c(C#N)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1sc2nc(N)nc(N)c2c1C
Temperature: 25 °C
Yield: 5.2 %

Procedure:
A mixture of 2-amino-4,5-dimethylthiophene-3-carbonitrile (500 mg, 3.29 mmol), cyanoguanidine (276.6 mg, 3.29 mmol) and HCl (2 N, 1.5 mL) in water (10 mL) was refluxed under nitrogen for 2 h. The reaction mixture was cooled to room temperature, and basified with diluted NaOH aqueous solution to PH 7-8. After evaporation of water, the residue was purified by preparative HPLC eluting with acetonitrile and water to give the title compound (33 mg, 5%). 1H NMR (400 MHz, DMSO-d6) δ 2.22 (s, 3H), 2.27 (s, 3H), 5.85 (bs, 2H), 6.29 (bs, 2H). MS 195 (MH+).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][CH:7]1[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]1.C(=O)([O-])[O-].[K+].[K+].O1CCCC1.[NH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=1>O>[CH3:37][C:34]1[CH:35]=[CH:36][C:31]([NH:30][C:11]([N:9]2[CH2:10][CH:7]([O:6][C:5]3[CH:14]=[CH:15][CH:16]=[C:3]([C:2]([F:18])([F:17])[F:1])[CH:4]=3)[CH2:8]2)=[O:12])=[CH:32][CH:33]=1
Reactant: Cc1ccc(N)cc1
Reactant: O=C(Cl)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(NC(=O)N2CC(Oc3cccc(C(F)(F)F)c3)C2)cc1
Reaction time: 0.5 h

Procedure:
To a stirred mixture of 1.88 g (0.0067 mole) of 3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarbonyl chloride and 1 g (0.007 mole) of potassium carbonate was added 20 ml of tetrahydrofuran and 0.75 g (0.007 mole) of 4-toluidine. After stirring for 0.5 hr, ice was added and stirring continued for 18 hr. The reaction mixture was diluted with water and then decanted from an oil residue which separated. Upon standing, this residue solidified and was recrystallized from acetone to yield 1.1 g (47%) of large, white crystals, m.p. 191°-192° C.
Reaction SMILES: [Li]C(C)(C)C.[Cl:6][C:7]1[C:12]([Cl:13])=[CH:11][C:10](I)=[CH:9][N:8]=1.Cl([O-])(=O)(=O)=O.[CH2:20]1[C:27]2[CH2:26][CH2:25][CH2:24][N+:23]=2[CH2:22][CH2:21]1.Cl>CCCCC.CCOCC>[Cl:13][C:12]1[CH:11]=[C:10]([C:27]23[CH2:26][CH2:25][CH2:24][N:23]2[CH2:22][CH2:21][CH2:20]3)[CH:9]=[N:8][C:7]=1[Cl:6]
Reactant: Clc1cc(I)cnc1Cl
Reactant: C1CC2=[N+](C1)CCC2
Agent: Cl
Agent: [Li]C(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCOCC
Solvent: CCCCC
Product: Clc1cc(C23CCCN2CCC3)cnc1Cl
Temperature: -20 °C
Reaction time: 0.03 h
Yield: 54.3 %

Procedure:
A solution of 1.7M tBuLi (4.7 mL, 8.0 mmol) in pentane was added to 2,3-dichloro-5-iodopyridine (from step 8a, 1.0 g, 3.65 mmol) in Et2O (15 mL) precooled to -100° C. After stirring for 2 minutes, 1,2,3,5,6,7-hexahydropyrrolizinium perchlorate (1.5 g, 7.3 mmol) was added, and the reaction mixture was allowed to stir for 20 minutes at -100° C. then gradually warm to -20° C. A solution of 2N HCl was added, and the cold bath was removed. After warming to ambient temperature, the reaction mixture was poured over EtOAc and the phases were separated. The aqueous phase was basified with 15% NaOH solution and extracted with CH2Cl2 (2×). The CH2Cl2 phases were combined, dried (MgSO4), concentrated and the residue was chromatographed (silica gel; CHCl3 /MeOH, 99.5:0.5) to afford a light yellow oil (510 mg, 54%). MS (CI/NH3) m/e: 257 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ1.59-1.71 (m, 2H), 1.80-2.08 (m, 6H), 2.64-2.72 (m, 2H), 3.11-3.20 (m, 2H), 7.99 (d, J=2.2 Hz, 1H), 8.36 (d, J=2.2 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)=[CH:4][N:3]=1.C(N(CC)CC)C.[C:24](OC(=O)C)(=[O:26])[CH3:25]>C(Cl)Cl>[CH3:15][C:10]1([CH3:16])[C:11]([CH3:14])([CH3:13])[O:12][B:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:24](=[O:26])[CH3:25])=[N:3][CH:4]=2)[O:9]1
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (120 mg) in dry DCM (3 ml) and triethylamine (1.5 equiv., 114 uL) was added acetic anhydride (1.1 equiv., 57ul) and the reaction mixture was stirred at room temperature overnight. Dichloromethane/brine extraction and purification on silica gave 66 mg of N-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl]-acetamide.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[N:13][C:14]([NH:17][CH2:18][C:19]3([C:23]4[C:28]([F:29])=[CH:27][CH:26]=[CH:25][N:24]=4)[CH2:22][CH2:21][CH2:20]3)=[CH:15][CH:16]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].[NH2:30][CH2:31][CH2:32][NH:33][C:34](=[O:43])[O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[N:13][C:14]([NH:17][CH2:18][C:19]3([C:23]4[C:28]([F:29])=[CH:27][CH:26]=[CH:25][N:24]=4)[CH2:20][CH2:21][CH2:22]3)=[CH:15][CH:16]=2)=[CH:7][C:3]=1[C:4]([NH:30][CH2:31][CH2:32][NH:33][C:34](=[O:43])[O:35][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:5]
Reactant: O=C(O)c1cc(-c2ccc(NCC3(c4ncccc4F)CCC3)nn2)ccc1F
Reactant: NCCNC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCCNC(=O)c1cc(-c2ccc(NCC3(c4ncccc4F)CCC3)nn2)ccc1F)OCc1ccccc1
Reaction time: 4 h
Yield: 50.2 %

Procedure:
To a 20 dram vial was added 2-fluoro-5-(6-((1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)benzoic acid (320 mg, 0.8 mmol, 1.0 equiv), benzyl 2-aminoethylcarbamate (242 mg, 1.0 mmol, 1.3 equiv), HOBt (141 mg, 1.0 mmol, 1.3 equiv), EDC HCl (200 mg, 1.0 mmol, 1.3 equiv), DIPEA (550 μL, 3.8 equiv) and CH2Cl2 (5 mL). The reaction was stirred for 4 h and then concentrated and then purified using a silica gel column (50%-100% EtOAc/hexanes) to afford 230 mg (50%) of benzyl 2-(2-fluoro-5-(6-((1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)benzamido)ethylcarbamate as a white foam.