Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[N:4]=[CH:5][C:6]([N:9]2[C:16]3[C@@H:15]4[CH2:17][C@@H:14]4[CH2:13][C:12]=3[C:11]([C:18](O)=[O:19])=[N:10]2)=[N:7][CH:8]=1.[NH2:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26]>>[OH:26][CH2:25][C:24]([NH:23][C:18]([C:11]1[C:12]2[CH2:13][C@H:14]3[CH2:17][C@H:15]3[C:16]=2[N:9]([C:6]2[CH:5]=[N:4][C:3]([C:2]([F:22])([F:21])[F:1])=[CH:8][N:7]=2)[N:10]=1)=[O:19])([CH3:28])[CH3:27]
Reactant: CC(C)(N)CO
Reactant: O=C(O)c1nn(-c2cnc(C(F)(F)F)cn2)c2c1C[C@H]1C[C@@H]21
Product: CC(C)(CO)NC(=O)c1nn(-c2cnc(C(F)(F)F)cn2)c2c1C[C@H]1C[C@@H]21

Procedure:
The title compound was prepared in a manner similar to that described in Method G, using (1aR,5aR)-2-(5-trifluoromethylpyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid and 2-amino-2-methylpropan-1-ol. LCMS m/z=382.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.47 (td, J=4.3, 4.0 Hz, 1H), 1.28 (td, J=7.8, 5.2 Hz, 1H), 1.49 (s, 6H), 2.30-2.36 (m, 1H), 2.74-2.78 (m, 1H), 2.93 (d, J=16.8 Hz, 1H), 3.02 (dd, J=16.6, 6.2 Hz, 1H), 3.71 (s, 2H), 4.43 (bs, 1H), 6.94 (s, 1H), 8.77 (s, 1H), 9.32 (s, 1H).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[NH:3].[CH3:5][C@H:6]1[CH2:10][CH2:9][C@H:8]([CH3:11])[N:7]1[CH2:12][C:13](OC)=[O:14]>>[NH2:3][C:2]([NH2:4])=[N:1][C:13](=[O:14])[CH2:12][N:7]1[C@@H:8]([CH3:11])[CH2:9][CH2:10][C@@H:6]1[CH3:5]
Reactant: COC(=O)CN1[C@@H](C)CC[C@@H]1C
Reactant: N=C(N)N
Product: C[C@H]1CC[C@H](C)N1CC(=O)N=C(N)N

Procedure:
By a procedure analogous to Example 7, guanidine is reacted with methyl (trans-2,5-dimethyl-pyrrolidin-1-yl)acetate to yield the title compound.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH2:8].Cl[C:10]1[C:19]2[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2)[N:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>CN1CCCC1=O>[Cl:20][C:16]1[CH:15]=[C:14]2[C:19]([C:10]([NH:1][C@H:2]3[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]3[NH2:8])=[CH:11][CH:12]=[N:13]2)=[CH:18][CH:17]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: N[C@H]1CCCC[C@@H]1N
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: N[C@H]1CCCC[C@@H]1Nc1ccnc2cc(Cl)ccc12

Procedure:
13.6 g of (1S,2S)-(+)-1,2-diaminocyclohexane, 23.6 g of 4,7-dichloroquinoline and 16.6 ml of triethylamine were held at 150° C. in 150 ml of 1-methyl-2-pyrrolidone under argon for 16 hrs. The solvent was largely distilled off at 0.1 Torr/80° C. and the residue was triturated with 300 ml of 1.5N HCl. The resulting aqueous suspension was extracted three times with 300 ml of dichloromethane and then made basic with concentrated ammonia, with gum-like clumps separating. The supernatant solution was decanted off and extracted twice with 400 ml of dichloromethane. The crude product obtained from these extracts was purified by two-fold flash chromatography on neutral aluminium oxide (Brockmann activity II) with dichloromethane and dichloromethane/ethanol 30:1. Crystallization was effected from 40 ml of dichloromethane and 60 ml of ethyl acetate by distillation of the former. Yield: 4 g (12%) of (1S,2S)-N-(7-chloro-quinolin-4-yl)-cyclohexane-1,2-diamine; m.p. 160° C., [α]D =+129.30 (MeOH, c=1.0).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].C([Li])CCC.[CH3:16][CH2:17][C:18](=[O:21])[CH2:19][CH3:20].Cl>C1COCC1>[SH:8][C:4]1[CH:3]=[C:2]([C:18]([OH:21])([CH2:19][CH3:20])[CH2:17][CH3:16])[CH:7]=[CH:6][CH:5]=1
Reactant: CCC(=O)CC
Reactant: Sc1cccc(Br)c1
Agent: Cl
Agent: [H-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(O)(CC)c1cccc(S)c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To 3-Bromobenzenethiol (1.6 mL, 13.5 mmol) in THF (10 mL) at 0° C. was added sodium hydride (60 wt %, 600 mg, 14.9 mmol). After stirring for 10 minutes, the reaction was cooled to −78° C. and n-butyllithium (7.4 mL, 14.9 mmol) was added dropwise. After stirring for 20 minutes, 3-pentanone (1.6 mL, 14.9 mmol) was added, and the reaction was slowly warmed to room temperature and immediately acidified with 1N aqueous HCl to pH 3. The reaction mixture was extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (5% EtOAc in hexanes) to give the desired product, 10l.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([NH:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:17])[C:3]=1[C:18]1[NH:23][C:22]2[CH:24]=[CH:25][C:26]([OH:28])=[CH:27][C:21]=2[S:20](=[O:30])(=[O:29])[N:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:38][C:39]([NH2:41])=[O:40]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([NH:12][CH2:13][CH:14]([CH3:15])[CH3:16])[C:4](=[O:17])[C:3]=1[C:18]1[NH:23][C:22]2[CH:24]=[CH:25][C:26]([O:28][CH2:38][C:39]([NH2:41])=[O:40])=[CH:27][C:21]=2[S:20](=[O:29])(=[O:30])[N:19]=1
Reactant: CC(C)CNn1c(=O)c(C2=NS(=O)(=O)c3cc(O)ccc3N2)c(O)c2ccccc21
Reactant: NC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)CNn1c(=O)c(C2=NS(=O)(=O)c3cc(OCC(N)=O)ccc3N2)c(O)c2ccccc21
Temperature: 165 °C
Yield: 78.6 %

Procedure:
The product of Example 321C (0.048 g, 0.11 mmol) was reacted with cesium carbonate (0.11 g, 0.34 mmol), 2-bromoacetamide (0.023 g, 0.17 mmol) and a catalytic amount of tetrabuylammonium iodide in N,N-dimethylformamide (3 mL) at 25° C. for 2 hours. The reaction was concentrated to half the volume under a stream of nitrogen warmed through a manifold heated to 165° C. The resulting solution was diluted with water and the precipitate was collected by filtration and dried to give the title compound (0.042 g, 77%). MS (ESI−) m/z 484 (M−H)−. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.03 (m, 6 H) 1.86 (m, 1 H) 3.25 (m, 2 H) 4.50 (m, 2 H) 5.94 (t, J=7.35 Hz, 1 H) 7.07 (t, J=7.72 Hz, 1 H) 7.21 (m, 2 H) 7.40 (s, 1 H) 7.58 (m, 2 H) 8.07 (dd, J=7.72, 1.47 Hz, 1 H) 16.23 (s, 1 H).
Reaction SMILES: [CH:1]1([CH:4]([N:6]2[C:10]([NH2:11])=[CH:9][C:8]([CH3:12])=[N:7]2)[CH3:5])[CH2:3][CH2:2]1.[CH:13]1([C:16](=O)[CH2:17][C:18](=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1>C1(C)C=CC=CC=1>[CH:13]1([C:16]2[CH:17]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:9]3[C:8]([CH3:12])=[N:7][N:6]([CH:4]([CH:1]4[CH2:3][CH2:2]4)[CH3:5])[C:10]=3[N:11]=2)[CH2:14][CH2:15]1
Reactant: Cc1cc(N)n(C(C)C2CC2)n1
Reactant: CCOC(=O)C(=O)CC(=O)C1CC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(C2CC2)nc2c1c(C)nn2C(C)C1CC1
Temperature: 70 °C

Procedure:
1-(1-Cyclopropylethyl)-3-methyl-1H-pyrazol-5-amine (500 mg, 3.03 mmol) and ethyl 4-cyclopropyl-2,4-dioxobutanoate (557 mg, 3.03 mmol) were suspended in Toluene (10 mL) and heated at 70° C. for 16 h. The solvent was removed in vacuo and the crude residue was purified via silica gel chromatography (eluent: gradient of 0 to 10% EtOAc:Hex). The final product was collected as a solid, 0.722 g (76%). LCMS E-S (M+H)=314.3 1H NMR (400 MHz, DMSO-d6) ppm 0.17-0.32 (m, 2 H), 0.39 (m, J=9.69, 4.82, 4.82, 4.67 Hz, 1 H), 0.51-0.62 (m, 1 H), 0.94-1.11 (m, 4 H), 1.28-1.41 (m, 4 H), 1.58 (d, J=6.82 Hz, 3 H), 2.30-2.38 (m, 1 H), 2.56 (s, 3 H), 4.19 (dq, J=9.44, 6.87 Hz, 1 H), 4.43 (q, J=7.07 Hz, 2 H), 7.48 (s, 1 H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:12]([CH:16]=1)[C:13](O)=[O:14])=[O:6].O=C1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(N(C(C)C)CC)(C)C.[CH3:67][C:68]1[CH:74]=[C:73]([C:75]([F:84])([C:80]([F:83])([F:82])[F:81])[C:76]([F:79])([F:78])[F:77])[CH:72]=[C:71]([CH3:85])[C:69]=1[NH2:70]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([O:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[C:12]([CH:16]=1)[C:13]([NH:70][C:69]1[C:71]([CH3:85])=[CH:72][C:73]([C:75]([F:84])([C:76]([F:77])([F:78])[F:79])[C:80]([F:81])([F:82])[F:83])=[CH:74][C:68]=1[CH3:67])=[O:14])=[O:6]
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1N
Reactant: O=C(Nc1ccc(Oc2ccccc2)c(C(=O)O)c1)c1cccc(Cl)c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cc(NC(=O)c2cccc(Cl)c2)ccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 32 %

Procedure:
5-(3-Chloro-benzoylamino)-2-phenoxy-benzoic acid (200 mg, 0.54 mmol) (see Example I2) was suspended in dichloromethane (2 ml), followed by the addition of bis(2-oxo-3-oxazolidinyl)phosphonic chloride “BOP-Cl” (208 mg, 0.81 mmol), diisopropyl-ethylamine “Hunigs base” (280 μl, 1.63 mmol) and 2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-aniline (158 mg, 0.54 mmol) (=4-heptafluoroisopropyl-2,6-dimethylaniline, prepared according to US 2002/198399). The reaction mixture was stirred for 18 hours at ambient temperature, followed by extraction with aqueous sodium bicarbonate (1N) and dichloromethane. The organic phase was washed successively with aqueous hydrochloric acid (2N) and aqueous sodium bicarbonate (1N), dried over sodium sulfate and concentrated. The residue was purified by preparative reverse phase chromatography to yield Compound No. A1 of Table A below (113 mg, 32% yield over three steps).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11]C(=O)OC(C)(C)C)[CH:5]=[CH:4][C:3]=1[C:19]#[N:20].[ClH:21]>O1CCOCC1>[ClH:21].[ClH:21].[NH2:1][C:2]1[C:3]([C:19]#[N:20])=[CH:4][CH:5]=[C:6]([NH:8][CH2:9][CH2:10][NH2:11])[N:7]=1
Reactant: CC(C)(C)OC(=O)NCCNc1ccc(C#N)c(N)n1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1ccc(NCCN)nc1N
Reaction time: 0.5 h

Procedure:
6.76 g (24.38 mmol) of tert-butyl {2-[(6-amino-5-cyanopyridin-2-yl)amino]ethyl}carbamate (Example 110A) are dissolved in 122 ml of 4N hydrogen chloride in dioxane and stirred for 30 min. The reaction mixture is concentrated to one half, and an equal portion of diethyl ether is added. The reaction mixture is stirred for 20 min, and the product is filtered off and washed with diethyl ether. 5.43 g (89% of theory) of the product are obtained as a solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].O[C:19]1C=CC(C(C)CC(OCC)=O)=CC=1>>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:19])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(CCC(=O)OCC)cc1
Reactant: CCOC(=O)CC(C)c1ccc(O)cc1
Product: C=CCOc1ccc(C(C)CC(=O)OCC)cc1

Procedure:
Ethyl 3-(4-benzyloxyphenyl)but-2-enoate (3.4 g) in ethyl acetate (100 ml) was hydrogenated over a 10% palladium-on-carbon catalyst (250 mg) at atmospheric pressure/ambient temperature. The catalyst was removed by filtration and the filtrate evaporated to give an oil. The oil was purified by chromatography on silica gel using a 4/1 (v/v) mixture of hexane and ethyl acetate as eluent to give ethyl 3-(4-hydroxyphenyl)butanoate (1.51 g) as a pale yellow oil; NMR(CDCl3): 1.20(3H,t), 1.27(3H,d), 2.52(2H,q), 3.22(1H,m), 4.08(2H,q), 4.84(1H,s), 6.71(2H,m) and 7.08(2H,m); m/z 208(M). Ethyl 3-(4-allyloxyphenyl)butanoate was prepared using the procedue used to prepare ethyl 3-(4-allyloxyphenyl)propionate (see Example 1) but using ethyl 3-(4-hydroxyphenyl)butanoate in place of ethyl 3-(4-hydroxyphenyl)propionate; NMR(CDCl3) 1.17(3H,t), 1.25(3H,d), 2.51(2H,m), 3.22(1H,m), 4.05(2H,q), 4.50(2H,m), 5.33(2H,m), 6.06(1H,m), 6.82(2H,m) and 7.11(2H,m); m/z 249 (M+H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)=[CH:10][C:9]([CH:22]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:8][C:7]=2[N+:32]([O-])=O)[CH2:3][CH2:2]1.C([O-])=O.[NH4+]>C1(C)C=CC=CC=1.O.[Fe]>[NH2:32][C:7]1[CH:8]=[C:9]([CH:22]([CH2:28][CH:29]([CH3:30])[CH3:31])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:10]=[C:11]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=2)[C:6]=1[O:5][CH2:4][CH:1]1[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)c(OCC2CC2)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C(CC(C)C)c1cc(N)c(OCC2CC2)c(-c2ccc(C(F)(F)F)cc2)c1
Yield: 78.2 %

Procedure:
Ethyl 2-(6-(cyclopropylmethoxy)-5-nitro-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (300 mg, 0.626 mmol) was taken in 30 ml of Toluene:Water (1:1) and to it added Fe powder (203 mg, 3.62 mmol), Ammonium formate (228 mg, 3.62 mmol). The reaction mixture was refluxed for 3 h and then filtered through celite. The toluene was distilled off under reduced pressure and the crude residue was purified by column chromatography using Ethyl acetate:hexane (2:3) as eluent provided 220 mg of ethyl 2-(5-amino-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate. 1H NMR (CDCl3): δ 7.40-7.20 (m, 5H), 6.90(s 1H), 4.50(bs,2H),4.15 (q, 2H), 3.60 (t, 1H), 3.45 (d,2H),1.95-2.00(m,1H), 1.75-1.80 (m,1H), 1.45-1.50(m,1H), 1.20(t,3H), 1.00 (m,6H), 0.35-0.25 (m,5H). Mass: (450, M+1, 100%).
Reaction SMILES: [F:1][CH:2]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:15](Br)([CH3:17])[CH3:16].[H-].[Na+].CN(C)P(N(C)C)(N(C)C)=O>C1C=CC=CC=1>[F:1][C:2]([C:8]1[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=1)([CH:15]([CH3:17])[CH3:16])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CC(C)Br
Reactant: CCOC(=O)C(F)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: c1ccccc1
Product: CCOC(=O)C(F)(c1ccc(Cl)cc1)C(C)C
Temperature: 35 °C
Reaction time: 22 h
Yield: 61.4 %

Procedure:
A mixture of ethyl α-fluoro-4-chlorophenylacetate (2.3 g), isopropyl bromide (1.10 g), sodium hydride (0.56 g of a 50% mixture in oil), dry hexamethylphosphoramide (6 ml) and dry benzene (6 ml) was heated with stirring at a temperature of 35° C. under nitrogen for a period of 22 hours. The reaction mixture was poured into ice-water and the aqueous mixture extracted with methylene chloride. The methylene chloride extract was dried over anhydrous sodium sulfate and solvent removed by distillation under reduced pressure. The product was chromatographed over silica gel using 15% ethylene dichloride in petroleum ether as eluant to give ethyl α-fluoro-α-isopropyl-4-chlorophenylacetate (1.42 g; 62%).
Reaction SMILES: C(N(CC(O)=O)CC(O)=O)COCCOCCN(CC(O)=O)CC(O)=O.[F-].[Na+].CC(C[C@H](NC(C)=O)C(N[C@H](C(N[C@H](C(O)=O)CCCN=C(N)N)=O)CC(C)C)=O)C.C1N(CCO)CCN(CCS(O)(=O)=O)C1.[Mg+2].[Cl-].[Cl-].[CH:78]1[N:83]=[C:82]([NH2:84])[C:81]2[N:85]=[CH:86][N:87]([C@@H:88]3[O:92][C@H:91]([CH2:93][O:94][P:95]([O:98][P:99]([O:102][32P](O)(O)=O)([OH:101])=[O:100])([OH:97])=[O:96])[C@@H:90]([OH:107])[C@H:89]3[OH:108])[C:80]=2[N:79]=1>>[P:95]([O:94][CH2:93][C@H:91]1[O:92][C@@H:88]([N:87]2[C:80]3[N:79]=[CH:78][N:83]=[C:82]([NH2:84])[C:81]=3[N:85]=[CH:86]2)[C@H:89]([OH:108])[C@@H:90]1[OH:107])([O:98][P:99]([O:102][P:95]([OH:97])([OH:96])=[O:94])([OH:101])=[O:100])(=[O:96])[OH:97]
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)O[32P](=O)(O)O)[C@@H](O)[C@H]1O
Agent: CC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O
Agent: O=C(O)CN(CCOCCOCCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: O=S(=O)(O)CCN1CCN(CCO)CC1
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Reaction time: 0.08 h

Procedure:
Cells (30×106 ml-1), handled as in FIGS. 12A and 12B, were stimulated with IL-1β (10 ng ml-1) and homogenized at 4° C. with a Dounce homogenizer in buffer (25 mMHEPES, pH 7.4, 5 mM EGTA, 50 mM NaF and 10 μg/ml each of leupeptin and soybean trypsin inhibitor). Homogenates were centrifuged at 500×g for 5 minutes to remove nuclei and at 200,000×g for 30 minutes to prepare microsomal membranes. Membranes were resuspended into homogenizing buffer (2.2 μg membrane protein μl-1). For assay of kinase activity, the reaction mixture contained 20 μl of microsomal membrane, 40 μl EGFR peptide (4 mg ml-1 in 25 mM Hepes, pH 7.4) and 100 μl buffer (50 mM HEPES, pH 7.4, 20 mM MgCl2) (40). Phosphorylation was initiated at 22° C. by addition of 40 μl [γ-32P] ATP (100 μM final concentration) and terminated at the indicated times by addition of 40 μl of 0.5M ATP in 90% formic acid. Phosphorylated peptide was eluted from a C18Sep pak cartridge (Millipore), lyophilized, and resolved by C18 reverse phase HPLC using a linear gradient of acetonitrile. The peptide eluted at 30% acetonitrile as determined by measuring Cerenkov radiation in 1 ml fractions. All assays were performed under conditions determined as linear for time and enzyme concentration. Enzyme activity was determined from the percent conversion of substrate to product and the specific radioactivity of [γ-32P] ATP. Baseline kinetic analyses revealed a maximum reaction velocity of 12.5 pmol min-1 mg-1 of microsomal membrane protein and Michaelis constants (Km) of 70 μM ATP and 0.15 mg/ml for EGFR peptide. For most studies, 100 μM ATP was used to maintain a high 32 p specific radioactivity (4000 dpm pmol-1), although qualitatively similar results were obtained with 500 μM ATP. Ceramide and sphingosine (10 nM to 1 μM) enhanced kinass activity to 1.5-2.5 of control. Values (mean ± range) represent duplicate determinations from two experiments.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[N:7][C:8]=1[OH:9])=O.[CH3:23][C:24]1[CH:29]=[CH:28][N:27]2[CH:30]=[C:31]([CH2:33][C:34](OCC)=[O:35])[N:32]=[C:26]2[CH:25]=1.N1CCCCC1.C(O)(=O)C>CCO.O>[CH3:23][C:24]1[CH:29]=[CH:28][N:27]2[CH:30]=[C:31]([C:33]3[C:34](=[O:35])[O:9][C:8]4=[N:7][C:6]([N:10]5[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]5)=[CH:5][CH:4]=[C:3]4[CH:1]=3)[N:32]=[C:26]2[CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)c(O)n2)CC1
Reactant: CCOC(=O)Cc1cn2ccc(C)cc2n1
Solvent: CC(=O)O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1ccn2cc(-c3cc4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)nc4oc3=O)nc2c1
Temperature: 120 °C
Yield: 60.7 %

Procedure:
To a mixture of t-butyl 4-(5-formyl-6-hydroxypyridin-2-yl)piperazine-1-carboxylate (120 mg, 0.4 mmol) and ethyl 2-(7-methylimidazo[1,2-a]pyridin-2-yl)acetate (96 mg, 0.44 mmol) in EtOH (0.2 mL) were added piperidine (0.3 mL) and acetic acid (0.1 mL). The reaction mixture was heated to 120° C. for 15 hours, and cooled to room temperature. To the mixture was added water (6 mL) to give a precipitate. The precipitate was filtered and washed with water and then ether. After drying under nitrogen, 112 mg (60%) of t-butyl 4-(3-(7-methylimidazo[1,2-a]pyridin-2-yl)-2-oxo-2H-pyrano[2,3-b]pyridin-7-yl)piperazine-1-carboxylate was obtained as a yellow solid. MS m/z 462.4 [M+H]+.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[N:10][C:9]([O:12][CH:13]3[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[CH2:20][C:21]1[CH:29]=[CH:28][C:24]2[O:25][CH2:26][O:27][C:23]=2[CH:22]=1.C([O-])([O-])=O.[K+].[K+].N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1>CN(C=O)C>[N:1]1([C:6]2[N:11]=[N:10][C:9]([O:12][CH:13]3[CH2:18][CH2:17][CH2:16][N:15]([CH2:20][C:21]4[CH:29]=[CH:28][C:24]5[O:25][CH2:26][O:27][C:23]=5[CH:22]=4)[CH2:14]3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1cn(-c2ccc(OC3CCCNC3)nn2)cn1
Reactant: ClCc1ccc2c(c1)OCO2
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1cn(-c2ccc(OC3CCCN(Cc4ccc5c(c4)OCO5)C3)nn2)cn1
Temperature: 50 °C

Procedure:
A mixture of 3-[(6-(imidazol-1-yl)pyridazin-3-yl)oxy]piperidine (220 mg), 5-chloromethyl-1,3-benzodioxole (0.26 mL), K2CO3 (1.0 g), and Nal (0.1 g) in DMF (15 mL) was heated at 50° C. under N2 for 3 hours. After filtration and concentration in vacuo, the residual oil was dissolved in CH2Cl2 (100 mL), washed with water (20 mL×3) and brine, dried (MgSO4), and concentrated. Purification by column chromatography gave 3-[(6-(imidazol-1-yl)pyridazin-3-yl)oxy]-1-[(1,3-benzodioxol-5-yl)methyl]piperdine, (77 mg) as a white solid, NMR: (CDCl3) 8.30 (s, 1), 7.68 (s, 1), 7.52 (d, 1), 7.22 (s, 1), 7.16 (d, 1), 6.75 (s, 2), 5.90 (d, 2), 5.41 (m, 1), 3.46 (Abq, 2), 2.88 (d, 1), 2.58-2.48 (m, 2), 2.32 (m, 1), 2.10 (m, 1), 1.70-1.60 (m, 2) ppm.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26](=[NH:34])[NH:27][O:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:16][CH:15]=2)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:35]([O:37][C:38](OCC)(OCC)OCC)[CH3:36].C(O)(=O)C>O1CCOCC1>[CH2:35]([O:37][C:38]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26](=[NH:34])[NH:27][O:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:16][CH:15]=2)[C:3]2[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=[CH:11][C:2]=2[N:1]=1)[CH3:36]
Reactant: CCOC(OCC)(OCC)OCC
Reactant: CCOC(=O)ONC(=N)c1ccccc1-c1ccc(CNc2c(N)cccc2C(=O)OC)cc1
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CCOC(=O)ONC(=N)c1ccccc1-c1ccc(Cn2c(OCC)nc3cccc(C(=O)OC)c32)cc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
The pale brown syrup (8.58 g) obtained in Example (57a) was dissolved in dioxane (20 ml). To the solution were added tetraethoxymethane (8.64 g) and acetic acid (1.56 g). The mixture was stirred for 2 hours at 100° C. The reaction mixture was concentrated to dryness. The residue was crystallized from ethyl acetate (50 ml). Resulting crystalline precipitates were collected by filtration to obtain the title compound.
Reaction SMILES: N1CCC[C@H]1C(O)=O.[C:9]([C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=O)#[N:10].[CH3:19][C:20]1([CH3:28])[O:27][C:25](=[O:26])[CH2:24][C:22](=[O:23])[O:21]1.CC1NC(C)=C(C(OCC)=O)CC=1C(OCC)=O>C(O)C>[CH3:19][C:20]1([CH3:28])[O:27][C:25](=[O:26])[CH:24]([CH2:14][C:13]2[CH:12]=[C:11]([CH:18]=[CH:17][CH:16]=2)[C:9]#[N:10])[C:22](=[O:23])[O:21]1
Reactant: N#Cc1cccc(C=O)c1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CC1(C)OC(=O)C(Cc2cccc(C#N)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Proline (0.459 g, 3.95 mmol) was added to a mixture of 3-cyanobenzaldehyde (2.59 g, 19.7 mmol) and Meldrum's acid (2.84 g, 19.7 mmol) in ethanol (200 mL). The mixture was stirred at room temperature for 45 minutes and then diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (5 g, 20 mmol) was added. The mixture was stirred for an additional hour at room temperature before being concentrated to dryness. The residue was triturated with isopropanol and filtered to provide the title compound as a white solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([OH:27])[CH:19]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[OH:20])=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl.CS(C)=O.C(Cl)Cl.O>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:27])[C:19]([C:21]2[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=2)=[O:20])=[CH:14][CH:13]=1
Reactant: OC(c1ccncc1)C(O)c1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C(=O)c1ccc(F)cc1)c1ccncc1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
To a stirred cooled solution (−60° C.) of oxalyl chloride (3.55 mL, 40.8 mmol) in CH2Cl2 (16 mL) a solution of dimethyl sulfoxide (4.0 mL) in CH2Cl2 was added dropwise. Five minutes later a solution of 1-(4-fluorophenyl)-2-pyridin-4-ylethane-1,2-diol (4.0 g, 17 mmols) in DMSO/CH2Cl2 (32 mL/13 mL) was dropped. The mixture was allowed to stir for 30 min at −60° C. and then triethylamine (24 mL) was added. When the reaction reached room temperature was diluted with water and dichloromethane. The organic phases were washed with water and brine and dried (MgSO4). After removal of the solvent under vacuum, the resulting solid was triturated with hexane to afford the title compound as an orange solid (3.68 g, 94%).