Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([S@@]([N:7]=[CH:8][CH2:9][CH2:10][C:11]([CH3:23])([CH3:22])[C:12](OCC1C=CC=CC=1)=[O:13])=O)(C)(C)C.[F:24][C:25]1[CH:26]=[C:27]([Mg]Br)[CH:28]=[CH:29][C:30]=1[CH3:31]>C1(C)C=CC=CC=1.C1COCC1>[F:24][C:25]1[CH:26]=[C:27]([C@H:8]2[NH:7][C:12](=[O:13])[C:11]([CH3:23])([CH3:22])[CH2:10][CH2:9]2)[CH:28]=[CH:29][C:30]=1[CH3:31]
Reactant: Cc1ccc([Mg]Br)cc1F
Reactant: CC(C)(CCC=N[S@@](=O)C(C)(C)C)C(=O)OCc1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1ccc([C@@H]2CCC(C)(C)C(=O)N2)cc1F
Temperature: 25 °C

Procedure:
To a stirred solution of benzyl (SS)-5-[(tert-butylsulfinyl)imino]-2,2-dimethylpentanoate (1.00 g, 2.96 mmol, described in Intermediate 3) in toluene (28 mL) at −78° C. was added 3-fluoro-4-methylphenylmagnesium bromide (11.9 mL of a 0.5 M solution in THF, 5.93 mmol). The reaction mixture was warmed to ambient temperature for 2 h, and then heated at reflux for 2 h. The solvent was removed in vacuo and the crude solid dissolved in DMSO (5 mL). The crude product was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. Lyophilization provided the title compound. MS: m/z=236 (M+1).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:11](=[O:14])[CH2:12][CH3:13]>>[CH3:13][CH:12]([CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH:11]=[O:14]
Reactant: CCC=O
Reactant: O=CCCc1ccccc1
Product: CC(C=O)CCCc1ccccc1

Procedure:
The 2-methyl-5-phenyl aldehyde derivatives are conveniently prepared by a number of methods known in the art. For example, by an Aldol condensation between 3-phenylpropanal and proprionaldehyde, followed by hydrogenation of the resulting α,β-unsaturated aldehyde to form the saturated aldehyde, 2-methyl-5-phenylpentanal. This aldehyde is the direct precursor for the alcohol, 2-methyl-5-phenylpentan-1-ol via reduction with, e.g. sodium borohydride, as well as the nitrile, 2,4-dimethyl-5-phenyl-pentanitrile via oxidation dehydration chemistry by reaction of hydroxylamine/formic acid as described above. Alternatively, aldehyde derivatives may be prepared by oxidation of the corresponding primary alcohol, i.e. 2-methyl-5-phenylpentan-1-ol, a known compound. The corresponding nitrile, 2-methyl-5-phenylpentanenitrile, is prepared by converting the aldehyde via reaction with hydroxylamine to form the aldoxime intermediate and subsequent formic acid catalyzed dehydration. The primary alcohol may also be converted to the corresponding acid as described above.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Br[C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=1)[C:16](OC)=[O:17]>>[CH3:7][O:6][C:4]([C:3]1[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=1[C:22]1[CH:21]=[CH:20][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1)=[O:5]
Reactant: COC(=O)c1cccc(Br)c1
Reactant: COC(=O)c1ccccc1I
Product: COC(=O)c1ccccc1-c1ccc(C=O)cc1

Procedure:
Using essentially the same procedure used in reference example 97b except using methyl 2-iodo-benzoate as substrate in place of methyl 3-bromo-benzoate. MS (EI) m/z 240 (M)+.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]1(OC)C=CC=CC=1.CCS.[Al+3].[Cl-].[Cl-].[Cl-]>C(=S)=S.[Cl-].[Al+3].[Cl-].[Cl-]>[CH2:11]1[C:6]2[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=2)[CH:7]=[CH:8]1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: S=C=S
Product: C1=Cc2ccccc2C1

Procedure:
Treatment of p-methoxydeoxybenzoic (32) (FIG. 4) with PCl5 in refluxing benzene provided p-methoxy-α'-chlorostilbene 33 (Nagano, 1955), which underwent Friedel-Crafts conditions with anisole to furnish the triarylethylene 34. The carbonyl group in deoxybenzoic 32 was converted to a gem-dichloride intermediate, using phosphorus pentachloride, and with the subsequent elimination of HCl, the vinyl chloride 33 was obtained. Compound 32 was prepared using Friedel-Crafts conditions involving phenylacetyl chloride and anisole in carbon disulfide and aluminum chloride (BUCK, J. S. and IDE, W. S. (1932), "The isomeric desoxybenzanisoins", Journal of the American Chemical Society, 54, 3012). Demethylation of 35 was accomplished with EtSH/AlCl3, and 36 was isolated by column chromatography. Drying of phenol 36 at a high temperature resulted in the formation of an indene, which was observed previously (MAGARIAN, R. A., MELTON, S. AND NATARELLI, G. (1972), "2-Chloro-1-phenylindene from 1,1-dichloro-trans-2,3-diphenylcyclopropane", Journal of Pharmaceutical Sciences, 61, 1216). Compound 36 was isolated as the diacetate (37) using column chromatography.
Reaction SMILES: CO[C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:14][O:15][CH:16]=2)=[N:6][CH:5]=1.COC(=O)C1C=CC(OC[C:35]2[C:36]([C:41]3C=CC=CC=3F)=[N:37]OC=2C)=NC=1.C(N)(C)C>>[CH:36]([NH:37][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[N:14][O:15][CH:16]=2)=[N:6][CH:5]=1)([CH3:41])[CH3:35]
Reactant: COC(=O)c1ccc(OCc2conc2-c2ccccc2)nc1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3F)noc2C)nc1
Solvent: CC(C)N
Product: CC(C)NC(=O)c1ccc(OCc2conc2-c2ccccc2)nc1
Yield: 81 %

Procedure:
As described for example 84f, 6-(3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (67 mg, 0.21 mmol) was converted, instead of [6-[3-(2-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester, using isopropylamine instead of 2,2,2-trifluoroethylamine, to the title compound (59 mg, 81%) which was obtained as an off white solid. MS: m/e=338.2 [M+H]+.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[O:9]1[C:17]2[CH:16]=[CH:15][NH:14][C:13](=[O:18])[C:12]=2[CH:11]=[CH:10]1.CO>C(#N)C>[Br:1][C:16]1[C:17]2[O:9][CH:10]=[CH:11][C:12]=2[C:13](=[O:18])[NH:14][CH:15]=1
Reactant: O=c1[nH]ccc2occc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: CO
Product: O=c1[nH]cc(Br)c2occc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Add N-bromosuccinimide (63.16 g, 354.9 mmol) as a solution in anhydrous acetonitrile (480 mL) to a suspension of 5H-furo[3,2-c]pyridin-4-one (36.9 g, 273 mmol) in anhydrous acetonitrile (740 mL) at 0° C. over 1 hour. Warm to room temperature, add anhydrous methyl alcohol (1.5 L) and stir at room temperature for 18 hours. Quench with water (20 ml) and saturated sodium bicarbonate (20 mL), concentrate to a volume of 1.3 liters, and pour into water (1.3 L). Collection of the precipitate by filtration and drying (vacuum oven 2 days 40-60° C.) gives the title compound as an off-white solid.
Reaction SMILES: [NH2:1][C@H:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][C:4]([O:6][C:7](C)(C)C)=[O:5]>Cl>[CH3:7][O:6][C:4](=[O:5])[CH2:3][C@H:2]([NH2:1])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)C[C@H](N)c1ccccc1
Agent: Cl
Product: COC(=O)C[C@H](N)c1ccccc1

Procedure:
t-Butyl (3S)-3-amino-3-phenylpropanoate (1.0 g, 4.97 mmol) was dissolved in methanolic hydrochloric acid (2.25M, 25 ml). The reaction mixture was heated under reflux for 3 hours, after which time the solvent was evaporated under reduced pressure and the residue basified with aqueous saturated sodium carbonate solution. The product was then extracted using dichloromethane (x2), the combined organic layers were dried (MgSO4), filtered and the solvent removed under reduced pressure to afford the title compound as a white solid, 778 mg.
Reaction SMILES: CC1[N:3]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH2:15][CH3:16])[N:9]=2)C(C)=CC=1.NO.Cl>CCO>[CH2:14]([C:10]1[N:9]=[C:8]([NH2:3])[CH:13]=[CH:12][CH:11]=1)[CH2:15][CH3:16]
Reactant: CCCc1cccc(-n2c(C)ccc2C)n1
Agent: Cl
Agent: NO
Solvent: CCO
Product: CCCc1cccc(N)n1
Temperature: 100 °C
Yield: 107.7 %

Procedure:
A solution of the product from Example 2b (348 mg, 1.52 mmol) and NH2OH HCl (530 mg, 7.62 mmol) in 4 mL of EtOH/1.5 mL water. Heated at 100° C. for 16 h, cooled to room temperature and extracted with CH2Cl2. Dried over MgSO4 filtered and concentrated under vacuum giving the title compound as an amber oil (223 mg, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:18][NH:19][O:20][CH3:21].C(Cl)CCl>CN(C1C=CN=CC=1)C.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[C@H:9]1[C:14](=[O:16])[N:19]([O:20][CH3:21])[CH3:18])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)[C@H]1C(=O)O
Reactant: CNOC
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: CON(C)C(=O)[C@@H]1[C@@H](O)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.1 %

Procedure:
A mixture of compound 64 (8.42 g), N,O-dimethyl hydroxylamine HCl (10.66 g), DMAP (26.69 g), and EDC (10.47 g) in dichloromethane (500 ml) was stirred at ambient temperature for 16 hours. The reaction mixture was then applied directly to a silica flash column and eluted with ethyl acetate to give (2S,3S)-1-(tert-butoxycarbonyl)-3-hydroxy-2-(N-methoxy-N-methylcarbamoyl)pyrrolidine (compound 65) as a clear gum(7.6 g).
Reaction SMILES: [CH2:1]1[C:4]2([CH2:7][N:6]([CH:8]3[CH2:13][CH2:12][CH:11]([O:14][C:15]4[N:16]=[CH:17][N:18]=[C:19]5[C:26]=4[C:25]4[C@@H:24]([CH2:27][OH:28])[CH2:23][CH2:22][C:21]=4[S:20]5)[CH2:10][CH2:9]3)[CH2:5]2)[CH2:3][O:2]1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl>[CH3:29][S:30]([O:28][CH2:27][C@H:24]1[CH2:23][CH2:22][C:21]2[S:20][C:19]3[C:26](=[C:15]([O:14][CH:11]4[CH2:12][CH2:13][CH:8]([N:6]5[CH2:7][C:4]6([CH2:3][O:2][CH2:1]6)[CH2:5]5)[CH2:9][CH2:10]4)[N:16]=[CH:17][N:18]=3)[C:25]1=2)(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: OC[C@H]1CCc2sc3ncnc(OC4CCC(N5CC6(COC6)C5)CC4)c3c21
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@H]1CCc2sc3ncnc(OC4CCC(N5CC6(COC6)C5)CC4)c3c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
To a solution of [(3S)-12-[(4-[2-oxa-6-azaspiro[3.3]heptan-6-yl]cyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]methanol (250 mg, 0.62 mmol, 1.00 equiv) and TEA (188 mg, 1.86 mmol, 2.99 equiv) in dichloromethane (10 mL) was added MsCl (142 mg, 1.25 mmol, 2.00 equiv) and the resulting mixture was stirred for 1 h at 25° C. under nitrogen. After completion, the reaction was quenched with water and extracted with 3×50 mL of ethyl acetate. The organic layers were combined, washed with brine and dried over anhydrous sodium sulfate. The solvents were concentrated under reduced pressure vacuum to afford [(3S)-12-[(4-[2-oxa-6-azaspiro[3.3]heptan-6-yl]cyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]methyl methanesulfonate (250 mg, crude) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:29](=[O:39])[N:30]([CH2:35][CH2:36][CH2:37][CH3:38])[CH2:31][CH2:32][CH2:33][CH3:34])=[N:4][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=2[C:17]([N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20]2)=[O:18])[C:6]=1C.ClC1C(C(=O)N(CCCC)CCCC)=NN(C2C=CC(C(OCC)=O)=CC=2C(N2CCC3C(=CC=CC=3)C2)=O)C=1>>[Cl:1][C:2]1[C:3]([C:29](=[O:39])[N:30]([CH2:35][CH2:36][CH2:37][CH3:38])[CH2:31][CH2:32][CH2:33][CH3:34])=[N:4][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=2[C:17]([N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20]2)=[O:18])[CH:6]=1
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)O)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl
Agent: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)OCC)cc2C(=O)N2CCc3ccccc3C2)cc1Cl
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)O)cc2C(=O)N2CCc3ccccc3C2)cc1Cl
Yield: 94 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 1F, ethyl 4-(4-chloro-3-(dibutylcarbamoyl)-1H-pyrazol-1-yl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (155 mg, 0.27 mmol) was converted to the title compound (138 mg, 94%). MS(ESI+) m/z 537.3 (M+H)+.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@@H:3]([CH2:6][OH:7])[CH2:2]1.ClC1N=C2C(N=CN2CC2CCOCC2)=C(Cl)N=1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl>[CH3:33][S:34]([O:7][CH2:6][CH:3]1[CH2:4][CH2:5][O:1][CH2:2]1)(=[O:36])=[O:35]
Reactant: OC[C@@H]1CCOC1
Reactant: CS(=O)(=O)Cl
Agent: Clc1nc(Cl)c2ncn(CC3CCOCC3)c2n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CCOC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (3S)-tetrahydro-3-furanylmethanol, Isomer 2 (1.4 g) in dry dichloromethane (40 ml) at 0° C. and under nitrogen, was added triethylamine (3.83 ml) followed by methanesulfonyl chloride (1.39 ml). The reaction was stirred at room temperature overnight. The orange solution was diluted with dichloromethane (50 ml) and washed with saturated aqueous sodium bicarbonate (20 ml). The organic layer was separated, dried through a hydrophobic frit and concentrated in vacuo to yield the title compound as an orange oil (2.6 g).
Reaction SMILES: C(OC(=O)[NH:10][CH:11]1[CH2:16][CH2:15][CH:14]([C:17]2[NH:18][C:19]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[N:32]=3)=[C:20]([C:22]3[CH:30]=[CH:29][C:25]4[O:26][CH2:27][O:28][C:24]=4[CH:23]=3)[N:21]=2)[CH2:13][CH2:12]1)C1C=CC=CC=1>[Pd].CO>[O:26]1[C:25]2[CH:29]=[CH:30][C:22]([C:20]3[N:21]=[C:17]([CH:14]4[CH2:15][CH2:16][CH:11]([NH2:10])[CH2:12][CH2:13]4)[NH:18][C:19]=3[C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[N:32]=3)=[CH:23][C:24]=2[O:28][CH2:27]1
Reactant: Cc1cccc(-c2[nH]c(C3CCC(NC(=O)OCc4ccccc4)CC3)nc2-c2ccc3c(c2)OCO3)n1
Agent: [Pd]
Solvent: CO
Product: Cc1cccc(-c2[nH]c(C3CCC(N)CC3)nc2-c2ccc3c(c2)OCO3)n1
Reaction time: 4 h
Yield: 91.6 %

Procedure:
Palladium on activated carbon (0.017 g) was added to a solution of {4-[4-Benzo[1,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-1H-imidazol-2-yl]-cyclohexyl}-carbamic acid benzyl ester (see Example 18; 0.370 g, 0.725 mmol) in methanol (5 mL). The reaction mixture was stirred under hydrogen atmosphere for 4 hours. The mixture was then filtered and concentrated to give 0.250 g (92%) of the title compound as a yellow oil. MS (ESP+) m/z 377.2 (M+1). 1H NMR (300 MHz, Methanol-d4) δ 7.80 (t, 1H, J=7.8 Hz), 7.36 (m, 2H), 7.01 (m, 3H), 6.07 (s, 2H), 3.47 (m, 1H), 3.32 (m, 1H), 2.29 (m, 2H), 2.03 (m, 4H), 1.90 (m, 2H).
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][CH:13]=[O:14])=[CH:4][CH:3]=1.Cl[CH2:16][C:17]12[CH2:24][CH2:23][CH2:22][N:21]1[CH2:20][CH2:19][CH2:18]2>>[N:21]12[CH2:22][CH2:23][CH2:24][C:17]1([CH2:16][N:12]([C:5]1[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([F:1])=[CH:3][CH:4]=1)[CH:13]=[O:14])[CH2:18][CH2:19][CH2:20]2
Reactant: ClCC12CCCN1CCC2
Reactant: O=CNc1ccc(F)c2ccccc12
Product: O=CN(CC12CCCN1CCC2)c1ccc(F)c2ccccc12

Procedure:
The procedures described in Example 2 were repeated except that 4-fluoro-N-formyl-1-naphthylamine (1.90 g, 10.0 mmol) and 5-chloromethyl-1-azabicyclo[3.3.0]octane (hydrochloride, 2.17 g, 11.l mmol) were employed. In this case, the desired compound was obtained as a pale yellow liquid (2.90 g, 92.8%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14](I)=[C:15]([NH:17][C:18](=[O:20])[CH3:19])[N:16]=3)[N:13]=2)=[CH:4][C:3]=1[NH:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH:33]([F:35])[F:34])[CH:27]=1)(=[O:25])=[O:24].[N:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>[Pd+2].ClC1C=C[C-](P(C2C=CC=CC=2)C2C=CC=CC=2)C=1Cl.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:39]4[CH:40]=[CH:41][N:36]=[CH:37][CH:38]=4)=[C:15]([NH:17][C:18](=[O:20])[CH3:19])[N:16]=3)[N:13]=2)=[CH:4][C:3]=1[NH:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH:33]([F:35])[F:34])[CH:27]=1)(=[O:25])=[O:24]
Reactant: OB(O)c1ccncc1
Reactant: CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(NS(=O)(=O)c4cccc(OC(F)F)c4)c3)nn2c1I
Agent: [Fe+2]
Agent: [Pd+2]
Agent: Clc1cc[c-](P(c2ccccc2)c2ccccc2)c1Cl
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(NS(=O)(=O)c4cccc(OC(F)F)c4)c3)nn2c1-c1ccncc1
Temperature: 80 °C
Yield: 56.3 %

Procedure:
A sealable vial was charged with N-(6-(6-chloro-5-(3-(difluoromethoxy)phenylsulfonamido)pyridin-3-yl)-3-iodoimidazo[1,2-b]pyridazin-2-yl)acetamide (129.0 mg, 203 μmol), 4-pyridylboronic acid (30.0 mg, 244 μmol, Alfa Aesar, Ward Hill, Mass.), sodium carbonate (86.2 mg, 813 μmol), and dichloro 1,1′-bis(diphenylphosphino)ferrocene palladium(II) (11.3 mg, 20.3 μmol, Strem Chemical, Inc., Newburyport, Mass.). The vial was sealed with a septum cap, and 1,4-dioxane (2 mL) was added under positive N2 flow followed by water (0.2 mL). The mixture was sparged with N2 for 10 min and then heated at 80° C. for 18 h. The solution was cooled to rt and absorbed directly onto a 25 g silica loading cartridge and passed through a Redi-Sep® pre-packed silica gel column (80 g) (Teledyne Isco, Lincoln, Nebr.) using a gradient of 1% MeOH in CH2Cl2 to 10% MeOH in CH2Cl2 to afford the title compound, N-(6-(6-chloro-5-(3-(difluoromethoxy)phenylsulfonamido)pyridin-3-yl)-3-(pyridin-4-yl)imidazo[1,2-b]pyridazin-2-yl)acetamide (67.0 mg, 56.3% yield) as a yellow solid. LCMS (ESI positive ion) m/z: 586 (M+1); 1H NMR (400 MHz, MeOH) δ ppm 2.21 (s, 3H); 6.61-6.97 (m, 1H); 7.33-7.40 (m, 1H); 7.48 (t, J=8.07 Hz, 1H); 7.56 (s, 1H); 7.95 (d, J=9.49 Hz, 1H); 8.06 (d, J=4.99 Hz, 2H); 8.17 (d, J=9.49 Hz, 1H); 8.67-8.74 (m, 2H); 8.80 (d, J=1.96 Hz, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[N:22])[CH:16]=2)([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>N.CO.[Rh]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][NH2:22])[CH:16]=2)([OH:14])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cccc(C#N)c2)CC1
Agent: [Rh]
Agent: N
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cccc(CN)c2)CC1

Procedure:
A solution of 4-(3-Cyano-phenyl)-4-hydroxy-piperidine-1-carboxylic acid-tert-butyl ester (0.30 g, 0.99 mmol) in 7N ammonia/methanol (25 mL) and 5%Rhodium on alumina (0.15 g) was hydrogenated overnight on a Parr apparatus (45 psi). The reaction was filtered through celite, evaporated, and azeotroped with MeOH:toluene 1:1 (2×30 mL) to give 4-(3-Aminomethyl-phenyl)-4-hydroxy-piperidine-1-carboxylic acid-tert-butyl ester as a foam. This compound was used directly in the next step.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH3:21].C(N(CC)CC)C.[C:29]1([N:35]=[C:36]=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN1CCCC1=O>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH3:21])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:36]([NH:35][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:37])[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: O=C=Nc1ccccc1
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCOCCN
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: Cc1nc2c(N)nc3ccccc3c2n1CCOCCNC(=O)Nc1ccccc1
Reaction time: 18 h
Yield: 17.5 %

Procedure:
A solution of the compound of Example 45, 1-[2-(2-aminoethoxy)ethyl]-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (1.411 g, 4.95 mmol) in 40 mL of 1-methyl-2-pyrrolidinone was treated with triethylamine (1.38 mL, 9.89 mmol). With vigorous stirring, the solution was treated with phenyl isocyanate (0.538, 4.95 mmol). After 18 h, the reaction was concentrated to yield an off white solid. Purification by column chromatography (SiO2, 9:1 CH2Cl2:MeOH) gave 351 mg of N-{2-[2-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethyl}-N′-phenylurea as a white powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:11]([CH3:13])([OH:12])[CH:10]([O:14][C:15]2[CH:20]=[CH:19][C:18](=[O:21])[NH:17][N:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:22]#[N:23])[CH:8]=2)[O:3]1.[C:25]([O-])([O-])=O.[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:1][C:2]1([CH3:24])[C:11]([CH3:13])([OH:12])[CH:10]([O:14][C:15]2[CH:20]=[CH:19][C:18](=[O:21])[N:17]([CH3:25])[N:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:22]#[N:23])[CH:8]=2)[O:3]1
Reactant: O=C([O-])[O-]
Reactant: CC1(C)Oc2ccc(C#N)cc2C(Oc2ccc(=O)[nH]n2)C1(C)O
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: Cn1nc(OC2c3cc(C#N)ccc3OC(C)(C)C2(C)O)ccc1=O

Procedure:
A mixture of 327 mg of 2,2,3-trimethyl-4-(1,6-dihydro-6-oxo-3-pyridazinyl-oxy)-6-cyano-chroman-3-ol, 20 ml of acetone, 400 mg of K2CO3 and 0.2 ml of dimethyl sulfate is refluxed for 2 hours. The mixture is filtered, concentrated and chromatographed on silica gel. There is obtained with ethyl acetate/methanol (9:1) 2,2,3-trimethyl-4-(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl-oxy)-6-cyano-chroman-3-ol, m.p. 197-199°.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][C:10]=1[NH2:19].[C:20](Cl)(=[O:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>N1C=CC=CC=1>[CH3:1][S:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][C:10]=1[NH:19][C:20](=[O:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCC(=O)Cl
Reactant: CSCCCCCNc1c(N)cnc2ccccc12
Solvent: c1ccncc1
Product: CCCCCCC(=O)Nc1cnc2ccccc2c1NCCCCCSC
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A round bottom flask was charged with a magnetic stir bar, N4-[5-(methylthio)pentyl]quinoline-3,4-diamine (3.17 g, 11.46 mmol) and anhydrous pyridine (46 mL) under a nitrogen atmosphere. The resulting homogeneous solution was cooled to 0° C. in an ice-water bath. To the cooled solution was added neat heptanoyl chloride (1.87 g, 12.61 mmol). The reaction was judged to be complete after stirring at ambient temperature for 1 hour. The volatiles were removed under reduced pressure and the resulting oil was partitioned between chloroform and water. The layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford N-(4-{[5-(methylthio)pentyl]amino}quinolin-3-yl)heptanamide (4.44 g, 11.46 mmol) which was isolated as a brown oil and used without further purification.
Reaction SMILES: [C:1]([C:3]1[C:12](I)=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([C:14]([F:17])([F:16])[F:15])[CH:4]=1)#[N:2].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+].[C@H:66]([NH2:70])([CH2:68][CH3:69])[CH3:67]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C@H:66]([NH:70][C:12]1[C:3]([C:1]#[N:2])=[CH:4][C:5]([C:14]([F:17])([F:16])[F:15])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])([CH2:68][CH3:69])[CH3:67]
Reactant: CC[C@@H](C)N
Reactant: COC(=O)c1cc(I)c(C#N)cc1C(F)(F)F
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC[C@@H](C)Nc1cc(C(=O)OC)c(C(F)(F)F)cc1C#N
Temperature: 95 °C
Reaction time: 20 h
Yield: 30.6 %

Procedure:
Methyl 4-cyano-5-iodo-2-(trifluoromethyl)benzoate (174 mg, 0.49 mmol) was dissolved in dioxane (2 mL) and was sparged with nitrogen for 15 minutes. XANTPHOS (57 mg, 0.098 mmol), cesium carbonate (350 mg, 1.07 mmol), (R)-sec-butylamine (0.1 mL, 0.986 mmol), and tris(dibenzylideneacetone)dipalladium (45 mg, 0.049 mmol) were added, and the mixture was stirred in a sealed tube at 95° C. for 20 h. The reaction mixture was cooled to ambient temperature and was filtered through celite. The filter cake was washed with ethyl acetate and the filtrate was concentrated to afford an orange oil which was purified by column chromatography (silica gel, 5-15% ethyl acetate in hexanes) to afford (R)-methyl 5-(sec-butylamino)-4-cyano-2-(trifluoromethyl)benzoate (45 mg, 0.150 mmol, 31% yield) as a yellow oil. GCMS for C14H15F3N2O2: 300 (M+).