Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.Cl[C:3]1[C:12]2[N:13]=[C:14]([NH2:21])[N:15]([CH2:16][C:17]([F:20])([CH3:19])[CH3:18])[C:11]=2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]=1.[NH3:22]>CO>[F:20][C:17]([CH3:19])([CH3:18])[CH2:16][N:15]1[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[C:3]([NH2:22])[C:12]=2[N:13]=[C:14]1[NH2:21]
Reactant: N
Reactant: CC(C)(F)Cn1c(N)nc2c(Cl)nc3ccccc3c21
Agent: Br
Solvent: CO
Product: CC(C)(F)Cn1c(N)nc2c(N)nc3ccccc3c21
Temperature: 150 °C

Procedure:
Crude 4-chloro-1-(2-fluoro-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-amine hydrobromide (1.14 g) and ammonia (approximately 100 mL of a 7 N solution in methanol) were added to a pressure vessel, which was sealed and heated at 150° C. for five days. Additional ammonia in methanol was added after three days and again after four days. When the reaction was complete, the volatiles were removed under reduced pressure, and the residue was combined with material from another run. The crude product was purified by automated flash chromatography (silica cartridge, eluting with aqueous ammonium hydroxide:methanol:dichloromethane in a gradient from 0:0:100 to 1:14:85) to provide 270 mg of 1-(2-fluoro-2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2,4-diamine as a light tan solid, mp 251° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:7]([OH:17])=[C:6]([C:18](=[O:23])[CH2:19][CH2:20][CH:21]=[O:22])[C:5]2=[O:24].[OH:25]OS([O-])=O.[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:7]([OH:17])=[C:6]([C:18](=[O:23])[CH2:19][CH2:20][C:21]([OH:25])=[O:22])[C:5]2=[O:24]
Reactant: O=CCCC(=O)C1=C(O)C2(CCOCC2)c2ccc(Cl)cc2C1=O
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)CCC(=O)C1=C(O)C2(CCOCC2)c2ccc(Cl)cc2C1=O
Temperature: 25 °C
Yield: 91.4 %

Procedure:
A mixture of 4-(6-chloro-2-hydroxy-4-oxo-2′,3′,5′,6′-tetrahydro-4H-spiro[naphthalene-1,4′-pyran]-3-yl)-4-oxobutanal (0.2 g, 0.6 mmol) in 3 mL DMF was stirred at room temperature and treated with oxone (0.3 mL, 0.6 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was quenched with 10 mL H2O and adjusted to pH=5 with concentrated HCl. The solid was collected by filtration and washed with 10 mL H2O. The crude product was dissolved in 50 mL EtOAc and washed with 20 mL H2O and then with 20 mL brine. The organic layer was dried over anhydrous Na2SO4, and concentrated in vacuo to give 0.20 g white solid. MS m/e: 365 (M+H)+. Calculated for C18H17ClO6: 364.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]2)[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].CC1(C)C(C)(C)OB([C:32]2[CH2:33][CH2:34][O:35][CH2:36][CH:37]=2)O1>O1CCOCC1>[O:35]1[CH2:34][CH:33]=[C:32]([C:2]2[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]3)[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][CH:3]=2)[CH2:37][CH2:36]1
Reactant: CC1CCN(c2nc(Br)ccc2[N+](=O)[O-])CC1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC1CCN(c2nc(C3=CCOCC3)ccc2[N+](=O)[O-])CC1
Temperature: 80 °C

Procedure:
A mixture of 6′-bromo-4-methyl-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl (as prepared in Example 61, step (a)) (237 mg, 0.79 mmol), anhydrous K2CO3 (311 mg, 2.25 mmol) and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (Murata, M., Synthesis, 778, (2000)) (157 mg, 0.750 mmol) in dioxane (5 mL) was heated at 80° C. overnight under Ar. The reaction mixture was allowed to cool to RT, concentrated and the resulting residue was purified on silica (10% EtOAc/hexane) to obtain the expected coupled compound (71 mg, 30%). 1H-NMR (CDCl3; 400 MHz): δ 8.15 (d, 1H, J=8.4 Hz), 6.80 (m, 2H), 4.39 (m, 2H), 3.92 (t, 2H, J=5.4 Hz), 3.76 (m, 2H), 3.04 (m, 2H), 2.62 (m, 2H), 1.67 (m, 3H), 1.33 (m, 2H), 0.99 (d, 3H, J=6.3 Hz).
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]3)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>ClCCl>[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([C:9]3[CH:10]=[C:11]4[C:16](=[CH:17][CH:18]=3)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]4)=[O:8])[CH2:2][CH2:3]2)(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1CCc2cc(C(=O)N3CCNCC3)ccc2N1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CCN(C(=O)c3ccc4c(c3)CCC(=O)N4)CC2)cc1
Reaction time: 3 h

Procedure:
1.5 Grams of 6-(1-piperazinylcarbonyl)-3,4-dihydrocarbostyril and 1.5 g of triethylamine were suspended in 10 ml of dichloromethane. Under ice-cooled and stirring condition, 1.4 g of p-toluenesulfonylchloride in 10 ml of dichloromethane solution was added dropwise to the suspension and the reaction was continued for additionally 3 hours at a room temperature, further continued for 1 hour under ice-cooled condition. The crystals formed in the reaction mixture were collected by filtration and recrystallized from chloroform-ether to obtain 1.4 g of 6-[4-(p-toluenesulfonyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril. Colorless granular crystals. Melting point: 280°-282° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[CH:15]=[CH:14][N:13]([CH3:16])[N:12]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH3:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][NH:20][C@@H:19]1[CH2:24][NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1>>[CH3:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:7]([C:6]2[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[C:11]2[CH:15]=[CH:14][N:13]([CH3:16])[N:12]=2)=[O:9])[C@@H:19]1[CH2:24][NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:28][N:27]=1
Reactant: Cc1ccc(-c2ccn(C)n2)c(C(=O)O)c1
Reactant: C[C@@H]1CCCN[C@@H]1CNc1ccc(C(F)(F)F)cn1
Product: Cc1ccc(-c2ccn(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using 5-methyl-2-(1-methyl-1H-pyrazol-3-yl)benzoic acid and N-(((2S,3R)-3-methylpiperidin-2-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine. ESI-MS (m/z): 472 [M+1]+.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[C:7]([CH2:19][CH3:20])=[N:8][N:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:10]=1[CH2:11][CH3:12])C.[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1>[CH2:19]([C:7]1[C:6]([CH2:5][CH2:4][OH:3])=[C:10]([CH2:11][CH3:12])[N:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:8]=1)[CH3:20]
Reactant: CCOC(=O)Cc1c(CC)nn(-c2ccccn2)c1CC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: CCc1nn(-c2ccccn2)c(CC)c1CCO
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 65 %

Procedure:
Dissolve (3,5-diethyl-1-pyridin-2-yl-1H-pyrazol-4-yl)-acetic acid ethyl ester (0.54 g, 1.88 mmol) in tetrahydrofuran (20 mL) and cool to −78° C. Add diisobutyl-aluminum hydride (7.52 mL, 7.52 mmol, 1 M in toluene) dropwise and continue to stir for 2.5 hr. Warm to room temperature over 1 hr. then quench with saturated aqueous potassium sodium tartrate solution (50 mL). Add ethyl acetate (100 mL) and stir at room temperature for 16 hr. Separate the organic layer, dry (sodium sulfate), filter and concentrate. Purify using silica gel chromatography, eluting with 80:20 hexanes:ethyl acetate, to give 2-(3,5-diethyl-1-pyridin-2-yl-1H-pyrazol-4-yl)-ethanol as a white solid (0.30 g, 66%). 1H-NMR (400 MHz, CDCl3) δ 8.39 (m, 1H), 7.80 (d, 1H), 7.73 (m, 1H), 7.12 (m, 1H), 3.72 (m, 2H), 3.08 (q, 2H), 2.67 (m, 4H), 1.58 (bs, 1H), 1.28 (t, 3H), 1.15 (t, 3H).
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.[CH3:12][C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1.C1(N2[CH2:38][CH2:37][CH:36]([O:39]C3C=CC(N)=CC=3)[CH2:35][CH2:34]2)CCC1>>[CH3:12][C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([N:26]2[CH2:38][CH2:37][C:36](=[O:39])[CH2:35][CH2:34]2)=[CH:27][CH:28]=1
Reactant: C[C@@H]1CCCN1CCCOc1ccc(N)cc1
Reactant: Nc1ccc(OC2CCN(C3CCC3)CC2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: C[C@@H]1CCCN1CCCOc1ccc(N2CCC(=O)CC2)cc1

Procedure:
The entitled compound was obtained as a brown oily substance, according to the same method as in Reference Example 21 or according to a method similar to it but using 4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}aniline 4-methylbenzenesulfonate produced according to a method described in a patent (WO2005/077905), as the starting compound in place of 4-[(1-cyclobutylpiperidin-4-yl)oxy]aniline.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][C:8]([OH:14])=[CH:7][C:6]=1[CH:15]([CH3:17])[CH3:16])(=[O:3])[CH3:2].C1N2CN3CN(C2)CN1C3.O.FC(F)(F)[C:31](O)=[O:32]>>[C:1]([O:4][C:5]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][C:8]([OH:14])=[C:7]([C:6]=1[CH:15]([CH3:17])[CH3:16])[CH:31]=[O:32])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C(C)C)cc(O)cc1C(C)C
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Product: CC(=O)Oc1c(C(C)C)cc(O)c(C=O)c1C(C)C
Temperature: 0 °C
Yield: 70 %

Procedure:
1.00 g of 4-acetoxy-3,5-diisopropylphenol and 0.71 g of hexamethylenetetramine were dissolved in 4 ml of trifluoroacetic acid and the mixture was heated under reflux for 20 minutes. The reaction solution was cooled to 0° C., then combined with water and extracted with ethyl acetate. The organic layers were washed with a saturated aqueous sodium bicarbonate solution and then saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was dissolved in 10 ml of methanol, 13 ml of 1N hydrochloric acid was added, and the solution was heated under reflux for 1.5 hours. The reaction mixture was cooled to room temperature, then combined with water and extracted with ethyl acetate. The organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (in n-hexane containing 5%-10% ethyl acetate) to give 0.78 g of 5-acetoxy-2-hydroxy-4,6-diisopropylbenzaldehyde as a pale yellow oil (yield 70%).
Reaction SMILES: [OH:1]O.[CH3:3][O:4][C:5](=[O:36])[CH2:6][C@H:7]1[C:11]2[CH:12]=[CH:13][C:14]([O:16][C@H:17]3[C:25]4[C:20](=[C:21](B5OC(C)(C)C(C)(C)O5)[CH:22]=[CH:23][C:24]=4[F:26])[CH2:19][CH2:18]3)=[CH:15][C:10]=2[O:9][CH2:8]1.[OH-].[Na+]>C(O)(=O)C>[CH3:3][O:4][C:5](=[O:36])[CH2:6][C@H:7]1[C:11]2[CH:12]=[CH:13][C:14]([O:16][C@H:17]3[C:25]4[C:20](=[C:21]([OH:1])[CH:22]=[CH:23][C:24]=4[F:26])[CH2:19][CH2:18]3)=[CH:15][C:10]=2[O:9][CH2:8]1
Reactant: OO
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Temperature: 25 °C

Procedure:
Aqueous hydrogen peroxide solution (35%, 3.7 mL) is added dropwise to a solution of {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (5.0 g) in acetic acid (30 mL) chilled in an ice bath. The solution is stirred with cooling for 0.5 h and at room temperature for another 2 h. Ice-cold water (50 mL) and 2 N aqueous NaOH solution (20 mL) are added, and the mixture is stirred at room temperature overnight. The mixture is extracted with ethyl acetate, and the combined extracts are washed with brine and dried (MgSO4). The solvent is evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 80:20→60:40) to give the title compound. LC (method 2): tR=1.01 min; Mass spectrum (ESI+): m/z=359 [M+H]+.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)(O)[O-].[Na+].O.[Cl:10][C:11]1[CH:12]=[C:13]([C:17]2[C:22]3[N:23]([CH2:38][C@H:39]4[CH2:44][CH2:43][C@H:42]([CH3:45])[CH2:41][CH2:40]4)[C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][C@H:27]4[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[N:25][C:21]=3[CH:20]=[C:19]([C:46]#[N:47])[N:18]=2)[CH:14]=[N:15][CH:16]=1>C(O)C>[Cl:10][C:11]1[CH:12]=[C:13]([C:17]2[C:22]3[N:23]([CH2:38][C@H:39]4[CH2:44][CH2:43][C@H:42]([CH3:45])[CH2:41][CH2:40]4)[C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][C@H:27]4[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[N:25][C:21]=3[CH:20]=[C:19]([C:46](=[N:2][OH:3])[NH2:47])[N:18]=2)[CH:14]=[N:15][CH:16]=1
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCOC[C@H]3c3ccccc3)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C[C@H]1CC[C@H](Cn2c(N3CCOC[C@H]3c3ccccc3)nc3cc(C(N)=NO)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
Hydroxylamine hydrochloride (5.4 mg, 0.08 mmol), sodium bicarbonate (9.9 mg, 0.12 mmol), and water (0.12 mL) were combined in a vial and stirred for 15 minutes. This solution was added to a vial containing 4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (20.6 mg, 0.04 mmol) dissolved in ethanol (0.3 mL). The mixture was sealed and heated at 100° C. for 1 hour. The reaction was cooled to room temperature, quenched with water, and extracted with ethyl acetate (2×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to afford 4-(5-chloropyridin-3-yl)-N′-hydroxy-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide. MS ESI calc'd. for C30H34ClN7O2 [M+H]+ 560. found 560.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:8][CH2:9][C:10]#[N:11])=[CH:3][CH:2]=1.CN(P(N(C)C)(N(C)C)=O)C.[Li+].CC([N-]C(C)C)C.Cl[CH:38]([C:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[N:43]=[CH:42][CH:41]=1)[CH3:39]>C1COCC1>[C:7](=[N:8][CH:9]([CH:38]([C:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[N:43]=[CH:42][CH:41]=1)[CH3:39])[C:10]#[N:11])([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N#CCN=C(c1ccccc1)c1ccccc1
Reactant: CC(Cl)c1ccnc2ccccc12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(c1ccnc2ccccc12)C(C#N)N=C(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
To N-(Diphenylmethylene)aminoacetonitrile (2.26 g, 10.2 mmol) in 10 ml of anhydrous THF and HMPA (2.17 ml, 12.14 mmol), at −78° C. LDA (2.0 M, 6.0 ml, 12.14 mmol) was added dropwise over a period of 5 minutes. The color of solution turns from coloress to yellow to dark brown. It was then stirred at −78° C. for one hour. Then 4-(1-Chloroethyl)-quinoline (1.79 g, 9.34 mmol), was added dropwise and the reaction mixture was slowly brought to room temperature over a period of five minutes, quenched by addition of ice and partitioned between EtOAc (20 ml) and water (5 ml). The organic layer was dried over sodium sulfate, filtered, concentrated and column purified (hexanes:EtOAc; 3.5:1.5) to give 3.0 g (86%) of the product as a syrup which was used as such for the subsequent step.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([CH3:14])[S:7][C:6]=2[CH:15]=1.Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]2[CH:23]=[C:24]([C:26]([N:28]3[CH2:32][CH2:31][CH2:30][C@H:29]3[CH2:33][O:34][CH3:35])=[O:27])[S:25][C:18]=12>>[CH3:35][O:34][CH2:33][C@@H:29]1[CH2:30][CH2:31][CH2:32][N:28]1[C:26]([C:24]1[S:25][C:18]2[C:19](=[N:20][CH:21]=[CH:22][C:17]=2[O:1][C:2]2[CH:3]=[CH:4][C:5]3[C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([CH3:14])[S:7][C:6]=3[CH:15]=2)[CH:23]=1)=[O:27]
Reactant: COC[C@@H]1CCCN1C(=O)c1cc2nccc(Cl)c2s1
Reactant: COC(=O)c1c(C)sc2cc(O)ccc12
Product: COC[C@@H]1CCCN1C(=O)c1cc2nccc(Oc3ccc4c(C(=O)OC)c(C)sc4c3)c2s1
Yield: 40 %

Procedure:
This material was prepared from the reaction of methyl 6-hydroxy-2-methylbenzo[b]thiophene-3-carboxylate 11a (85.8 mg, 0.386 mmole) with 7-chloro-2-{[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridine 2a (100 mg, 0.322 mmole) and CS2CO3 (524 mg, 1.61 mmole) in a manner similar to that previously described for example 1 to give a brown solid (64 mg,40%). 1H NMR (DMSO-d6, 300 MHz) δ8.70 (1H, d, J=4.90 Hz), 8.51 (1H, d, J=9.04 Hz), 8.15 (1H, s), 8.14 (1H, s), 7.54 (1H, dd, J=2.17, 8.95 Hz), 6.91 (1H, d, J=5.46 Hz), 4.47-4.38 (1H, m), 4.07-3.90 (2H, m), 4.03 (3H, s), 3.72-3.50 (2H, m), 3.42, 3.39 (3H, s), 2.94 (3H, s), 2.21-1.93 (4H, m).
Reaction SMILES: [CH3:1][CH:2]([NH:12][C:13]([C@@H:15]1[CH2:17][C@H:16]1[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=1)=[O:14])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]>C(O)(=O)C.[Fe]>[CH3:1][CH:2]([NH:12][C:13]([C@@H:15]1[CH2:17][C@H:16]1[C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1)=[O:14])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCC(C)NC(=O)[C@@H]1C[C@H]1c1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Solvent: CC(=O)O
Product: CCCCCCCCCC(C)NC(=O)[C@@H]1C[C@H]1c1ccc(N)cc1

Procedure:
The title compound was prepared in essentially quantitative yield by reducing trans-N-(1-methyldecyl)-2-(4-nitrophenyl)cyclopropanecarboxamide with iron powder in glacial acetic acid, in a manner analogous to Preparation 34.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH2:16]([O:23][C:24]([NH:26][CH2:27][CH2:28][CH2:29][C@H:30]([NH:34]C(OC(C)(C)C)=O)[C:31](O)=[O:32])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[NH2:34][C@H:30]([C:31]([NH:11][C:10]1[CH:12]=[CH:13][C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1)=[O:32])[CH2:29][CH2:28][CH2:27][NH:26][C:24](=[O:25])[O:23][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Product: N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 80 %

Procedure:
Proceeding as in Reference 5, but substituting 4-(4-fluorophenoxy)aniline and (S)-5-(benzyloxycarbonylamino)-2-(tert-butoxycarbonylamino)pentanoic acid, gave (S)-benzyl 4-amino-5-(4-(4-fluorophenoxy)phenylamino)-5-oxopentylcarbamate (1901 mg, 80%).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:12][CH3:13])=[C:4]([CH2:10]O)[C:5]([CH2:8][CH3:9])=[CH:6][CH:7]=1.S(Cl)([Cl:16])=O>ClCCl.CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[C:4]([CH2:10][Cl:16])[C:3]=1[CH2:12][CH3:13]
Reactant: CCc1ccc(Br)c(CC)c1CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCc1ccc(Br)c(CC)c1CCl
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 5.84 g (24 mmol) (3-bromo-2,6-diethyl-phenyl)-methanol in 60 ml dichloromethane were added 10 drops N,N-dimethylformamide and drop-wise within 5 minutes 5.71 g (3.5 ml, 5.71 mmol) thionyl chloride. The mixture was stirred at ambient temperature over night, then the volatile parts distilled off under reduced pressure. 1-Bromo-3-chloromethyl-2,4-diethyl-benzene was obtained as an oily residue which was used immediately for the following reaction.
Reaction SMILES: [F:1][C:2]1([C:15]([O:17]CC)=O)[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[C:20](=[N:23]O)([NH2:22])[CH3:21].C[O-].[Na+]>O1CCCC1>[F:1][C:2]1([C:15]2[O:17][N:23]=[C:20]([CH3:21])[N:22]=2)[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:3]1
Reactant: CC(N)=NO
Reactant: CCOC(=O)C1(F)CCCN(C(=O)OC(C)(C)C)C1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(C2(F)CCCN(C(=O)OC(C)(C)C)C2)n1

Procedure:
The mixture of 1-tert-butyl 3-ethyl 3-fluoropiperidine-1,3-dicarboxylate 33 and 1a,b (0.8 g, 0.0029 mol) and acetamide oxime (0.54 g, 0.0073 mol) were dissolved in 30 mL tetrahydrofuran. Sodium methoxide (0.79 g, 0.0146 mol) was added and the mixture was heated at reflux for 1.75 hours. The mixture was concentrated and partitioned between water (25 mL) and ethyl acetate (1×100 mL). The aqueous layer was extracted with an additional 50 mL ethyl acetate. The combined organics were washed with 1×25 mL water, 1×40 mL saturated sodium chloride, and dried over Na2SO4. The dried organics were evaporated to an oil. The residue was chromatographed to remove 1a,b with 15 g silica gel, 100% dichloromethane to 5% ethyl acetate/dichloromethane, to obtain 0.18 g of clear colorless oil. MS (ESI) m/z 324 [M+K]+. 1H NMR (CDCl3) δ 1.45 (s, 9H), 1.55-62 (m, 1H), 1.70-1.74 (d, 1H), 1.92-1.95 (m, 1H), 2.17 (m, 1H), 2.29-2.32 (m, 1H), 2.43 (s, 3H), 3.06-3.12 (m, 1H), 3.89-3.92 (m, 2H).
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])[CH:2]=[CH2:3].Br[C:14]1[CH:23]=[CH:22][C:21]2[NH:20][C:19](=[O:24])[N:18]3[C:25](=[O:35])[N:26]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)[N:27]=[C:17]3[C:16]=2[CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.CCN(CC)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:34][C:31]1[CH:32]=[CH:33][C:28]([N:26]2[C:25](=[O:35])[N:18]3[C:19](=[O:24])[NH:20][C:21]4[CH:22]=[CH:23][C:14](/[CH:3]=[CH:2]/[C:1]([O:5][CH2:6][C:7]5[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=5)=[O:4])=[CH:15][C:16]=4[C:17]3=[N:27]2)=[CH:29][CH:30]=1
Reactant: Cc1ccc(-n2nc3c4cc(Br)ccc4[nH]c(=O)n3c2=O)cc1
Reactant: C=CC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(-n2nc3c4cc(/C=C/C(=O)OCc5ccccc5)ccc4[nH]c(=O)n3c2=O)cc1
Temperature: 120 °C
Reaction time: 15 h
Yield: 46.8 %

Procedure:
To a stirred solution of benzyl acrylate (44 μg, 0.274 mmol) and 8a (50.6 mg, 0.137 mmol) in a mixture of 8 mL of DMF and 4 mL of NEt3, was added Pd(OAc)2 (3.06 mg, 13.7 mmol) and triphenylphosphine (7.14 mg, 27.4 μmol) in a seal tube. The tube was sealed under argon and the mixture was stirred at 120° C. for 15 h. The mixture was cooled and concentrated to dryness in vacuo and the crude product was precipitated from acetone to give 17 as a white solid (29 mg, 47%). mp: 242° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:12]2[C:13]3[N:14]([C:28]([CH2:31][CH3:32])=[CH:29][CH:30]=3)[N:15]=[C:16]([CH3:27])[C:17]=2[CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:9]=[N:10][CH:11]=1)=[CH2:5])C>CO.Cl.[Cl-].[Na+].O>[C:4]([C:6]1[CH:7]=[C:8]([C:12]2[C:13]3[N:14]([C:28]([CH2:31][CH3:32])=[CH:29][CH:30]=3)[N:15]=[C:16]([CH3:27])[C:17]=2[CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:9]=[N:10][CH:11]=1)(=[O:3])[CH3:5]
Reactant: C=C(OCC)c1cncc(-c2c(CCCCC(=O)OCC)c(C)nn3c(CC)ccc23)c1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)CCCCc1c(C)nn2c(CC)ccc2c1-c1cncc(C(C)=O)c1
Yield: 90 %

Procedure:
A solution of ethyl 5-{4-[5-(1-ethoxyvinyl)-3-pyridinyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}pentanoate (190 mg) in methanol (5 mL) and 1N hydrochloric acid (5 mL) was stirred at ambient temperature for 2 hours. The solution was diluted with brine and extracted with chloroform. The organic layer was separated, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (10:1–2:1) to give ethyl 5-[4-(5-acetyl-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate as an yellow oil (160 mg).