Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:3](CC)CC)C.Cl.[O:9]=[C:10]1[NH:15][C:14]2[C:16]3[CH:17]=[CH:18][C:19]([CH2:23][C:24](O)=[O:25])=[CH:20][C:21]=3[CH2:22][C:13]=2[N:12]2[CH:27]=[CH:28][N:29]=[C:11]12.C(N1C=CN=C1)(N1C=CN=C1)=O.N>CN(C)C=O>[O:9]=[C:10]1[NH:15][C:14]2[C:16]3[CH:17]=[CH:18][C:19]([CH2:23][C:24]([NH2:3])=[O:25])=[CH:20][C:21]=3[CH2:22][C:13]=2[N:12]2[CH:27]=[CH:28][N:29]=[C:11]12
Reactant: O=C(O)Cc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12
Reactant: CCN(CC)CC
Agent: Cl
Agent: N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: NC(=O)Cc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12
Temperature: -10 °C
Reaction time: 2 h

Procedure:
1.21 ml of triethylamine are added to a suspension, under nitrogen, of 2.9 g of [4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-8-yl]acetic acid hydrochloride and 108 ml of dimethylformamide. After stirring for 30 minutes at a temperature in the region of 20° C., 3.5 g of 1,1'-carbonyldiimidazole are added to the reaction mixture and stirring is continued for 2 hours at a temperature in the region of 20° C. The reaction mixture is then cooled to -10° C. and a stream of gaseous ammonia is passed into the mixture for 15 minutes. After returning to a temperature in the region of 20° C., the reaction mixture is concentrated to dryness under reduced pressure. The evaporation residue is taken up in 100 ml of distilled water and the suspended solid is filtered, washed with water and then dissolved in 125 ml of dimethyl sulphoxide. The addition of 250 ml of acetone to the solution causes the appearance of a precipitate which is collected by filtration, washed with acetone and dried under reduced pressure (1 mbar) at 60° C. 1.1 g of [4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-8-yl]acetamide are thus obtained in the form of a beige solid with a melting point greater than 260° C. (Analysis; % Calculated C: 64.28, H: 4.32, N: 19.99, O: 11.42; % Found C: 63.9, H: 4.3, N: 19.8, O: 10.9).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:11][CH2:10]1.[C:21](#[N:23])[CH3:22]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[C:22]4[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=4[O:2][N:23]=3)[CH2:17][CH2:16]2)[CH2:13][CH2:14]1
Reactant: CC#N
Reactant: COc1ccccc1N1CCN(C2CCNCC2)CC1
Product: COc1ccccc1N1CCN(C2CCN(c3noc4ccccc34)CC2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1,2-benz-isoxazole-3-trifluoromethyl sulfonate I (Step 1, 0.50 g) and 4-(4-(2-methoxyphenyl)piperazin-1-yl)piperidine (Example G, Step 2, above, 0.514 g) were added to a cold suspension of CsCO3 (0.92 g) in acetonitrile (6 mL) under vigorous stirring. The reaction mixture was stirred at room temperature for 48 hours. The mixture was then filtered and concentrated on a rotary evaporator. The residue was dissolved in water extracted with CH2Cl2, dried over anhydrous MgSO4, filtered and concentrated on a rotary evaporator. The desired product was purified by flash chromatography on silica gel using ethyl acetate/hexane to give 0.34 g as an off-white solid; MP 71-73° C.; MS (ES) m/z (relative intensity): 393 (M+H)+ (100).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:24]=[CH:25]/[C:26]([O:28]C(C)(C)C)=[O:27])=[CH:4][N:3]=1>C(O)(C(F)(F)F)=O>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:15][CH:16]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1cnc(N)c2c(-c3ccc(Oc4ccccc4)cc3)csc12
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc(/C=C/C(=O)O)c2scc(-c3ccc(Oc4ccccc4)cc3)c12

Procedure:
A solution of Example 11A (0.25 g, 0.57 mmol) in TFA (5 mL) was stirred at room temperature for 14 hours then concentrated under a stream of nitrogen to provide the desired product. MS (ESI(+)) m/e 388.9 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH2:6][CH3:7])[C:3](Cl)=[O:4].[CH3:9][C:10]1([CH3:37])[CH2:15][O:14][CH:13](/[CH:16]=[CH:17]/[C:18]2[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=2[CH:26]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[OH:27])[O:12][CH2:11]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:9][C:10]1([CH3:37])[CH2:11][O:12][CH:13](/[CH:16]=[CH:17]/[C:18]2[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=2[CH:26]([O:27][C:3](=[O:4])[C:2]([CH3:8])([CH3:1])[CH2:6][CH3:7])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[O:14][CH2:15]1
Reactant: CCCCCCCCCC(O)c1cc(C)cc(C)c1/C=C/C1OCC(C)(C)CO1
Reactant: CCC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCC(OC(=O)C(C)(C)CC)c1cc(C)cc(C)c1/C=C/C1OCC(C)(C)CO1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88 %

Procedure:
2,2-Dimethylbutyryl chloride (1.2 mL, 8.66 mmol) and 4-dimethylaminopyridine (1.17 g, 9.58 mmol) were added under a nitrogen atmosphere at room temperature to a solution of the alcohol prepared in the preceding paragraph (880 mg, 2.18 mmol) in 50 mL of methylene chloride. After the addition, the solution was stirred at room temperature for 5 hours. The solution was washed with 10% HCl, 10% NaHCO3, dried (anh. K2CO3) and the solvent removed under reduced pressure. Purification of the residual oil on silica gel (230-400 mesh) using 4:1 methylene chloride:hexane as an eluent gave 2,2-dimethylbutanoic acid (E)-1-[2-[2-(5,5-dimethyl-1,3-dioxan-2-yl)-ethenyl]-3,5-dimethylphenyl]decyl ester as an oil (960 mg, 88%): IR (film) 2910, 2840 and 1720 cm-1 ; NMR (DMSO-d6) δ 0.66-0.78 (6H, m), 0.86 (3H, t, J=9 Hz), 1.02-1.20 (9H, m), 1.20-1.40 (14H, m), 1.50-1.70 (2H, m), 2.20 (3H, s), 2.24 (3H, s), 3.56 (2H, d, J=10 Hz), 3.64 (2H, d, J=10 Hz), 5.10 (1H, d, J=4 Hz), 5.68 (1H, dd, J=4, 15 Hz), 5.74-5.84 (1H, m), 6.78 (1H, d, J=15 Hz), 6.98 (2H, s).
Reaction SMILES: [C:1]([O:8][CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[N:12]([CH3:17])[C:11]([CH3:19])([CH3:18])[CH2:10]1)(=[O:7])[CH2:2][CH2:3][C:4]([O-:6])=[O:5].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].C(N(CC)CC)C>>[C:4]([O:6][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH3:21])(=[O:5])[CH2:3][CH2:2][C:1]([O:8][CH:9]1[CH2:14][C:13]([CH3:15])([CH3:16])[N:12]([CH3:17])[C:11]([CH3:19])([CH3:18])[CH2:10]1)=[O:7]
Reactant: CN1C(C)(C)CC(OC(=O)CCC(=O)[O-])CC1(C)C
Reactant: CCCCCCCCCCCCBr
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCOC(=O)CCC(=O)OC1CC(C)(C)N(C)C(C)(C)C1

Procedure:
The product is prepared as described in Example 4b by reacting 27.1 g (0.1 mol) of mono(1,2,2,6,6-pentamethyl-4-piperidyl) succinate with 24.9 g (0.1 mol) of 1-bromododecane in the presence of 10.1 g (0.1 mol) of triethylamine. The product has a boiling point of 190° C./4 mbar.
Reaction SMILES: [H-].[Na+].O[CH:4]1[CH:11]2[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:13][CH:5]1[C:6]3=[O:14])[CH2:10]2.C(Br)C1C=CC=CC=1.O[C:24]12[CH2:33][CH:28]3[CH2:29][CH:30](CC(C3)[C:25]1=[O:34])[CH2:31]2>C1COCC1.[N+](CCCC)(CCCC)(CCCC)CCCC.[I-]>[CH2:25]([O:34][C:11]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:13][CH:5]([C:6]3=[O:14])[CH2:4]1)[CH2:10]2)[C:24]1[CH:33]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C1C2CC3CC(C2)CC1(O)C3
Reactant: O=C1C2CC3CC(C2)C(O)C1C3
Agent: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Solvent: C1CCOC1
Product: O=C1C2CC3CC1CC(OCc1ccccc1)(C3)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a suspension of NaH (60% dispersed in nujol, 1.92 g, 80 mmol) in THF (80 mL) cooled to ice bath temperature was added 4-hydroxyadamantanone (6.64 g, 40 mmol) dissolved in THF (80 mL) via a syringe over a period of 15 minutes. After stirring the reaction mixture for 30 min., nBu4NI (1.4 g, 4 mmol) was added followed by the addition of benzylbromide (5.26 mL). The reaction mixture was warmed to room temperature and stirred for 16 h until TLC revealed disappearance of hydroxyadamantanone. Excess NaH was quenched by adding sat. aq NH4Cl solution to the ice cooled reaction mixture. The two layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and the solvent was evaporated under reduced pressure to obtain a crude reaction mass which was purified by column chromatography to obtain 5-(benzyloxy)adamantan-2-one as a gummy liquid (7.93 g) in 77% yield. m/z (M+1), 257; 1H NMR (CDCl3) 300 MHz δ 7.60-7.20 (m, 5H), 4.51 (s, 2H), 2.72-2.63 (m, 2H), 2.40-2.36 (m, 1H), 2.35-1.92 (m, 10H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=3[NH:13][C:12](=O)[C:11]=2[CH2:10][CH2:9]1.P(N)([NH2:32])(=O)OC1C=CC=CC=1.[OH-].[Na+]>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=3[N:13]=[C:12]([NH2:32])[C:11]=2[CH2:10][CH2:9]1
Reactant: Cc1ccccc1N1CCc2c1c1cccc(C)c1[nH]c2=O
Reactant: NP(N)(=O)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1ccccc1N1CCc2c(N)nc3c(C)cccc3c21
Temperature: 230 °C
Yield: 15.2 %

Procedure:
Impure 1-(2-methylphenyl)-4-oxo-6-methyl-2,3,4,5-tetrahydropyrrolo[3,2-c]quinoline (10.0 g) and phenyl phosphorodiamidate (12 g) were fused at 230° C. After 30 minutes the mixture was diluted with diphenyl ether (50 ml), further phenyl phosphorodiamidate (4 g) added, and heated for a further 30minutes at 230° C. Aqueous sodium hydroxide was added and the product extracted into dichloromethane. Chromatography (silica gel, 3% methanolic ammonia in dichloromethane) to remove unchanged starting material was followed by recrystallisation from ethanol to yield 1-(2-methylphenyl)-4-amino-6-methyl-2,3-dihydropyrrolo[3,2-c]quinoline (1.51 g), m.p. 173°-174°.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[C:8]=1[Br:19])(=O)=O.[CH3:22][O:23][C:24]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)=[O:25].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO>[Br:19][C:8]1[C:9]2[C:14](=[CH:13][C:12]([O:17][CH3:18])=[CH:11][CH:10]=2)[CH:15]=[CH:16][C:7]=1[C:29]1[CH:30]=[CH:31][C:26]([C:24]([O:23][CH3:22])=[O:25])=[CH:27][CH:28]=1
Reactant: COc1ccc2c(Br)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccc3cc(OC)ccc3c2Br)cc1
Temperature: 80 °C
Yield: 45 %

Procedure:
Followed the coupling procedure described for Example 1, starting from 1-bromo-6-methoxynaphthalen-2-yl trifluoromethanesulfonate (Intermediate 2) and 4-(methoxycarbonyl)phenylboronic acid with modifications: the base used was Na2CO3, the solvent was toluene/EtOH (4/1), and the reaction was heated to 80° C. for 3 h. The crude product was purified by silica gel column (PE/EtOAc=300/1 to 100/1), then washed with EtOAc (10 mL×5) to give the product (980 mg, yield 45%) as a white solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]=[C:7]2[CH2:13][CH2:14][NH2:15].[C:16](Cl)(=[O:19])[CH2:17][CH3:18]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]=[C:7]2[CH2:13][CH2:14][NH:15][C:16](=[O:19])[CH2:17][CH3:18]
Reactant: COc1ccc2c(c1)C(CCN)=CC2
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)NCCC1=CCc2ccc(OC)cc21

Procedure:
Using (E)-2-(6-methoxyindan-1-ylidene)ethylamine, the procedure of Reference Example 14 was otherwise repeated to provide 2-(5-methoxy-1H-inden-3-yl)ethylamine hydrochloride. Then, starting with this 2-(5-methoxy-1H-inden-3-yl)ethylamine hydrochloride and propionyl chloride, the title compound was synthesized in otherwise the same manner as Example 8 (yield 86%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O.O.NN>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:16][CH2:17]2)[CH:6]=[CH:7][C:8]=1[NH2:9]
Reactant: COc1cc(N2CCN(CC(C)C)CC2)ccc1[N+](=O)[O-]
Agent: NN
Solvent: CO
Solvent: O
Product: COc1cc(N2CCN(CC(C)C)CC2)ccc1N
Yield: 82.5 %

Procedure:
A solution of 1-[3-(methyloxy)-4-nitrophenyl]-4-(2-methylpropyl)piperazine (1.7 g, 5.82 mmol), FeCl3 (0.280 g, 1.75 mmol), activated carbon (2.0 g), and hydrazine hydrate (2.23 mL, 70 mmol) was heated in methanol (50 mL) for 3 hours. The mixture was filtered over celite and concentrated to give 2-(methyloxy)-4-[4-(2-methylpropyl)-1-piperazinyl]aniline as a white solid (1.24 g, 4.80 mmol, 83% yield). 1H NMR (400 MHz, CDCl3) δ ppm 0.94 (d, J=6.22 Hz, 6 H), 1.85 (s, 1 H), 2.20 (s, 2 H), 2.61 H), 3.10 (s, 4 H), 3.54 (s, 2 H), 3.83 (s, 3 H), 6.43 (m, 1 H), 6.52 (d, J=1.83 Hz, 1 H), 6.64 (d, J=8.42 Hz, 1 H).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:8]=[CH:9][C:10]3[C:11]([CH:21]=2)=[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:13][N:14]=3)[O:6][CH2:5][CH2:4][O:3]1.C(N(CC)CC)C>[Pd].O1CCCC1>[NH2:14][C:10]1[CH:9]=[CH:8][C:7]([C:2]2([CH3:1])[O:3][CH2:4][CH2:5][O:6]2)=[CH:21][C:11]=1[C:12]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:13]
Reactant: CC1(c2ccc3noc(-c4ccccc4)c3c2)OCCO1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(c2ccc(N)c(C(=O)c3ccccc3)c2)OCCO1
Yield: 89.4 %

Procedure:
5-(2-Methyl-1,3-dioxolan-2yl)-3-phenyl-2,1-benzisoxazole (1.50 g, 5.3 m mol), triethyl amine (0.3 ml) and 5% palladium on carbon (0.15 g) were combined in dry tetrahydrofuran (13 ml). The apparatus wa flushed with nitrogen and then hydrogen. A static hydrogen atmosphere was maintained (1 atm.) and the progress of the reaction followed by gas chromatography. The starting material and product have retention times of 11.15 and 11.33 min. respectively. When conversion was complete, the mixture was filtered through a pad of Celite to yield a clear yellow solution. Evaporation of the solution yielded a yellow solid (1.35 g) of mp. 108°-111° C.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Br[C:37]1[CH:38]=[CH:39][C:40]2[C:41]3[N:50]([CH2:51][CH2:52][CH2:53][CH2:54][N:55]4[CH2:59][CH2:58][CH2:57][S:56]4(=[O:61])=[O:60])[C:49]([CH2:62][O:63][CH2:64][CH3:65])=[N:48][C:42]=3[C:43]([NH2:47])=[N:44][C:45]=2[CH:46]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[NH2:47][C:43]1[C:42]2[N:48]=[C:49]([CH2:62][O:63][CH2:64][CH3:65])[N:50]([CH2:51][CH2:52][CH2:53][CH2:54][N:55]3[CH2:59][CH2:58][CH2:57][S:56]3(=[O:61])=[O:60])[C:41]=2[C:40]2[CH:39]=[CH:38][C:37](/[CH:3]=[CH:2]/[C:1]([O:5][CH3:6])=[O:4])=[CH:46][C:45]=2[N:44]=1
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCCN1CCCS1(=O)=O
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOCc1nc2c(N)nc3cc(/C=C/C(=O)OC)ccc3c2n1CCCCN1CCCS1(=O)=O
Temperature: 90 °C

Procedure:
A 50-mL thick walled glass vessel was charged with palladium (II) acetate (67 mg, 0.3 mmol), acetonitrile (2 mL), methyl acrylate (0.26 g, 3.0 mmol), triethylamine (0.9 g, 9.0 mmol), tri-o-tolylphosphine (0.18 g, 0.6 mmol) and 7-bromo-1-[4-(1,1-dioxidoisothiazolidin-2-yl)butyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine (U.S. Patent Application Publication No. US 2004/0147543 Example 152-156, 1.5 g, 3.0 mmol). An additional 13 mL of acetonitrile was added. The reaction mixture was purged with nitrogen then heated to 90° C. The turbid orange mixture was maintained at 90° C. overnight. Anhydrous DMF (30 mL) was added to dissolve the 7-bromoquinoline starting material. The reaction was then heated at 120° C. overnight. The reaction mixture was filtered to remove the catalyst then concentrated to dryness. The desired product was isolated by column chromatography on silica gel (eluting with a gradient of 2%-8% methanol in dichloromethane). The resulting peach solid was taken up in saturated potassium carbonate solution and dichloromethane and stirred overnight at ambient temperature. The organic layer was separated and concentrated to dryness. The residue was recrystallized from acetonitrile to yield 0.65 g of Methyl(2E)-3-[4-amino-1-[4-(1,1-dioxidoisothiazolidin-2-yl)butyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl]prop-2-enoate as a pale yellow solid, mp 162-163° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=2[NH2:15])=[CH:5][CH:4]=1.C([C:20]1[C:21]([N:29]=[CH:30][N:31]([CH3:33])C)=[N:22][C:23]([CH:26]2[CH2:28][CH2:27]2)=[CH:24][CH:25]=1)#N.NC1C=C(C)C=CC=1SC1C=CC(O)=CC=1.C(C1C(N=CN(C)C)=NC(C)=CC=1)#N>>[CH:26]1([C:23]2[CH:24]=[CH:25][C:20]3[C:33]([NH:15][C:9]4[CH:10]=[C:11]([CH3:14])[CH:12]=[CH:13][C:8]=4[O:7][C:6]4[CH:16]=[CH:17][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)=[N:31][CH:30]=[N:29][C:21]=3[N:22]=2)[CH2:27][CH2:28]1
Reactant: COc1ccc(Oc2ccc(C)cc2N)cc1
Reactant: CN(C)C=Nc1nc(C2CC2)ccc1C#N
Agent: Cc1ccc(C#N)c(N=CN(C)C)n1
Agent: Cc1ccc(Sc2ccc(O)cc2)c(N)c1
Product: COc1ccc(Oc2ccc(C)cc2Nc2ncnc3nc(C4CC4)ccc23)cc1

Procedure:
The product from Example 116B was reacted with the product from Example 119A using the procedure from Example 102 substituting the product from Example 116B for the product from Example 6c and substituting the product from Example 119A for the product from Example 10B to provide the crude residue which was purified by trituration with methanol to provide the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.02-1.20 (m, J=6.25 Hz, 4H), 2.21-2.37 (m, 1H), 2.31 (s, 3H), 3.66 (s, 3H), 6.75-6.92 (m, 5H), 7.06 (dd, J=8.64, 0.92 Hz, 1H), 7.37 (s, 1H), 7.51 (d, J=8.46 Hz, 1H), 8.49 (s, 1H), 8.63 (d, J=8.82 Hz, 1H), 9.74 (s, 1H); MS (ESI)+ m/z 399 (M+H)+.
Reaction SMILES: C(OC(=O)[N:7]([C:19]1[CH:24]=[CH:23][C:22]([CH:25]([C:27]2[C:35]3[C:34]([CH:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)=[N:33][CH:32]=[N:31][C:30]=3[N:29]([S:41]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)(=[O:43])=[O:42])[CH:28]=2)O)=[CH:21][N:20]=1)[CH2:8][C:9]1[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=1)(C)(C)C.FC(F)(F)C(O)=O.C([SiH](CC)CC)C.C(#N)C>O>[C:44]1([S:41]([N:29]2[C:30]3[N:31]=[CH:32][N:33]=[C:34]([CH:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)[C:35]=3[C:27]([CH2:25][C:22]3[CH:23]=[CH:24][C:19]([NH:7][CH2:8][C:9]4[CH:10]=[N:11][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:13][CH:14]=4)=[N:20][CH:21]=3)=[CH:28]2)(=[O:42])=[O:43])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(C(F)(F)F)nc1)c1ccc(C(O)c2cn(S(=O)(=O)c3ccccc3)c3ncnc(C4CCCC4)c23)cn1
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccccc1)n1cc(Cc2ccc(NCc3ccc(C(F)(F)F)nc3)nc2)c2c(C3CCCC3)ncnc21

Procedure:
{5-[(7-Benzenesulfonyl-4-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-hydroxy-methyl]-pyridin-2-yl}-(6-trifluoromethyl-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (52, 0.014 g, 0.020 mmol), trifluoroacetic acid (0.028 mL, 0.37 mmol), triethylsilane (0.071 mL, 0.45 mmol), and 0.21 mL of acetonitrile were combined in a round bottom flask. The reaction mixture was heated at reflux for 3 hours, then poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with 25% methanol in dichloromethane. Appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]=[CH2:10])=[CH:4][CH:3]=1.Cl[CH2:12]I.ClC(Cl)C.C([Zn]CC)C>[NH4+].[Cl-]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:12][CH2:10]2)=[CH:4][CH:3]=1
Reactant: ClCI
Reactant: C=COc1ccc(Br)cc1
Agent: CC[Zn]CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(Cl)Cl
Product: Brc1ccc(OC2CC2)cc1
Reaction time: 0.5 h
Yield: 94.7 %

Procedure:
To mixture of 1-bromo-4-vinyloxybenzene (11.5 g, 58 mmol), chloroiodomethane (41 g, 232 mmol) and dichloroethane (180 mL) was added diethylzinc (15% solution in hexanes-95.5 mL, 116 mmol) over 3 h at 0° C. After 30 min stirring, NH4Cl solution (200 mL, aq. sat.) and light petrol (300 mL) was added. The organic phase was separated and concentrated in vacuo (8 bar, 50° C.). The residue was redissolved in light petrol and the insoluble material was filtered off. The filtrate was concentrated to afford sub-title compound (11.7 g, 94%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[CH2:12](OC1C=CC(O)=CC=1CCCC1C=CC(C(OC)=O)=CC=1)C1C=CC=CC=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([O:7][CH3:12])=[O:6]
Reactant: Cc1ccc(C(=O)O)cc1F
Reactant: COC(=O)c1ccc(CCCc2cc(O)ccc2OCc2ccccc2)cc1
Product: COC(=O)c1ccc(C)c(F)c1

Procedure:
Methyl 3-fluoro-4-methylbenzoate was prepared from 3-fluoro-4-methylbenzoic acid by the process described in Example 6 for the synthesis of methyl 4-(3-(2-benzyloxy-5-hydroxyphenyl)propyl]-benzoate.
Reaction SMILES: CO[C:3]1[C:4](=[O:10])[C:5](=[O:9])[C:6]=1[O:7][CH3:8].C[Si](C)(C)[Sn:13]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH2:16][CH3:17]>C1COCC1.[C-]#N.C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:8][O:7][C:6]1[C:5](=[O:9])[C:4](=[O:10])[C:3]=1[Sn:13]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: COc1c(OC)c(=O)c1=O
Reactant: CCCC[Sn](CCCC)(CCCC)[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [C-]#N
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1c(OC)c(=O)c1=O
Temperature: 25 °C

Procedure:
To a solution of 3,4-dimethoxy-cyclobut-3-ene-1,2-dione (1.5 g, 10.6 mmol) and trimethyl(tributylstannyl)silane (3.7 mL, 10.6 mmol) in anhydrous THF (75 mL) at −30° C. was added drop-wise a solution of tetrabutylammonium cyanide (57 mg, 0.2 mmol) in THF (3 mL). The clear solution quickly turned yellow and was left to warm to rt overnight. The reaction was concentrated in vacuo revealing a black oil which was dissolved in ether and filtered through a plug of silica (100% ether). The crude material was further purified by silica gel chromatography (100% hexanes to 3% Et2O in hexanes) to yield 3-methoxy-4-tributylstannanylcyclobut-3-ene-1,2-dione as a light yellow oil. 1H NMR (DMSO-d6, 400 MHz): δ0.90 (t, J=7.2 Hz, 9H), 1.09-1.23 (m, 6H), 1.23-1.38 (m, 6H), 1.43-1.63 (m, 6H), 4.38 (s, 3H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][N:23]=3)[C:20]=2[OH:21])=[C:12]([CH3:31])[CH:11]=1)#[N:9].[N:32]1([CH2:38][CH2:39][CH2:40][NH2:41])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([NH:41][CH2:40][CH2:39][CH2:38][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[O:28])=[CH:24][N:23]=3)[C:20]=2[OH:21])=[C:12]([CH3:31])[CH:11]=1)#[N:9]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: NCCCN1CCCCC1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NCCCN3CCCCC3)cn2)c1O

Procedure:
The title compound, as a TFA salt, was prepared in a manner similar to Example 74 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 3-(piperidin-1-yl)propan-1-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20-1.47 (m, 1H) 1.52-1.75 (m, 3H) 1.82 (d, J=14.40 Hz, 2H) 1.88-2.02 (m, 2H) 2.44 (s, 3H) 2.78-2.98 (m, 2H) 3.11 (dt, J=10.55, 4.96 Hz, 2H) 3.37 (q, J=6.48 Hz, 2H) 3.46 (d, J=11.87 Hz, 2H) 7.67 (d, J=7.83 Hz, 1H) 7.74 (s, 1H) 7.78 (br. s., 1H) 8.20 (br. s., 1H) 8.42 (d, J=7.58 Hz, 1H) 8.53 (br. s., 1H) 8.89 (t, J=5.18 Hz, 1H) 8.91-8.98 (m, 1H) 9.13 (br. s., 1H) 13.25 (br. s., 1H). MS m/z [M+H]+ 445.2.