Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=O.[F:8][C:9]([F:15])([F:14])[C:10]([NH:12][NH2:13])=[O:11]>C1C=CC=CC=1>[F:8][C:9]([F:15])([F:14])[C:10]([NH:12][NH:13][C:3](=[O:5])[C:2]([F:7])([F:6])[F:1])=[O:11]
Reactant: NNC(=O)C(F)(F)F
Reactant: O=C(O)C(F)(F)F
Solvent: c1ccccc1
Product: O=C(NNC(=O)C(F)(F)F)C(F)(F)F
Reaction time: 3 h

Procedure:
Trifluoroacetic acid (7.6 mL, 0.1 mol) was added to a stirred solution of trifluoroacethydrazide (12.8 g, 0.1 mol) in benzene (100 mL) and the mixture was heated under reflux for 2 h. A Dean and Stark trap was fitted, and reflux was continued for 3 h. Reflux was continued in the absence of the Dean and Stark trap (3 h) and then with the trap refitted (20 h). The resulting white solid was collected by filtration, dried in vacuum and identified as 1,2-bis(trifluoroacetyl)hydrazine (16.5 g, 73%). M.p. 173-175° C.
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH2:10][NH2:11])=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:14]([C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH:19]=[C:20]([CH3:27])[N:21]=[CH:22]2)=[C:15]=[O:16].N(C1C=CC=C2C=1C=CN=C2)=C=O>>[CH3:27][C:20]1[N:21]=[CH:22][C:23]2[C:18]([CH:19]=1)=[C:17]([NH:14][C:15]([NH:11][CH2:10][C:9]1[CH:12]=[CH:13][C:6]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:7][CH:8]=1)=[O:16])[CH:26]=[CH:25][CH:24]=2
Reactant: NCc1ccc(N2CCCC2)cc1
Reactant: Cc1cc2c(N=C=O)cccc2cn1
Agent: O=C=Nc1cccc2cnccc12
Product: Cc1cc2c(NC(=O)NCc3ccc(N4CCCC4)cc3)cccc2cn1

Procedure:
The title compound was prepared using the procedure described in Example 61B using 4-(1-pyrrolidinyl)benzylamine and the product from Example 154A instead of 4-cyanobenzyl alcohol and the product from Example 61A. 1H NMR (300 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.54 (s, 1H), 8.27 (d, 1H, J=7.5 Hz), 7.73 (s, 1H), 7.67 (d, 1H, J=7.5 Hz), 7.49 (t, 1H, J=7.5 Hz), 7.16 (d, 2H, J=9 Hz), 6.84 (t, 1H, J=6 Hz), 6.53 (d, 2H, J=9 Hz), 4.22 (d, 2H, J=6 Hz), 3.20 (m, 4H), 2.63 (s, 3H), 1.94 (m, 4H); MS (ESI) 361 (M+H)+. Anal. Calcd for C22H24N4O.0.2H2O: C, 72.58; H, 6.76; N, 15.39. Found: C, 72.33; H, 6.64; N, 15.22.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([O:11][C:12]1[C:21]3[C:16](=[CH:17][C:18]([O:22][CH2:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[CH:19][CH:20]=3)[N:15]=[CH:14][N:13]=1)=[CH:6][CH:5]=2.[CH3:30][O:31][CH2:32][CH:33]=O>>[CH3:30][O:31][CH2:32][CH2:33][N:27]1[CH2:28][CH2:29][CH:24]([CH2:23][O:22][C:18]2[CH:17]=[C:16]3[C:21]([C:12]([O:11][C:7]4[CH:8]=[C:9]5[C:4](=[CH:5][CH:6]=4)[NH:3][C:2]([CH3:1])=[CH:10]5)=[N:13][CH:14]=[N:15]3)=[CH:20][CH:19]=2)[CH2:25][CH2:26]1
Reactant: Cc1cc2cc(Oc3ncnc4cc(OCC5CCNCC5)ccc34)ccc2[nH]1
Reactant: COCC=O
Product: COCCN1CCC(COc2ccc3c(Oc4ccc5[nH]c(C)cc5c4)ncnc3c2)CC1
Yield: 46.4 %

Procedure:
Using an analogous procedure to that described for Example 71, 4-(2-methylindol-5-yloxy)-7-(piperidin-4-ylmethoxy)quinazoline (150 mg, 0.386 mmol), (prepared as described in Example 122), was reacted with methoxyacetaldehyde (83 mg, 0.772 mmol), (prepared as described for the starting material in Example 71), to give 7-(1-(2-methoxyethyl)piperidin-4-ylmethoxy)-4(2-methylindol-5-yloxy)quinazoline (80 mg, 46%).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH3:3].[C:5]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]2[C@H:15]3[C@H:24]([CH2:25][CH2:26][C@:10]12[CH3:11])[C@@H:23]1[C:18](=[CH:19][C:20](=[O:27])[CH2:21][CH2:22]1)[CH:17]=[CH:16]3)(=[O:7])[CH3:6].[NH4+].[Cl-]>C1COCC1.[Cu]I>[C:5]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]2[C@H:15]3[C@H:24]([CH2:25][CH2:26][C@:10]12[CH3:11])[C@@H:23]1[C:18](=[CH:19][C:20](=[O:27])[CH2:21][CH2:22]1)[CH2:17][C@H:16]3[CH2:1][CH2:2][CH3:3])(=[O:7])[CH3:6]
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]12C
Reactant: [Li]CCC
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC[C@@H]1CC2=CC(=O)CC[C@@H]2[C@H]2CC[C@]3(C)[C@@H](OC(C)=O)CC[C@H]3[C@H]12
Reaction time: 0.5 h
Yield: 35.4 %

Procedure:
A solution of propyl lithium (prepared from 1.4 g of Li and 9 ml of propyl bromide in 60 ml of ether at -20 C) was added at -40 C to 7.6 g of CuI in 60 ml of dry THF. After stirring for an additional 0.5 hr, a solution of 5.2 g of (17 beta)-17-(acetyloxy)estra-4,6-dien-3-one (1) in 20 ml of THF was added dropwise at -40 C. Upon stirring for an additional 15 minutes the reaction was complete, and the mixture was poured onto 300 ml of saturated NH4Cl solution, followed by extraction with ethyl acetate. The organic material, isolated after washing, drying and evaporation of the solvent, was taken up in 30 ml of THF and stirred in the presence of 3 ml of 6N H2SO4 to isomerize some Δ5,6 isomer to Δ4,5 isomer. After 1 hr the mixture was neutralized with saturated NaHCO3 solution and extracted with ethyl acetate. Chromatography of the crude product over silica gel (heptane/ethyl acetate 8/2) provided 2.1 g of 2, m.p. 97-100° C.
Reaction SMILES: [NH:1]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@@H:2]([C:19]([O:21]CC1C=CC=CC=1)=[O:20])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:5]=1>C(O)C.[Pd]>[NH:1]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[C@@H:2]([C:19]([OH:21])=[O:20])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:5]=1
Reactant: CCOC(=O)Cn1cc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)c2ccccc21
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)Cn1cc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)c2ccccc21
Yield: 91 %

Procedure:
To a solution of Boc-D-Trp(CH2CO2Et)-OBzl (4.14 g) in ethanol (60 ml) was added 5% palladium on carbon (0.7 g) and the mixture was hydrogenated for one and half an hour under atmospheric pressure. Filtration of the catalyst and concentration of the filtrate under vacuum gave Boc-D-Trp(CH2CO2Et)-OH as an amorphous solid (3.06 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N:15]([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:16][CH2:17][CH2:18][CH2:19][O:20][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:12]=[CH:11][C:10]=1[CH:42]=[CH:43][C:44]1[S:48][C:47]([CH:49]=[O:50])=[CH:46][CH:45]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(OCC)(=O)C>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N:15]([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH:12]=[CH:11][C:10]=1[CH:42]=[CH:43][C:44]1[S:48][C:47]([CH:49]=[O:50])=[CH:46][CH:45]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCN(CCCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1ccc(C=Cc2ccc(C=O)s2)c(OCc2ccccc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCCCN(CCCCO)c1ccc(C=Cc2ccc(C=O)s2)c(OCc2ccccc2)c1
Temperature: 25 °C
Yield: 69.9 %

Procedure:
In 10 ml of tetrahydrofuran was dissolved 1.2 g (1.71 mmol) of 5-[2-[2-benzyloxy-4-[butyl[4-(tert-butyldiphenylsiloxy) butyl]amino]phenyl]vinyl]thiophene-2-carboaldehyde. To this mixture, 7.6 ml of tetrabutylammonium fluoride (1 mol/L solution in tetrahydrofuran) (7.6 mmol) was added dropwise with stirring at room temperature. The mixture was stirred for 1.5 hours. After the reaction mixture was poured into water, extraction with ethyl acetate, washing with a saturated saline solution, drying over anhydrous sodium sulfate, and concentration were performed. The residual liquid was purified by silica gel column chromatography to give 554 mg of a red crystal (yield: 70.1%).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][N:10]([CH3:19])[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])=[C:7]([C:22]([F:25])([F:24])[F:23])[CH:6]=1)[NH2:4].[CH3:26][O:27][CH2:28][C:29]1[CH:34]=[C:33]([C:35](O)=O)[CH:32]=[CH:31][C:30]=1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[CH3:44].C(Cl)CCl>CC#N.N1C=CC=CC=1>[CH3:26][O:27][CH2:28][C:29]1[CH:34]=[C:33]([C:35]2[O:1][N:2]=[C:3]([C:5]3[CH:21]=[CH:20][C:8]([CH2:9][N:10]([CH3:19])[CH2:11][C:12]([OH:14])=[O:13])=[C:7]([C:22]([F:24])([F:23])[F:25])[CH:6]=3)[N:4]=2)[CH:32]=[CH:31][C:30]=1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[CH3:44]
Reactant: CN(CC(=O)OC(C)(C)C)Cc1ccc(C(N)=NO)cc1C(F)(F)F
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Solvent: c1ccncc1
Solvent: ClCCCl
Solvent: CC#N
Product: COCc1cc(-c2nc(-c3ccc(CN(C)CC(=O)O)c(C(F)(F)F)c3)no2)ccc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of Intermediate 74 (0.112 g, 0.31 mmol) and Intermediate 3 (0.067 mg, 0.26 mmol) in MeCN (2 mL) was added EDC (0.069 g, 0.36 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with pyridine (2 mL) and heated at 150° C. in the microwave for 30 minutes. The reaction was repeated and combined to work up. The solvent was removed in vacuo and the residue dissolved in DCM. The mixture was washed with water and the organic phase passed through a hydrophobic frit. The solvent was evaporated in vacuo. The residue was purified by SCX chromatography. The material was treated with a 4N solution of HCl in dioxane (4 mL) and the resulting mixture was stirred at 70° C. for 18 hours. The solvent was evaporated in vacuo and the residue purified by preparative HPLC, affording the title compound as an orange oil. 1H NMR (CDCl3, 400 MHz) δ 8.98 (1H, br s), 8.50 (1H, s), 8.43-8.34 (2H, m), 8.14 (2H, d, J=8.0 Hz), 7.34-7.21 (4H, m), 7.12 (1H, d, J=7.4 Hz), 4.26-4.18 (4H, m), 3.56 (2H, s), 3.32 (3H, s), 2.62 (3H, s), 2.07 (3H, s). LC/MS (Method A): 526 (M+H)+. HPLC (Method F) Rt 3.74 min (Purity: 99.4%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[N:20]1[NH:21][N:22]=[N:23][C:24]=1[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][NH2:32])=[CH:27][CH:26]=1>>[F:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7]([NH:32][CH2:31][C:28]1[CH:27]=[CH:26][C:25]([C:24]2[N:20]=[N:21][NH:22][N:23]=2)=[CH:30][CH:29]=1)=[O:9]
Reactant: NCc1ccc(-c2nn[nH]n2)cc1
Reactant: O=C(O)c1cc(F)cnc1Cc1ccc(F)cc1
Agent: Cl
Product: O=C(NCc1ccc(-c2nn[nH]n2)cc1)c1cc(F)cnc1Cc1ccc(F)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 75 from 5-fluoro-2-(4-fluorobenzyl)nicotinic acid (step 3 of Example 58) and 1-[4-(2H-tetrazol-5-yl)phenyl]methanamine hydrochloride: 1H-NMR (DMSO-d6) δ 9.20 (1H, t, J=5.7 Hz), 8.59 (1H, d, J=2.8 Hz), 7.98 (2H, d, J=8.1 Hz), 7.83 (1H, dd, J=8.8, 2.9 Hz), 7.44 (2H, d, J=8.1 Hz), 7.20–7.16 (2H, m), 7.03 (2H, t, J=8.9 Hz), 4.50 (2H, d, J=5.7 Hz), 4.21 (2H, s); MS (ESI) m/z 407 (M+H)+, 405 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH:17]3[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:19][CH2:18]3)=[CH:11][CH:10]=2)[C:5]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)=[CH:4][CH:3]=1.O[C@@H:36]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]([O:39][CH2:40][CH3:41])=[O:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.O>[CH3:1][C:2]1[N:6]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH:17]3[CH2:18][CH2:19][CH:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:21][CH2:22]3)=[CH:11][CH:10]=2)[C:5]([C:28]2[CH:33]=[CH:32][C:31]([O:34][C@H:36]([CH2:42][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:30][CH:29]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)[C@@H](O)Cc1ccccc1
Reactant: CCCCCC1CCC(COc2ccc(CCn3c(C)ccc3-c3ccc(O)cc3)cc2)CC1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCC1CCC(COc2ccc(CCn3c(C)ccc3-c3ccc(O[C@H](Cc4ccccc4)C(=O)OCC)cc3)cc2)CC1
Temperature: 80 °C
Reaction time: 12 h
Yield: 48.7 %

Procedure:
To a solution of 4-(5-methyl-1-{2-[4-(4-pentylcyclohexylmethoxy)phenyl]ethyl}-1H-pyrrol-2-yl)phenol (830 mg, 1.81 mmol), ethyl (S)-2-hydroxy-3-phenylpropanoate (526 mg, 2.71 mmol) and triphenylphosphine (711 mg, 2.71 mmol) in toluene (1 ml) was added 1,1′-(azodicarbonyl)dipiperidine (684 mg, 2.71 mmol) and the mixture was stirred at 80° C. for 12 hours. The reaction solution was poured into water and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate anhydride and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=30:1) to give the object compound as an oily substance. 560 mg (yield: 48.7%)
Reaction SMILES: [CH2:1]([Sn](CCCC)(CCCC)C=C)[CH2:2]CC.Br[C:17]1[CH:18]=[N:19][CH:20]=[C:21]([CH:24]=1)[C:22]#[N:23].[Cl-].[NH4+].C(OCC)(=O)C>C1(C)C=CC=CC=1.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:1]([C:17]1[CH:18]=[N:19][CH:20]=[C:21]([CH:24]=1)[C:22]#[N:23])=[CH2:2]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: N#Cc1cncc(Br)c1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=Cc1cncc(C#N)c1
Temperature: 110 °C
Reaction time: 2.5 h
Yield: 70.3 %

Procedure:
Add bis(triphenylphosphine)palladium (II) dichloride (0.460 g, 0.66 mmol) and tributyl-vinyl-stannane (7.2 mL, 24.6 mmol) to a solution of 5-bromonicotinonitrile (3.0 g, 16.4 mmol) in toluene (50 mL) and stir at 110° C. for 150 min. Add an aqueous saturated solution of ammonium chloride and ethyl acetate and separate the layers. Wash the organic layer twice with an aqueous saturated solution of potassium fluoride and once with water. Dry (sodium sulfate), filter, and concentrate. Purify the residue by silica gel chromatography, eluting with 3:1 hexane:ethyl acetate, to give the title compound (1.5 g, 70%).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[CH2:13]1)[CH3:2].[Cl:24][CH2:25][C:26](Cl)=[O:27]>>[Cl:24][CH2:25][C:26]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[CH2:13]1)=[O:27]
Reactant: O=C(Cl)CCl
Reactant: CCNc1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Product: CCN(C(=O)CCl)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1

Procedure:
Synthesized from ethyl [5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (100 mg) and chloroacetyl chloride (0.04 ml) according to an analogous synthetic method to Preparation Example 87, the title compound (133 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](I)[C:3]=1[C:4]#[N:5].[Cl:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:11][C:12]1[CH:17]=[C:16]([C:6]2[C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=[CH:8][CH:7]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: N#Cc1c(F)cccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: N#Cc1c(F)cccc1-c1cccc(Cl)c1
Temperature: 25 °C
Yield: 32.1 %

Procedure:
In a dry round bottom flask were added 2-fluoro-6-iodobenzonitrile (500 mg; 2.02 mmol), 3-chlorophenyl boronic acid (380 mg; 2.43 mmol), sodium carbonate (2.32 g; 21.86 mmol), tetrakis(triphenylphosphine)palladium(0) (77 mg; 0.07 mmol), DME (20 mL) and water (20 mL) and heated to reflux for 8 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (3×), washed with brine (1×) and water (1×). Organic layers were combined and dried over sodium sulfate and then filtered and solvent removed to yield crude material which was purified by column chromatography (4% ethyl acetate/hexane) to obtain 150 milligrams of 3′-chloro-3-fluorobiphenyl-2-carbonitrile.
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][CH:20]=[O:21])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].N[C:23]1C2N=C(CCCC)N(CCCC(N(OC)C)=O)C=2C2N=CC=CC=2N=1>>[CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][CH:20]([OH:21])[CH3:23])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCC=O
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCCC(=O)N(C)OC
Product: CCCc1nc2cnc3ccccc3c2n1CCCC(C)O

Procedure:
The preparation of 4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyraldehyde is described in parts A-C of Example 6. The general procedure of Part G of Example 4 was repeated using 4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyraldehyde (6.4 g, 22.74 mmol) in lieu of 4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)-N-methoxy-N-methylbutanamide to provide 5.2 g of 5-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-ol as a tan oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][N:3]=1.[CH2:10]([O:12][C:13](=[O:18])[CH2:14][N:15]=[N+:16]=[N-:17])[CH3:11].CC(O)(C)C>O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH2:10]([O:12][C:13](=[O:18])[CH2:14][N:15]1[CH:9]=[C:8]([C:5]2[CH:4]=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:17]=[N:16]1)[CH3:11]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: C#Cc1ccc(Cl)nc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CC(C)(C)O
Solvent: O
Product: CCOC(=O)Cn1cc(-c2ccc(Cl)nc2)nn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-Chloro-5-ethynylpyridine (100 mg, 0.73 mmol) and ethylazidoacetate (0.41 ml, 0.73 mmol) were taken up in water (1.5 ml) and 2-methylpropan-2-ol (1.5 ml) at room temperature. Aqueous solutions of copper(II) sulfate pentahydrate (9.08 mg, 0.036 mmol) in 1 mL of water and L-sodium ascorbate (28.8 mg, 0.145 mmol) in 1 mL of water were sequentially added, and the reaction was stirred at room temperature for 18 hours. The reaction was then quenched with saturated aqueous sodium bicarbonate, and extracted three times with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated. The resulting crude product was purified by silica gel chromatography (0-65% ethyl acetate/hexanes) to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7](=[N:17][O:18][S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)[N:5]=[C:4]([CH3:29])[CH:3]=1.O.[CH3:31][C:32](OC(C)=O)=[O:33]>>[C:32]([NH:1][C:2]1[N:6]([C:7](=[N:17][O:18][S:19]([C:22]2[CH:23]=[CH:24][C:25]([CH3:26])=[CH:27][CH:28]=2)(=[O:21])=[O:20])[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)[N:5]=[C:4]([CH3:29])[CH:3]=1)(=[O:33])[CH3:31]
Reactant: Cc1ccc(S(=O)(=O)ON=C(c2cccc([N+](=O)[O-])c2)n2nc(C)cc2N)cc1
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Nc1cc(C)nn1C(=NOS(=O)(=O)c1ccc(C)cc1)c1cccc([N+](=O)[O-])c1
Yield: 86 %

Procedure:
2 g (4.8 mmol) of 5-amino-3-methyl-1-(O-tosyl-3-nitrobenzohydroximoyl)-pyrazole are heated for 5 minutes under reflux in 5 ml of acetanhydride. This is then cooled down and hydrolysed with water. The solid mass which forms after a little while is separated off, washed with water, dried in the air and recrystallised from acetonitrile. 1.9 g (86%) of 5-acetamido-3-methyl-1-(O-tosyl-3-nitrobenzohydroximoyl)-pyrazole with a m. pt. of 208°-212° C. (decomp.) are obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:15]1C[CH2:18][CH2:17][CH2:16]1.[OH2:20]>C1(C)C=CC=CC=1.ClCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2[NH:15][C:16](=[O:20])[CH:17]=[CH:18][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: C1CCNC1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=c1ccc2c([nH]1)CCN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
1-Benzyl-4-piperidone (15 g, 79.3 mmol) and pyrrolidine (7.5 mL, 90 mmol) were dissolved in toluene (90 mL) and the solution was heated under reflux, with the removal of water under Dean and Stark conditions, for 5 hours. The solution was then cooled to room temperature and the product of preparation 1 (10.5 g, 150 mmol) was added. The mixture was re-heated under reflux, using Dean and Stark conditions, for a further 8 hours. The reaction mixture was then allowed to cool to room temperature and was triturated with toluene (150 mL) to yield an orange coloured solid. The solid was filtered off and the filtrate was evaporated under reduced pressure to give a red oily residue. The residue was dissolved in dichloromethane (400 mL), washed with saturated sodium hydrogen carbonate solution (2×300 mL), dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluting with dichloromethane:methanol:0.88 ammonia, 97:3:0.2 to 93:7:0.7, followed by trituration with diethyl ether afforded the title product in 30% yield, 5.57 g.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].[CH3:13][O:14][S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16]>>[C:21]1([CH3:24])[CH:20]=[CH:19][C:18]([S:15]([O-:17])(=[O:14])=[O:16])=[CH:23][CH:22]=1.[CH3:13][N+:8]1[C:7]2[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=2[S:10][CH:9]=1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: O=[N+]([O-])c1ccc2ncsc2c1
Product: C[n+]1csc2cc([N+](=O)[O-])ccc21
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 140 °C
Yield: 54.1 %

Procedure:
See FIG. 3A. A mixture of 6-nitrobenzothiazole (1 g) and methyl-p-toluenesulfonate (1.2 g) was heated to 140° C. for 20 min. The solid was washed with acetone and filtered to provide a bluish solid (1.1 g).
Reaction SMILES: CC1(C)[CH2:7][CH2:6][CH2:5][C:4](C)(C)[NH:3]1.C([Li])CCC.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([OH:24])=[O:23].O=C1CCN(C(OC(C)(C)C)=O)C1>CCCCCC.C1COCC1>[NH:3]1[CH2:4][CH2:5][C:6]2([C:18]3[C:17](=[N:16][CH:21]=[CH:20][CH:19]=3)[C:22](=[O:24])[O:23]2)[CH2:7]1
Reactant: CC1(C)CCCC(C)(C)N1
Reactant: O=C(O)c1ccccn1
Agent: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1OC2(CCNC2)c2cccnc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 2,2,6,6-tetramethyl-piperidine (0.820 mL, 0.00486 mol) in tetrahydrofuran (5 mL, 0.06 mol) at −75 Celsius was added to 1.600 M of n-butyllithium in hexane (4.05 mL). After the mixture was stirred for 15 min, a solution of 2-pyridinecarboxylic acid (199 mg, 0.00162 mmol) was added. The resulting mixture was stirred at −75 Celsius for 10 minutes, then at −20 Celsius for 30 minutes. A solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (250 mg, 0.0013 mol) in THF (2 mL) was then added to the above mixture. The reaction mixture continued to be stirred at −20 Celsius for 20 minutes, then was warmed up to r.t. and then stirred for additional 1 hour. The reaction mixture was quenched with water, then concentrated to remove THF, and then acidified to pH ˜1 using 6M aqueous HCl solution, and then stirred at r.t. overnight. The resulting mixture was extracted with methylene chloride. The aqueous layer was concentrated and the residue was directly purified by flash chromatography on silica gel column with 10% methanol in methylene chloride to give the desired compound. MS (ESI): 190.9 (M+H+).