Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH:8]1[C:17](=O)[C:16]2[C:15]([C:19](OCC)=[O:20])=[CH:14][CH:13]=[CH:12][C:11]=2[NH:10][CH:9]1[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[CH3:2].O.[NH2:32][NH2:33]>CO>[CH2:1]([N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH:8]1[C:17]2=[N:32][NH:33][C:19](=[O:20])[C:15]3[CH:14]=[CH:13][CH:12]=[C:11]([C:16]=32)[NH:10][CH:9]1[C:24]1[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=1)[CH3:2]
Reactant: NN
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1nccn1CC)C(c1ccc(F)cc1)N2
Solvent: O
Solvent: CO
Product: CCn1ccnc1C1c2n[nH]c(=O)c3cccc(c23)NC1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 47 %

Procedure:
A mixture of ethyl 3-(1-ethyl-1H-imidazol-2-yl)-2-(4-fluorophenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (90 mg, 0.22 mmol) in 85% hydrazine monohydrate (4 mL) and methanol (10 mL) was stirred for 4 h at room temperature. Methanol was removed under reduced pressure. The mixture was filtered and washed with water to give the crude product. The crude product was purified by prep-HPLC to give the title compound (38.5 mg, yield: 47%). 1H-NMR (400 MHz, MeOD) δ (ppm): 1.06-1.09 (t, J=7.2 Hz, 3H), 3.74-3.78 (m, 2H), 4.60-4.62 (d, J=11.6 Hz, 1H), 4.98-5.01 (d, J=11.6 Hz, 1H), 6.91-7.02 (m, 4H), 7.19-7.21 (m, 1H), 7.39-7.43 (m, 2H), 7.56-7.64 (m, 2H); LC-MS (ESI) m/z: 376 (M+1)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](O)[C:7](=[CH:9][CH:10]=1)O)([O-:3])=[O:2].N1C=CC=CC=1.C(Cl)(=[O:28])CCCCCCCCC.O>C(Cl)Cl.C1COCC1>[O:28]=[C:10]1[CH:9]=[CH:7][CH:6]=[CH:5][CH:4]1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)c(O)c1
Reactant: CCCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: O=C1C=CC=CC1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 323.2 %

Procedure:
To a stirred, ice bath cooled solution of 1.0 g (6.45 mmol) of 4-nitrocatechol and 2 ml of pyridine in 25 ml of methylene chloride and 5 ml of THF under argon was added 3.2 ml (15.5 mmol) of decanoyl chloride in 5 ml of THF. The reaction mixture was allowed to warm to room temperature and stirred for 18 hours when it was poured into water and extracted with methylene chloride. The dried extract was concentrated to an oil which was purified by chromatography on 70 g of silica gel using 5% ethyl acetate-hexane to give 2.9 g (97% yield, mp 45°-47°) of 3,4-bis-[(1-oxo]nitrobenzene.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15](O)=[O:16])=[CH:13][N:12]3[CH:18]=[CH:19][N:20]=[C:11]3[C:10]=2[Cl:21])=[C:4]([F:22])[CH:3]=1.COC(C1C(NC2C=CC(Br)=CC=2F)=C(Cl)C2N(C=CN=2)C=1)=O.[NH2:46][NH2:47]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]([NH:46][NH2:47])=[O:16])=[CH:13][N:12]3[CH:18]=[CH:19][N:20]=[C:11]3[C:10]=2[Cl:21])=[C:4]([F:22])[CH:3]=1
Reactant: NN
Reactant: O=C(O)c1cn2ccnc2c(Cl)c1Nc1ccc(Br)cc1F
Agent: COC(=O)c1cn2ccnc2c(Cl)c1Nc1ccc(Br)cc1F
Solvent: CCO
Product: NNC(=O)c1cn2ccnc2c(Cl)c1Nc1ccc(Br)cc1F

Procedure:
7-(4-Bromo-2-fluoro-phenylamino)-8-chloro-imidazo[1,2-a]pyridine-6-carboxylic acid was converted to the hydrazide according to the coupling conditions described in Step A of Example 3. Alternatively, the hydrazide can be prepared directly from 7-(4-Bromo-2-fluorophenylamino)-8-chloroimidazo[1,2-a]pyridine-6-carboxylic acid methyl ester by refluxing with hydrazine in ethanol. MS ESI (+) m/z 398, 400 (M+, Cl, Br pattern) detected.
Reaction SMILES: [C:1]1([C@@H:7]2[C:9]3([CH2:13][CH2:12][CH2:11][CH2:10]3)[C@H:8]2[C:14](O)=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][C:19]1[C:24]([NH2:25])=[CH:23][CH:22]=[C:21]([O:26][CH3:27])[N:20]=1>>[CH3:17][O:18][C:19]1[C:24]([NH:25][C:14]([C@@H:8]2[C:9]3([CH2:13][CH2:12][CH2:11][CH2:10]3)[C@H:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:15])=[CH:23][CH:22]=[C:21]([O:26][CH3:27])[N:20]=1
Reactant: O=C(O)[C@H]1[C@H](c2ccccc2)C12CCCC2
Reactant: COc1ccc(N)c(OC)n1
Product: COc1ccc(NC(=O)[C@H]2[C@H](c3ccccc3)C23CCCC3)c(OC)n1
Yield: 53.1 %

Procedure:
trans-2-Phenylspiro[2.4]heptane-1-carboxylic acid (300 mg, 1.39 mmol) and 2,6-dimethoxy-pyridin-3-ylamine (214 mg, 1.39 mmol) were reacted as described under General Procedure D to furnish the title compound (260 mg, 52%) as a purple solid. 1H NMR (300 MHz, CDCl3) δ 8.54 (d, J=8.2 Hz, 1H), 7.61 (br s, 1H), 7.32-7.14 (m, 5H), 6.30 (d, J=8.2 Hz, 1H), 4.02 (s, 3H), 3.89 (s, 3H), 2.87 (d, J=5.7 Hz, 1H), 2.05 (d, J=5.7 Hz, 1H), 1.93-1.90 (m, 2H), 1.67-1.42 (m, 6H). mp 131-133° C. ESIMS m/z [M+H]+ 353.2.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]([NH2:14])[CH3:13])=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[Cl:15][C:16]1[CH:36]=[CH:35][C:34]([O:37][C@@H:38]([CH3:43])[C:39]([O:41][CH3:42])=[O:40])=[CH:33][C:17]=1[CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([C:28](O)=[O:29])=[CH:25][CH:26]=2)[C:21]([CH3:31])=[C:20]1[CH3:32]>>[C:2]([C:6]1[CH:7]=[CH:8][C:9]([C@@H:12]([NH:14][C:28]([C:24]2[CH:23]=[C:22]3[C:27](=[CH:26][CH:25]=2)[N:19]([CH2:18][C:17]2[CH:33]=[C:34]([CH:35]=[CH:36][C:16]=2[Cl:15])[O:37][C@@H:38]([CH3:43])[C:39]([O:41][CH3:42])=[O:40])[C:20]([CH3:32])=[C:21]3[CH3:31])=[O:29])[CH3:13])=[CH:10][CH:11]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: C[C@H](N)c1ccc(C(C)(C)C)cc1
Reactant: COC(=O)[C@H](C)Oc1ccc(Cl)c(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c1
Agent: Cl
Product: COC(=O)[C@H](C)Oc1ccc(Cl)c(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4ccc(C(C)(C)C)cc4)ccc32)c1

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(4-(tert-butyl)phenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride the (S)-1-(2-chloro-5-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH3:22])[N:14]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH2:23][CH2:24][C:25](O)=[O:26])=[CH:5][C:4]=2[N:3]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.[NH:49]1[CH2:54][CH2:53][S:52](=[O:56])(=[O:55])[CH2:51][CH2:50]1>N1C=CC=CC=1>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH3:22])[N:14]([CH2:15][C:16]([CH3:17])([OH:19])[CH3:18])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH2:23][CH2:24][C:25]([N:49]3[CH2:54][CH2:53][S:52](=[O:56])(=[O:55])[CH2:51][CH2:50]3)=[O:26])=[CH:5][C:4]=2[N:3]=1
Reactant: O=S1(=O)CCNCC1
Reactant: COCc1nc2c(N)nc3cc(CCC(=O)O)ccc3c2n1CC(C)(C)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Product: COCc1nc2c(N)nc3cc(CCC(=O)N4CCS(=O)(=O)CC4)ccc3c2n1CC(C)(C)O
Reaction time: 0.5 h
Yield: 66.2 %

Procedure:
3-[4-Amino-1-(2-hydroxy-2-methylpropyl)-2-(methoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl]propanoic acid (1.25 g, 3.30 mmol), anhydrous pyridine (75 mL) and 1-hydroxybenzotriazole (892 mg, 6.60 mmol) were combined and the reaction was stirred for 30 minutes. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (1.27 g, 6.60 mmol) was added and the reaction mixture was stirred for an additional 15 minutes. Thiomorpholine 1,1-dioxide (895 mg, 6.60 mmol) was added in one portion. After stirring for 18 hours the solution was concentrated under reduced pressure and the residual foam was dissolved in chloroform (50 mL) and washed with 1% aqueous sodium carbonate (2×25 mL). The combined aqueous washes were extracted with chloroform. The combined organic fractions were concentrated under reduced pressure and purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a CMA:chloroform gradient; 0-25% CMA over 1500 mL, followed by 25-30% CMA over 500 mL, finally 30% CMA over 1000 mL). The resulting material was subjected to a second chromatography purification using a HORIZON HPFC system (silica cartridge, eluting with CMA:chloroform gradient; 0-25% CMA over 1500 mL, followed by 25-30% CMA over 500 mL) followed by recrystallization from acetonitrile to provide 1.07 g of 1-[4-amino-7-[3-(1,1-dioxidothiomorpholin-4-yl)-3-oxopropyl]-2-(methoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as a white solid, mp 190-192° C.
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]3[C:21]4[N:22]=[CH:23][CH:24]=[CH:25][C:20]=4[C:19]4=[N:26][N:27]([CH:30]5[CH2:35][CH2:34][CH2:33][O:32][CH2:31]5)[C:28](=[O:29])[C:18]4=[N:17]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.I[Si](C)(C)C.CO.O>ClCCl>[OH:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([CH2:15][N:16]3[C:21]4[N:22]=[CH:23][CH:24]=[CH:25][C:20]=4[C:19]4=[N:26][N:27]([CH:30]5[CH2:35][CH2:34][CH2:33][O:32][CH2:31]5)[C:28](=[O:29])[C:18]4=[N:17]3)=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccc(Cn3nc4c(=O)n(C5CCCOC5)nc-4c4cccnc43)cc2)cn1
Agent: C[Si](C)(C)I
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: O=c1c2nn(Cc3ccc(-c4ccc(O)nc4)cc3)c3ncccc3c-2nn1C1CCCOC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
(±)-5-({4-[6-(Methyloxy)pyridin-3-yl]phenyl}methyl)-2-(tetrahydro-2H-pyran-3-yl)-2,5-dihydro-3H-pyrazolo[4,3-c]pyrido[3,2-e]pyridazin-3-one (Example 14, 20 mg, 0.043 mmol) was dissolved in dichloromethane (3 mL), cooled to 0° C. and treated with iodotrimethylsilane (26 μL, 0.13 mmol, 3 equiv). After stirring for 15 minutes at 0° C., the mixture was warmed to ambient temperature and stirred for an additional 14 hours. The mixture was cooled to 0° C. treated with additional iodotrimethylsilane (26 μL, 0.13 mmol, 3 equiv) and after stirring for 15 minutes at 0° C., the mixture was warmed to ambient temperature and stirred for an additional 14 hours. The mixture was treated with methanol (1 mL), poured into water (10 mL) and extracted with ethyl acetate (2×20 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified via silica gel gradient chromatography (100:0 to 90: 10; dichloromethane:methanol), providing the titled compound as a deep red solid: high resolution mass spectrometry (ES+) m/z 455.1839 [(M+H)+; calculated for C25H23N6O3: 455.1826].
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[N:12]([CH2:19][CH3:20])[C:11]=2[N:10]=[C:9]1[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:32])([F:31])[F:30])[CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:34][C:35]1[O:39][N:38]=[CH:37][CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[I-]>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:34][C:35]3[O:39][N:38]=[CH:37][CH:36]=3)[C:13](=[O:18])[N:12]([CH2:19][CH3:20])[C:11]=2[N:10]=[C:9]1[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:31])([F:30])[F:32])[CH:23]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCc1ccno1
Reactant: CCn1c(=O)[nH]c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCn1c(=O)n(Cc2ccno2)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccccc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 12.4 %

Procedure:
To a solution of 7-benzyl-3-ethyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (40 mg, 0.090 mmol, intermediate 47) in DMF (3 mL) was added 5-(chloromethyl)isoxazole (30 mg, 0.256 mmol), followed by potassium carbonate (50 mg, 0.362 mmol) and TBAI (5 mg, 0.014 mmol). The reaction was stirred at 60° C. overnight. The mixture was cooled and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, and concentrated to give a crude product, which was purified by preparative HPLC to give 7-benzyl-3-ethyl-1-(isoxazol-5-ylmethyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (5.9 mg, 12.6% yield) as white solid. 1H-NMR (CD3OD) δ 8.33-8.32(d, 1H), 7.57-7.53(t, 1H), 7.47-7.45(d, 2H), 7.38-7.31(m, 5H), 7.25-7.23(d, 1H), 6.34-6.33(dd, 1H), 5.52(s, 2H), 5.36(s, 2H), 4.06-4.01(q, 2H), 1.27-1.24(t, 3H). LCMS retention time 3.269 min; LCMS MH+528.
Reaction SMILES: C(N1C=CN=C1)([N:3]1C=CN=C1)=O.[CH:13]1([O:18][C:19]2[CH:20]=[C:21]([CH:37]=[CH:38][C:39]=2[O:40][CH3:41])[CH2:22][C:23]2[O:24][C:25]3[C:31]([CH2:32][C:33]([OH:35])=O)=[CH:30][C:29]([Cl:36])=[CH:28][C:26]=3[N:27]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1.[NH4+].[OH-]>O1CCCC1>[CH:13]1([O:18][C:19]2[CH:20]=[C:21]([CH:37]=[CH:38][C:39]=2[O:40][CH3:41])[CH2:22][C:23]2[O:24][C:25]3[C:31]([CH2:32][C:33]([NH2:3])=[O:35])=[CH:30][C:29]([Cl:36])=[CH:28][C:26]=3[N:27]=2)[CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: COc1ccc(Cc2nc3cc(Cl)cc(CC(=O)O)c3o2)cc1OC1CCCC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(Cc2nc3cc(Cl)cc(CC(N)=O)c3o2)cc1OC1CCCC1
Reaction time: 1 h
Yield: 76.1 %

Procedure:
A solution of 1,1′-carbonyl diimidazole (0.31 g, 0.0019 mol) was dissolved in 15 ml of tetrahydrofuran and 2-(3-cyclopentyloxy-4-methoxybenzyl)-5-chlorobenzoxazole-7-acetic acid (1.14 g, 0.0027 mol) was added in a tetrahydrofuran (THF) solution. After stirring for 1 hour, the reaction mixture was treated with 2 ml of concentrated NH4OH and stirred a further 3.5 hours. The tetrahydrofuran was removed under reduced pressure and the remaining material was extracted with CH2Cl2. The organic layer was separated and washed with 50 ml of CH2Cl2. A crystalline solid (0.6 g) was isolated after drying and evaporating the CH2Cl2. The solid was recrystallized from 20 ml of CH3OH to yield 0.3 g of title compound, mp 162-164° C.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:10]([O:17][CH2:18][CH2:19][NH:20][C:21]1[CH:26]=[C:25]([CH3:27])[N:24]=[C:23](Cl)[C:22]=1[N+:29]([O-:31])=[O:30])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>COCCOCCOC.C(OCC)(=O)C>[CH2:10]([O:17][CH2:18][CH2:19][NH:20][C:21]1[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:22]=1[N+:29]([O-:31])=[O:30])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Oc1ccccc1
Reactant: Cc1cc(NCCOCc2ccccc2)c([N+](=O)[O-])c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOCCOC
Product: Cc1cc(NCCOCc2ccccc2)c([N+](=O)[O-])c(Oc2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
Under a nitrogen atmosphere, diglyme (20 mL) was added to sodium hydride (0.548 g, 13.7 mmol), which is available as a 60% dispersion in mineral oil, and the mixture was cooled to 0° C. A solution of phenol (1.35 g, 14.4 mmol) in diglyme (20 mL) was added, and the addition flask was rinsed with additional diglyme (2×5 mL), which was added to the reaction flask. The reaction became homogeneous and was stirred for 30 minutes. Solid [2-(benzyloxy)ethyl]-(2-chloro-6-methyl-3-nitropyridin-4-yl)amine (4.2 g, 13 mmol) was added, and the resulting dark solution was heated at 60° C. for 90 minutes. The reaction was allowed to cool and then slowly poured into water (500 mL) and stirred rapidly for 90 minutes. A yellow solid formed, which was isolated by filtration and dissolved in ethyl acetate. The solution was then dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide a yellow oil, which began to crystallize over three days. The product was triturated with hexane, and the resulting solid was isolated by filtration and dried for two hours under high vacuum at 55° C. to provide 4.44 g of [2-(benzyloxy)ethyl]-(6-methyl-3-nitro-2-phenoxy-pyridin-4-yl)amine as a yellow solid.
Reaction SMILES: C1COCC1.Br[C:7](Br)=[CH:8][CH2:9][CH2:10]/[CH:11]=[C:12](\[CH3:22])/[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[Li]CCCC>CCCCCC>[CH3:22]/[C:12](/[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:11]\[CH2:10][CH2:9][C:8]#[CH:7]
Reactant: CCCCCCCCC/C(C)=C/CCC=C(Br)Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C#CCC/C=C(\C)CCCCCCCCC
Temperature: 0 °C
Yield: 87.9 %

Procedure:
To a stirred and cooled THF (400 ml) solution of the (E)-1,1-dibromo-6-methyl-1,5-pentadecadiene (6) (37.0 g, 97.6 mmols), an n-hexane solution of n-BuLi (1.5 M, 150 ml, 225 mmols) was added dropwise at −70° C. under an Ar gas. The mixture was stirred for 1 hour at −70° C. and for 1.5 hours at room temperature. Then, the reaction mixture was poured into 1.5 liters of ice water, and extracted with n-hexane. The hexane solution was washed with water, dried with sodium sulfate, and concentrated in a vacuum. The residue was subjected to silica gel column chromatography, and eluted with n-hexane to obtain 18.9 g (88.0%) of (E)-6-methyl-5-pentadecen-1-yne (7) as oily matter.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Cl)=[CH:7][CH:6]=1.[CH:13]1[C:23]2[C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[CH2:20][C:19](=[O:28])[NH:18][C:17]=2[CH:16]=[CH:15][CH:14]=1.[Na+].[Cl-]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.ClCCl>[CH3:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][N:18]2[C:19](=[O:28])[CH2:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[C:23]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]2=3)=[CH:7][CH:6]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=C1Cc2ccccc2-c2ccccc2N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(CN2C(=O)Cc3ccccc3-c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 107.2 %

Procedure:
Tetrabutylammonium bromide (0.82 g), potassium hydroxide (1.7 g) and p-methoxybenzylchloride (4.3 g), in that order, were added to a suspension of 5H,7H-dibenzo[b,d]azepin-6-one (5.63 g) in THF (112.5 mL). The reaction mixture was stirred 3 hours at room temperature. Dichloromethane (250 mL) and half-saturated aqueous NaCl (1500 mL) were added. The phases were separated, the organic phase was washed with half-saturated aqueous NaCl (1000 mL) and the aqueous layers were extracted with dichloromethane (150 mL) three times. The combined organic layers were dried (MgSO4), concentrated under reduced pressure and dried under high vacuum affording 5-(4-methoxy-benzyl)-5H,7H-dibenzo[b,d]azepin-6-one (9.5 g, quant.) as a brown oil, which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH:9]=[CH2:10])=[CH:7][N:6]=[C:5]2[N:11]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=[CH:13][C:4]=12.I[C:23]1[CH:24]=[C:25]([CH:31]=[CH:32][C:33]=1[CH3:34])[C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[CH3:1][O:2][C:3]1[C:8](/[CH:9]=[CH:10]/[C:23]2[CH:24]=[C:25]([CH:31]=[CH:32][C:33]=2[CH3:34])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:7][N:6]=[C:5]2[N:11]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=[CH:13][C:4]=12
Reactant: C=Cc1cnc2c(ccn2COCC[Si](C)(C)C)c1OC
Reactant: CCOC(=O)c1ccc(C)c(I)c1
Product: CCOC(=O)c1ccc(C)c(/C=C/c2cnc3c(ccn3COCC[Si](C)(C)C)c2OC)c1
Yield: 57.8 %

Procedure:
(E)-ethyl 3-(2-(4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)vinyl)-4-methylbenzoate (302 mg, 58% yield) was prepared as described for Example 5-C starting from 4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-5-vinyl-1H-pyrrolo[2,3-b]pyridine (340 mg, 1.12 mmol) and ethyl 3-iodo-4-methylbenzoate (360 mg, 1.24 mmol). 1H NMR (600 MHz, CDCl3) δ 8.52 (s, 1H), 8.35 (d, J=1.2 Hz, 1H), 7.87 (dd, J=1.8, 7.8 Hz, 1H), 7.45 (d, J=16.2 Hz, 1H), 7.34 (d, J=16.2 Hz, 1H), 7.31-7.27 (m, 2H), 6.81 (d, J=3.6 Hz, 1H), 5.71 (s, 2H), 4.45 (q, J=7.2 Hz, 2H), 4.43 (s, 3H), 3.62 (t, J=8.4 Hz, 2H), 2.51 (s, 3H), 1.46 (t, J=7.2 Hz, 3H), 0.97 (t, J=8.4 Hz, 2H), 0 (s, 9H). MS m/z: 467 [M+1].
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H](C(O)=O)CC(C)C)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH3:27]>C1COCC1.O>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:14](=[O:15])[C@H:12]([CH2:11][CH:6]([CH3:7])[CH3:5])[NH2:27])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: N
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C[C@H](N)C(=O)NC(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 0.5 h
Yield: 36 %

Procedure:
A solution of N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-leucine, acid chloride (3.5 g, 10 mmol) in 10 mL of THF was charged with NH3 (29.6% water solution, 1.26 mL, 20 mmol) at room temperature. The reaction mixture was stirred for 30 min., then diluted with 100 mL of water and extracted with ethyl acetate (5×20 mL). The organic layers were combined, extracted with 10% potassium carbonate solution, washed with water, brine, dried and evaporated. Recrystallization of the product from ethanol afforded 1.26 g (36%) of N-(9-fluorenylmethoxycarbonyl)-L-leucine, amide as colorless solid, mp 79°-80° C.
Reaction SMILES: C[O:2][C:3](=[O:41])[C@H:4]([O:12][C:13]1[C:18]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:17][C:16]([C:24]2[C:36]3[C:35]([CH3:37])=[C:34]([CH3:38])[S:33][C:32]=3[C:31]([Br:39])=[C:30]3[C:25]=2[CH:26]=[CH:27][CH:28]=[CH:29]3)=[CH:15][C:14]=1[Br:40])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[K+]>O1CCCC1.CO>[Br:40][C:14]1[CH:15]=[C:16]([C:24]2[C:36]3[C:35]([CH3:37])=[C:34]([CH3:38])[S:33][C:32]=3[C:31]([Br:39])=[C:30]3[C:25]=2[CH:26]=[CH:27][CH:28]=[CH:29]3)[CH:17]=[C:18]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[C:13]=1[O:12][C@H:4]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:41])=[O:2]
Reactant: COC(=O)[C@@H](Cc1ccccc1)Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc1C1CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1sc2c(Br)c3ccccc3c(-c3cc(Br)c(O[C@H](Cc4ccccc4)C(=O)O)c(C4CCCC4)c3)c2c1C
Reaction time: 0.25 h
Yield: 97.3 %

Procedure:
To a solution of (2R)-2-[2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-cyclopentyl-phenoxy]-3-phenyl-propionic acid methyl ester (1.0 g, 1.5 mmol) in tetrahydrofuran (30 mL) and methanol (10 mL) at room temperature was added dropwise aqueous potassium hydroxide (3.0 mL of a 1 N solution, 3.0 mmol). After 4 h the reaction mixture was concentrated under reduced pressure. The residue was taken up in water (100 mL) and acidified with aqueous 10% hydrochloric acid. After stirring for 15 min the solid was filtered and washed with water:methanol (95:5). The solid was dried under a vacuum at 50° C. for 18 h to yield the title compound as a white solid (0.99 g, 100%): Opt. Rot. [a]25/D=+38.44° (9.624 mg/mL, MeOH); NMR (DMSO-d6): δ13.01 (broad s, 1H), 8.19 (d, 1H), 7.67-7.62 (m, 1H), 7.54-7.22 (m, 9H), 4.92 (m, 1H), 3.46 (m, 1H), 3.34 (m, 2H), 2.42 and 2.41 (two singlets 3H, rotational isomers), 1.99 (m, 1H), 1.98 (m, 1H), 1.72-1.27 (m containing two s at δ1.57 and 1.53 (rotational isomers), 6H); MS(−ESI): [M−H], 2 bromine isotope pattern, 675 (72%), 677 (100%), 679 (66%); Anal. Calc. for C34H30Br2O3S: C, 60.19; H, 4.46; N, 0.00. Found: C, 59.53; H, 4.35; N, −0.04.
Reaction SMILES: Cl.Cl.Br[C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][N:8]=[C:7]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[C:17]([CH3:29])[CH:16]=1.[S:30]1[CH:34]=[CH:33][CH:32]=[C:31]1B(OC(C)C)OC(C)C>>[CH3:29][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)[NH:14][C:7]1[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([C:31]3[S:30][CH:34]=[CH:33][CH:32]=3)[CH:5]=2)[N:10]=[CH:9][N:8]=1
Reactant: CC(C)OB(OC(C)C)c1cccs1
Reactant: Cc1cc(Nc2ncnc3ccc(Br)cc23)ccc1OCc1ccccn1
Agent: Cl
Product: Cc1cc(Nc2ncnc3ccc(-c4cccs4)cc23)ccc1OCc1ccccn1
Yield: 70 %

Procedure:
Using an analogous procedure to that described in Example 5, 6-bromo-4-[3-methyl-4-(2-pyridylmethoxy)anilino]quinazoline dihydrochloride salt was reacted with di-isopropyl 2-thienylboronate to give 4-[3-methyl-4-(2-pyridylmethoxy)anilino]-6-(2-thienyl)-quinazoline in 70% yield, m.p. 205-206° C.;