Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[C@@H:11]([O:12][CH2:13][CH2:14][O:15][CH3:16])[C:10]2[CH:9]=[CH:8][N:7]3[C:17]([CH3:21])=[C:18]([CH3:20])[N:19]=[C:6]3[C:5]=2[NH:4][C@@H:3]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[C:28]([O-])(=[O:30])[CH3:29].[Na+].C(OC(=O)C)(=O)C.[OH-].[Na+]>>[C:28]([O:1][C@H:2]1[C@@H:11]([O:12][CH2:13][CH2:14][O:15][CH3:16])[C:10]2[CH:9]=[CH:8][N:7]3[C:17]([CH3:21])=[C:18]([CH3:20])[N:19]=[C:6]3[C:5]=2[NH:4][C@@H:3]1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)[O-]
Reactant: COCCO[C@H]1c2ccn3c(C)c(C)nc3c2N[C@H](c2ccccc2)[C@H]1O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Product: COCCO[C@H]1c2ccn3c(C)c(C)nc3c2N[C@H](c2ccccc2)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 180.3 %

Procedure:
A mixture of 1 g of (7S,8R,9R)-8-hydroxy-7-(2-methoxyethoxy)-2,3-dimethyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine, 0.1 g of sodium acetate (anhydrous) and 12 ml of acetic anhydride is stirred vigorously at room temperature for 4 h, then poured onto ice water, neutralized with 2 molar aqueous sodium hydroxide solution and extracted three times with 50 ml of ethyl acetate each time, the collected organic extracts are dried over potassium carbonate, the solvent is stripped off in vacuo and the residue is well dried in a high vacuum. 0.9 g of the title compound is obtained.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][CH2:8][CH2:9][O:10][Si](C(C)(C)C)(C)C)[CH2:5][CH2:4][CH:3]=[CH:2]1.F>C(#N)C>[OH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:1]1[CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: CC(C)(C)[Si](C)(C)OCCCCC1C=CCC1
Agent: F
Solvent: CC#N
Product: OCCCCC1C=CCC1

Procedure:
The procedure followed is the same as that described in Example 12 substituting 3-(5-[(1,1-dimethylethyl)dimethylsiloxy]but-1-yl)cyclopentene {[4-(2-cyclopenten-1-yl)butoxy](1,1dimethylethyl)dimethylsilane} (100 g, 0.407 moles), 5% hydrofluoric acid (78 ml), acetonitrile (1500 ml). The crude product is kugelrohred under reduced pressure leaving a clear, colorless oil (51 g, 0.36 moles).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][N:12]=[C:11]([NH:14][C:15](=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19]Br)[CH:10]=2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[C:30]([N:33]1[CH2:39][CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)(=[O:32])[CH3:31].IC1C=CNN=1>CC(C)=O>[C:30]([N:33]1[CH2:39][CH2:38][CH2:37][N:36]([CH2:19][CH2:18][CH2:17][CH2:16][C:15]([NH:14][C:11]2[CH:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[NH:13][N:12]=2)=[O:21])[CH2:35][CH2:34]1)(=[O:32])[CH3:31]
Reactant: CC(=O)N1CCCNCC1
Reactant: COc1ccc(-c2cc(NC(=O)CCCCBr)n[nH]2)cc1
Agent: Ic1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Product: COc1ccc(-c2cc(NC(=O)CCCCN3CCCN(C(C)=O)CC3)n[nH]2)cc1
Temperature: 27.5 °C
Reaction time: 0.25 h

Procedure:
To a cylindrical, jacketed 3 L reactor equipped with nitrogen inerting, agitator, condenser/distillation head, and temperature control, 5-bromo-pentanoic acid [5-(4-methoxy-phenyl)-1H-pyrazol-3-yl]amide (0.15 kg, 0.426 mol), potassium carbonate (0.059 kg, 0.426 mol), potassium iodide (0.071 kg, 0.426 mol), and acetone (1.18 kg, 1.5 L) were added (at 20° C.) to form a white mixture. The mixture was stirred (235 rpm) at 25-30° C. for a minimum of 15 min. N-acetylhomopiperazine (0.062 kg, 0.057 L, 0.434 mol) was added via addition funnel to the reactor over a minimum of 45 min., maintaining the temperature in the range of 25-30° C. The addition funnel was rinsed with 0.05 L acetone. A white mixture persisted. The mixture was stirred (235 rpm) in the range of 25-30° C. for a minimum of 16 h, forming a white/yellow mixture. The reaction progress was monitored by HPLC and was considered complete when there was ≦2% of the starting material (bromopyrazole) and ≦2% of the iodopyrazole present.
Reaction SMILES: [Mg].Br[C:3]1[CH:14]=[CH:13][C:12]2=[C:15]3[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]3[C:9]([CH3:21])([CH3:20])[C:10]1[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=12>C1COCC1.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>[CH3:21][C:9]1([CH3:20])[C:8]2[C:15]3[C:4]([CH:5]=[CH:6][CH:7]=2)=[C:3]([C:3]2[CH:14]=[CH:13][C:12]4=[C:15]5[C:4]=2[CH:5]=[CH:6][CH:7]=[C:8]5[C:9]([CH3:20])([CH3:21])[C:10]2[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=24)[CH:14]=[CH:13][C:12]=3[C:11]2[CH:16]=[CH:17][CH:18]=[CH:19][C:10]1=2
Reactant: CC1(C)c2ccccc2-c2ccc(Br)c3cccc1c23
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: CC1(C)c2ccccc2-c2ccc(-c3ccc4c5c(cccc35)C(C)(C)c3ccccc3-4)c3cccc1c23
Reaction time: 1 h
Yield: 56 %

Procedure:
After addition of magnesium powder (659 mg, 27.1 mmol) to 200 mL of THF in a nitrogen atmosphere, the mixture was refluxed at the boiling point and thereafter a solution of the 3-bromo-7,7-dimethylbenzo[a]phenalene (17.5 g, 54.2 mmol) in 800 mL of THF was added dropwise and the mixture was stirred for 1 hour. Then, tetrakis(triphenylphosphine)palladium (624 mg, 0.542 mmol) was added to the reaction solution and the mixture was refluxed at the boiling point for 2 hours to obtain 3-(7,7-dimethylbenzo[a]phenalen-3-yl)7,7-dimethylbenzo[a]phenalene at a yield of 56%. The 3-(7,7-dimethylbenzo[a]phenalen-3-yl)7,7-dimethylbenzo[a]phenalene (3.00 g, 6.16 mmol) and anhydrous aluminum chloride (4.11 g, 30.8 mmol) were dispersed in 400 mL of chlorobenzene and the dispersion was heated to 80° C. and stirred for 5 hours to synthesize Illustrative Compound A-4 at a yield of 33%.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:15]=[N:14][C:13]([C:16]2[NH:17][C:18]([CH3:21])=[N:19][N:20]=2)=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2.Cl[C:23]([C:25]([O:27][CH3:28])=[O:26])=[O:24]>C(Cl)Cl.C[N+]([O-])=O>[CH3:28][O:27][C:25](=[O:26])[C:23]([C:9]1[C:8]2[C:12](=[C:13]([C:16]3[NH:17][C:18]([CH3:21])=[N:19][N:20]=3)[N:14]=[CH:15][C:7]=2[O:6][CH3:5])[NH:11][CH:10]=1)=[O:24]
Reactant: COc1cnc(-c2nnc(C)[nH]2)c2[nH]ccc12
Reactant: COC(=O)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: C[N+](=O)[O-]
Product: COC(=O)C(=O)c1c[nH]c2c(-c3nnc(C)[nH]3)ncc(OC)c12
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a solution of AlCl3 (0.321 g, 2.411 mmol) in CH2Cl2 (0.8 mL) and MeNO2 (0.2 mL) was added 4-methoxy-7-(5-methyl-1,3,4-triazol-2-yl)-6-azaindole (0.0435 g, 0.190 mmol) as a solid. After dissolution of the starting material (ca. 5 min), ClCOCO2Me (0.070 mL, 0.756 mmol) was added and the mixture was allowed to stir for 5 h. The mixture was then cooled at 0° C., quenched by the slow addition of 1 M aqueous NH4OAc and extracted with EtOAc (×3). The combined organic layers were washed (H2O, brine), dried (Na2SO4) and evaporated to give 4-methoxy-7-(5-methyl-1,3,4-triazol-2-yl)-6-azaindol-3-yl-oxoacetic acid methyl ester (0.0347 g, 60%: LCMS: m/e 316 (M+H)+. This material was dissolved in MeOH (2 mL) and treated with 2.5 M NaOH (0.2 mL, 0.5 mmol). The mixture was allowed to stir for 5 h, at which point the solvent was removed and the residue was diluted with H2O (2 mL). This mixture was acidified to pH 1 with 6 M HCl and the solution was lyophilized to give the title compound (0.062 g), which contained a nominal amount of inorganic salts. This material was used as such in the following step:
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([C:13]2[NH:17][C:16]3[CH:18]=[C:19]([C:22](=[O:34])[NH:23][C:24]4[CH:33]=[CH:32][C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:25]=4)[CH:20]=[CH:21][C:15]=3[N:14]=2)=[C:8]([Cl:35])[CH:7]=1.[OH-].[Na+].Cl>CO>[Cl:35][C:8]1[CH:7]=[C:6]([CH:11]=[C:10]([Cl:12])[C:9]=1[C:13]1[NH:17][C:16]2[CH:18]=[C:19]([C:22](=[O:34])[NH:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)[CH:20]=[CH:21][C:15]=2[N:14]=1)[O:5][CH2:4][C:3]([OH:36])=[O:2]
Reactant: COC(=O)COc1cc(Cl)c(-c2nc3ccc(C(=O)Nc4ccc5ccccc5n4)cc3[nH]2)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)COc1cc(Cl)c(-c2nc3ccc(C(=O)Nc4ccc5ccccc5n4)cc3[nH]2)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of {3,5-dichloro-4-[6-(quinolin-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-phenoxy}-acetic acid methyl ester (100 mg, 0.19 mmol) in MeOH (3 mL) was added 1N NaOH (3 mL) and the solution was stirred at ambient temperature for 3 h. The solution was carefully acidified to pH 3-4 with 1N HCl and the suspension was filtered, washed with water, and the pale yellow solid was dried in vacuum oven to give the title compound. 1H NMR (Methanol-d4, 400 MHz): δ 11.14 (s, 1H), 8.46 (s, 1H), 8.43 (q, 2H), 8.02 (dd, 1H), 7.97 (d, 1H), 7.91 (d, 1H), 7.76 (m, 2H), 7.55 (m, 1H), 7.32 (s, 2H), 4.93 (s, 2H). MS (m/z) 507.3 (M+1); Retention time: 1.11 min (Method 10).
Reaction SMILES: C(OC([NH:8][C:9]1([C:25](O)=[O:26])[CH2:14][CH2:13][N:12]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])(=[O:17])=[O:16])[CH2:11][CH2:10]1)=O)(C)(C)C.[F:28][C:29]([F:38])([F:37])[C:30]1[CH:31]=[C:32]([CH:34]=[CH:35][CH:36]=1)[NH2:33]>>[F:28][C:29]([F:37])([F:38])[C:30]1[CH:31]=[C:32]([NH:33][C:25]([C:9]2([NH2:8])[CH2:14][CH2:13][N:12]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:16])=[O:17])[CH2:11][CH2:10]2)=[O:26])[CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(S(=O)(=O)c2ccccc2Cl)CC1
Reactant: Nc1cccc(C(F)(F)F)c1
Product: NC1(C(=O)Nc2cccc(C(F)(F)F)c2)CCN(S(=O)(=O)c2ccccc2Cl)CC1

Procedure:
In analogy to the procedure of the synthesis of [4-(4-tert-Butyl-phenylcarbamoyl)-1-(toluene-4-sulfonyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (example 77, step 2) the title compound was prepared from 4-tert-Butoxycarbonylamino-1-(2-chloro-benzenesulfonyl)-piperidine-4-carboxylic acid through amide coupling with 3-trifluoromethyl-aniline (commercially available) followed by the removal of the protecting group with HCl in dioxane to afford the title compound after purification with preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. MS (m/e): 462.1 [(M+H)+].
Reaction SMILES: C[O:2][C:3](=[O:34])[C@@H:4]([O:31][CH2:32][CH3:33])[CH2:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([CH:27]([CH3:29])[CH3:28])=[CH:23][CH:22]=3)[O:18][C:19]=2[CH3:20])=[CH:8][C:7]=1[CH3:30].[Li+].[OH-]>>[CH2:32]([O:31][C@@H:4]([CH2:5][C:6]1[C:7]([CH3:30])=[CH:8][C:9]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:22]=[CH:23][C:24]([CH:27]([CH3:29])[CH3:28])=[CH:25][CH:26]=3)[O:18][C:19]=2[CH3:20])=[CH:10][C:11]=1[CH3:12])[C:3]([OH:34])=[O:2])[CH3:33]
Reactant: CCO[C@@H](Cc1c(C)cc(OCc2nc(-c3ccc(C(C)C)cc3)oc2C)cc1C)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Product: CCO[C@@H](Cc1c(C)cc(OCc2nc(-c3ccc(C(C)C)cc3)oc2C)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 1 g], (S)-2-ethoxy-3-{4-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2,6-dimethyl-phenyl}-propionic acid methyl ester was treated with LiOH to obtain (S)-2-ethoxy-3-{4-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2,6-dimethyl-phenyl}-propionic acid as colorless solid.
Reaction SMILES: P(N)(=O)([O-])[O-].[NH2:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[CH:16]2[C@:20]([CH3:22])([OH:21])[CH2:19][C@@H:18]([CH2:23][OH:24])[O:17]2)=[C:9]([O:25][CH3:26])[N:8]=1.C([Mg]Cl)(C)(C)C.Cl[C:34]1[CH:43]=[CH:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]=1[O:44][P:45](=[N:47][C@@H:48]([CH3:60])[C:49]([O:51][C@H:52]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[CH3:53])=[O:50])=[O:46]>C1COCC1>[NH2:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[CH:16]2[O:17][C@H:18]([CH2:23][O:24][C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:35]=3[O:44][P:45](=[N:47][C@@H:48]([CH3:60])[C:49]([O:51][C@H:52]([C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)[CH3:53])=[O:50])=[O:46])[CH2:19][C@:20]2([OH:21])[CH3:22])=[C:9]([O:25][CH3:26])[N:8]=1
Reactant: C[C@H](N=[P+]([O-])Oc1c(Cl)ccc2ccccc12)C(=O)O[C@@H](C)c1ccccc1
Reactant: COc1nc(N)nc2c1ncn2C1O[C@H](CO)C[C@@]1(C)O
Agent: CC(C)(C)[Mg]Cl
Agent: NP(=O)([O-])[O-]
Solvent: C1CCOC1
Product: COc1nc(N)nc2c1ncn2C1O[C@H](COc2ccc3ccccc3c2O[P+]([O-])=N[C@@H](C)C(=O)O[C@@H](C)c2ccccc2)C[C@@]1(C)O
Yield: 18.8 %

Procedure:
Using the general procedure for the synthesis of nucleoside 5′-phosphoramidates (Method A), to a solution of (3R,5S)-2-(2-amino-6-methoxy-9H-purin-9-yl)-5-(hydroxymethyl)-3-methyl-tetrahydrofuran-3-ol 93 mg (0.315 mmol) in 5 mL of THF was added tert-BuMgCl 0.63 mL (0.63 mmol) followed by (2S)-((S)-1-phenylethyl) 2-(chloro(naphthalen-1-yloxy)phosphorylamino)propanoate 282 mg (0.63 mmol) in 5 mL of THF. After work up and silica gel column chromatography, 40 mg of (2S)-((S)-1-phenylethyl) 2-((((2S,4R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-4-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)propanoate was obtained in a 19% yield, as an off-white solid. MS (ES+) m/e: 677.25 (MH+, 100%); Accurate mass: C33H38N6O8P calculated: 677.2489. found 677.2511.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[C:15]([O-])(O)=O.[Na+]>CO>[OH:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([O:9][CH3:15])=[O:8]
Reactant: O=C(O)c1cncc(O)c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)c1cncc(O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 5-hydroxynicotinic acid (10 g, 71.9 mmol) in MeOH (100 mL) was added sulfurous dichloride (1 mL) drop wise over 5 min. The resulting mixture was stirred at room temperature overnight. The resulted solution was added 100 mL of NaHCO3. The precipitate was filtrated and washed with MeOH for several cycles to give 8.5 g of A031-2 (75% yields), which was used for the nest step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[N:19]=[N:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2]>CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[N:19]=[N:20][C:21]([CH2:24][NH2:25])=[CH:22][CH:23]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3ccc(C#N)nn3)cc(C)c21
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC1OB(O)c2cc(Oc3ccc(CN)nn3)cc(C)c21
Reaction time: 1 h
Yield: 92.2 %

Procedure:
A mixture of [6-(6-cyano-pyridazin-3-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (0.3 g, 0.85 mmol) and 10% Pd/C (0.35 g) in EtOH (20 mL) was hydrogenated at 40 psi for 1 hour. The mixture was filtered through a pad of celite and concentrated in vacuo to give [6-(6-aminomethyl-pyridazin-3-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (0.28 g) which was used without further purification. 1H NMR (400 MHz, DMSO): δ 9.29 (s, 1H), 7.88 (d, J=8.8 Hz, 1H), 7.51 (d, J=9.6 Hz, 1H), 7.30 (d, J=2.0 Hz, 1H), 7.12 (d, J=1.2 Hz, 1H), 5.55 (dd, J=2.0, 9.2 Hz, 1H), 4.17 (s, 2H), 4.06 (q, J=7.6 Hz, 2H), 3.16 (dd, J=2.4, 15.6 Hz, 1H), 2.35-2.29 (m, 4H), 1.16 (t, J=7.6 Hz, 3H). MS (ESI) m/z=358 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]([O:10][CH3:11])=[O:9].C([Sn](CCCC)(CCCC)[C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1)CCC>C1(C)C=CC=CC=1.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>[N:18]1[CH:19]=[CH:20][N:21]=[CH:22][C:17]=1[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1cnccc1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cnccc1-c1cnccn1
Temperature: 100 °C
Reaction time: 3 h
Yield: 66.4 %

Procedure:
To a solution of methyl 4-chloro-3-pyridinecarboxylate (1200 mg; may be prepared as described in Intermediate 18) and 2-(tributylstannanyl)pyrazine (3000 mg) in toluene (20 mL), tetrakis(triphenylphosphine)palladium(0) (808 mg) in toluene (20 mL) was added and the reaction mixture was stirred at 100° C. for 3 h. Then the solvent was evaporated in vacuo and the crude product was added to a silica gel column and eluted with cyclohexane/EtOAc/MeOH=7/2.5/0.5. The evaporation of the collected fractions gave 1 g of the title compound as a white solid.
Reaction SMILES: [OH-].[Na+:2].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:10]([OH:14])(=[O:13])[CH:11]=[O:12].Cl>O>[OH:9][C:3]1[CH:8]=[CH:7][C:6]([CH:11]([OH:12])[C:10]([O-:14])=[O:13])=[CH:5][CH:4]=1.[Na+:2]
Reactant: Oc1ccccc1
Reactant: O=CC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])C(O)c1ccc(O)cc1
Reaction time: 3 h

Procedure:
Sodium hydroxide solution (50% w/w, ca 650 ml) was added dropwise over about one hour to a stirred mixture of phenol (1.098 kg), aqueous glyoxylic acid (50% w/w solution, 720 ml) and water (3 l) at 15° C. until a pH of 10.5 had been reached. The reaction mixture was then stirred and tested at 35° C. for 3 hours. The solution was adjusted to pH7 with concentrated hydrochloric acid and extracted at 35° C. with methyl isobutyl ketone to remove excess phenol. The aqueous solution was adjusted to pH2 with concentrated hydrochloric acid and continuously extracted in a counter-current extractor with ethyl acetate at an organic to aqueous flow rate of 1 to 1.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[C:11]([CH2:13][C:14]([NH:16][CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:18][CH2:19][CH3:20])=[O:15])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:33](Br)[CH:34]=[CH2:35]>>[CH2:35]([O:1][C:2]1[CH:12]=[C:11]([CH2:13][C:14]([NH:16][CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:18][CH2:19][CH3:20])=[O:15])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:34]=[CH2:33]
Reactant: C=CCBr
Reactant: CCCC(NC(=O)Cc1ccc(C(=O)OCC)c(O)c1)c1ccccc1N1CCCCC1
Product: C=CCOc1cc(CC(=O)NC(CCC)c2ccccc2N2CCCCC2)ccc1C(=O)OCC

Procedure:
Prepared from ethyl 2-hydroxy-4-[N-{1-(2-piperidinophenyl)-1-butyl}-aminocarbonylmethyl]-benzoate, using allyl bromide.
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13](=[O:16])[N:12]([CH3:17])[C:11]=1[NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[F:26])=[O:9])=C.COC(C1C=CC(=O)N(C)C=1NC1C=CC(C)=CC=1F)=O.C(OCCON)=C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[OH:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13](=[O:16])[N:12]([CH3:17])[C:11]=1[NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[F:26])=[O:9]
Reactant: C=COCCONC(=O)c1ccc(=O)n(C)c1Nc1ccc(C)cc1F
Agent: C=COCCON
Agent: COC(=O)c1ccc(=O)n(C)c1Nc1ccc(C)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: C1CCOC1
Product: Cc1ccc(Nc2c(C(=O)NOCCO)ccc(=O)n2C)c(F)c1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 77 %

Procedure:
Preparation of 2-(2-fluoro-4-methylphenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (2-vinyloxyethoxy)-amide: To a solution of 2-(2-fluoro-4-methylphenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (0.050 g, 0.17 mmol) in THF (1.5 mL) under N2 was added O-(2-vinyloxy-ethyl)-hydroxylamine (0.044 g, 0.43 mmol). The solution was cooled to 0° C. and lithium bis(trimethylsilyl)amide (0.86 mL, 0.86 mmol, 1 M solution in hexanes) was added dropwise. The reaction mixture was warmed to room temperature. After stirring for 40 minutes, the reaction mixture was quenched by the addition of NaHCO3 and partitioned between EtOAc and saturated NaCl. The layers were separated and the aqueous layer was reextracted with EtOAc. The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure. Purification by flash column chromatography (methylene chloride/methanol, 20:1) gave 0.048 g (77%) pure desired product as an off-white foamy solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.C(O)C.[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25]N.C(N)([NH2:31])CC>C(O)C.O>[CH3:21][N:22]([CH3:27])[CH:23]([NH2:31])[CH2:24][CH3:25].[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=2)([CH3:10])[CH3:9])=[CH:6][CH:7]=1
Reactant: CN(C)CCCN
Reactant: CCC(N)N
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Solvent: CCO
Solvent: O
Product: CCC(N)N(C)C

Procedure:
A 0.05 mole sample of bis-phenol A was dissolved in an ethanol-water solution containing 95% ethanol. This solution then was added dropwise to a 0.05 mole fraction of N,N-dimethyl-1,3-propanediamine sample dispersed in 50 milliliters of an ethanol-water solution containing 95% ethanol. The addition of the bis-phenol A fraction to the propanediamine sample was at room temperature (70° F.) over a 15 minute period. There was a slight exotherm during the addition. After all the bis-phenol A was added, the solution was stirred for an hour and then the solvent flashed using a rotary vacuum distillation apparatus. The residual solids were transferred to a vacuum oven to dry, and a N,N-dimethylpropanediamine salt of bis-phenol A was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[CH:14]=[C:13]3[O:18][CH2:19][O:20][C:12]3=[CH:11][C:10]=2[NH:9][CH:8]=1)=[O:6].[H-].[Na+].Br.Br[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[CH:14]=[C:13]3[O:18][CH2:19][O:20][C:12]3=[CH:11][C:10]=2[N:9]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[CH:8]=1)=[O:6]
Reactant: Cc1ccc(C(=O)c2c[nH]c3cc4c(cc3c2=O)OCO4)cc1C
Reactant: BrCc1ccccn1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2cn(Cc3ccccn3)c3cc4c(cc3c2=O)OCO4)cc1C

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 71 mg (0.22 mmol) of 7-(3,4-dimethyl-benzoyl)-5H-[1,3]dioxolo[4,5-g]quinolin-8-one, 23 mg of 60% sodium hydride, 72 mg of 2-bromomethylpyridine hydrobromide and 1.3 mL of N,N-dimethylformamide. Yield: 75 mg of a white solid: LC-MSD, m/z for C25H20N2O4 [M+H]+=413.5; HPLC retention time: 2.1 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=1.C([Li])CCC.[CH2:15]([Sn:19](Cl)([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH3:18]>CCOCC>[CH2:24]([Sn:19]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:20][CH2:21][CH2:22][CH3:23])[C:2]1[N:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: COc1cccc(Br)n1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1cccc(OC)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution containing 2-bromo-6-methoxypyridine (0.65 mL, 5.3 mmol) in ether (11 mL) at −78° C. was treated with n-butyllithium (4.0 mL, 1.6 M in hexanes) dropwise, warmed to 0° C. for 10 minutes, cooled to −78° C., treated with tributyltin chloride (2.25 mL, 8.30 mmol), stirred at −78° C. for 0.5 hours, and then at 0° C. for 0.5 hours. The reaction was quenched with saturated ammonium chloride solution and partitioned between ether and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated to give the title compound.