Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][CH2:8][CH2:9]C1C=C(S([O-])(=O)=O)C=CC=1C.[OH:21][C:22]1[C:23]([S:28]([NH2:31])(=[O:30])=[O:29])=[N:24][CH:25]=[CH:26][CH:27]=1>CC(N(C)C)=O>[Cl:7][CH2:8][CH2:9][O:21][C:22]1[C:23]([S:28]([NH2:31])(=[O:30])=[O:29])=[N:24][CH:25]=[CH:26][CH:27]=1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1CCCl
Reactant: NS(=O)(=O)c1ncccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: NS(=O)(=O)c1ncccc1OCCCl
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 61 %

Procedure:
First 17.9 g of potassium carbonate and then 28.14 g of 2-(2-chloroethyl)-toluene-4-sulfonate are added, with stirring, to a solution of 17.4 g of 3-hydroxy-pyrid-2-ylsulfonamide in 240 ml of dimethylacetamide. The reaction mixture is stirred for 1.5 hours at 80° C. and then cooled and filtered. The filtration residue is washed with acetonitrile. The filtrate and the washing liquid are adjusted to pH 5-6 with trifluoroacetic acid, filtered and concentrated using a rotary evaporator. For purification the residue is chromatographed on a silica gel column using ethyl acetate/n-hexane 4/1. Removal of the eluant by evaporation yields 14.42 g of the above sulfonamide in the form of colourless crystals which melt at 136°-138° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([O:16]CC2C=CC=CC=2)[C:10]=1[C:24](=[O:26])[CH3:25])C1C=CC=CC=1.[CH:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[CH:37]=O>>[OH:16][C:11]1[CH:12]=[C:13]([CH3:15])[CH:14]=[C:9]([OH:8])[C:10]=1[C:24](=[O:26])[CH2:25][CH2:37][C:28]1[CH:29]=[CH:30][C:31]2[CH2:32][CH2:33][CH2:34][CH2:35][C:36]=2[CH:27]=1
Reactant: CC(=O)c1c(OCc2ccccc2)cc(C)cc1OCc1ccccc1
Reactant: O=Cc1ccc2ccccc2c1
Product: Cc1cc(O)c(C(=O)CCc2ccc3c(c2)CCCC3)c(O)c1

Procedure:
The intermediate, 1-(2,6-bis-benzyloxy-4-methyl-phenyl)-ethanone, was treated with 2-naphthaldehyde as described in Example 1, Part B. Subsequent catalytic hydrogenation as described in Example 1, Part C, provided 1-(2,6-Dihydroxy-4-methyl-phenyl)-3-(5,6,7,8-tetrahydro-naphthalen-2-yl)-propan-1-one as a by-product. Further treatment of this by-product as described in Example 1, Part D and E, afforded the title compound. 1HNMR (400 MHz, CD3OD) δ 7.02 (s, 1H), 6.93 (m, 2H), 6.87 (s, 1H) 6.61 (s, 1H), 5.24 (d, J=7.73 Hz, 1H), 3.94 (d, J=12.05 Hz, 1H), 3.75–3.34 (m, 5H), 3.25–2.72 (m, 8H), 2.43 (s, 3H), 1.81–1.77 (m, 4H). MS: m/z (MH+) 469.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([OH:13])=O)=[CH:8][C:7]=2[CH:14]=1)#[N:2].[NH2:15][C:16]1[CH:28]=[CH:27][C:19]([O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][CH:17]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>CN(C)C=O.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:27][CH:28]=3)=[O:13])=[CH:8][C:7]=2[CH:14]=1)#[N:2]
Reactant: N#Cc1ccc2oc(C(=O)O)cc2c1
Reactant: CCOC(=O)COc1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc(NC(=O)c2cc3cc(C#N)ccc3o2)cc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 92.3 %

Procedure:
5-Cyano-2-benzofurancarboxylic acid (830 mg, 4.43 mmol) and ethyl 4-aminophenoxyacetate (910 mg, 4.66 mmol) were dissolved in N,N-dimethylformamide (40 ml), and 1-hydroxy-1H-benzotriazole (630 mg, 4.66 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (893 mg, 4.66 mmol) were added. The mixture was stirred at room temperature for 13 hours. Water (100 ml) was added to the reaction mixture. The resulting precipitate was collected by filtration and washed with water to give 1.49 g of ethyl 4-[(5-cyano-2-benzofuranyl)carbonylamino]phenoxyacetate as a colorless solid (92%).
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:21]=[CH:20][C:7]([N:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16](=[O:19])(=[O:18])[NH2:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)[CH3:2].C[Si]([C:26]#[N:27])(C)C>>[CH2:1]([S:3][C:4]1[CH:21]=[CH:20][C:7]([NH:8][CH:9]([C:10]2[CH:15]=[CH:14][C:13]([S:16](=[O:19])(=[O:18])[NH2:17])=[CH:12][CH:11]=2)[C:26]#[N:27])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCSc1ccc(N=Cc2ccc(S(N)(=O)=O)cc2)cc1
Reactant: C[Si](C)(C)C#N
Product: CCSc1ccc(NC(C#N)c2ccc(S(N)(=O)=O)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(ii), but using 4-ethylthio-N-(4-sulfamoylbenzylidene)aniline [prepared as described in step (i) above] and trimethylsilyl cyanide as starting materials, the title compound was obtained as a yellow powder (yield 100%).
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].N[C:23]1[CH:32]=[CH:31][C:30]([OH:33])=[C:29]2[C:24]=1[CH:25]=[CH:26][CH:27]=[N:28]2>C(O)C>[C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[NH:19][C:23]1[CH:32]=[CH:31][C:30]([OH:33])=[C:29]2[C:24]=1[CH:25]=[CH:26][CH:27]=[N:28]2)(=[O:3])[CH3:2]
Reactant: CCn1nc(-c2ccccc2)c(C(C)=O)c([N+](=O)[O-])c1=O
Reactant: Nc1ccc(O)c2ncccc12
Solvent: CCO
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2ccc(O)c3ncccc23)c1=O
Temperature: 25 °C
Reaction time: 40 h
Yield: 89.8 %

Procedure:
To a stirred solution of 80 mg (0.278 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) in ethanol (4 mL), 5-amino-8-quinolinol (67 mg, 0.417 mmol) was added. The resulting mixture was stirred at room temperature during 40 hours and the final product was collected by filtration and washed with diethylether to yield the title compound (100 mg, 90% yield).
Reaction SMILES: [Br:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.C(N(CC)CC)C.[CH2:17]([O:24][CH2:25][C:26](Cl)=[O:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[CH2:17]([O:24][CH2:25][C:26]([NH:8][C:7]1[C:2]([Br:1])=[N:3][CH:4]=[C:5]([Br:9])[CH:6]=1)=[O:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1cc(Br)cnc1Br
Reactant: O=C(Cl)COCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(COCc1ccccc1)Nc1cc(Br)cnc1Br
Temperature: 0 °C
Reaction time: 12 h
Yield: 23.4 %

Procedure:
To the solution of 2,5-Dibromo-pyridin-3-ylamine (8.6 g, 34.12 mmol) in 50 ml of DCM was added triethylamine (5.3 ml, 37.53 mmol). Cooled the reaction mixture to 0° C. To this added the solution of 2-benzyloxy acetyl chloride (7.45 g, 40.95 mmol) in 35 ml of DCM. The reaction mixture was stirred at 25° C. for 12 hr. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure. The residue was purified by column chromatography on silica (60-120 M) using ethyl acetate/hexane (10:90) as the eluent to provide the title compound (3.2 g, 24.17%).
Reaction SMILES: [CH2:1]([C:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2].Br[C:11]1[C:12](=[O:24])[N:13]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([CH3:17])=[CH:15][N:16]=1>[N+](C1C=CC=CC=1)([O-])=O>[CH2:1]([C:3]1[C:8]([NH:9][C:11]2[C:12](=[O:24])[N:13]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([CH3:17])=[CH:15][N:16]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2]
Reactant: CCOC(=O)Cn1c(C)cnc(Br)c1=O
Reactant: CCc1ncccc1N
Solvent: O=[N+]([O-])c1ccccc1
Product: CCOC(=O)Cn1c(C)cnc(Nc2cccnc2CC)c1=O
Temperature: 200 °C

Procedure:
A mixture of 2-ethyl-3-aminopyridine (0.35 g, 2.8 mMol, 2 eq) from step 2 above and 3-bromo-6-methyl-1-(ethoxycarbonylmethyl)pyrazinone (0.39 g, 1.4 mMol) in 1 mL of nitrobenzene was heated at 200 ° C. for 2 h. The reaction was concentrated in vacuo and the residue purified by flash silica gel chromatography using 1% methanol in methylene chloride as an eluent to afford the title compound as a yellow oil that crystallizes upon sitting. (0.058 g; HPLC RT=4.45 min, method A).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[N:10]=[C:9](Cl)[C:8]([Cl:12])=[C:7]([O:13][CH3:14])[N:6]=1.O.C(OCC)(=O)C.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[N:6]=[C:7]([O:13][CH3:14])[C:8]([Cl:12])=[C:9]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:10]=1
Reactant: COC(=O)Cc1nc(Cl)c(Cl)c(OC)n1
Reactant: C1COCCN1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1nc(OC)c(Cl)c(N2CCOCC2)n1

Procedure:
A solution of 4.08 g of (4,5-dichloro-6-methoxypyrimidin-2-yl)acetic acid methyl ester in 35 ml of morpholine is stirred at ambient temperature for one and a half hours. The reaction medium is concentrated under reduced pressure. The residue obtained is taken up with 50 ml of water and 200 ml of ethyl acetate. After settling out, the organic phase is dried over magnesium sulfate, filtered, and then concentrated under reduced pressure so as to give 4.61 g of (5-chloro-4-methoxy-6-morpholin-4-ylpyrimidin-2-yl)acetic acid methyl ester in the form of a beige solid, the characteristics of which are the following:
Reaction SMILES: [C:1]([O:4][C:5]1([CH2:11][CH3:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2].[CH:13]12[CH2:19][CH:16]([CH:17]=[CH:18]1)[CH2:15][CH:14]2[CH2:20][C:21](=[O:23])[CH3:22]>>[OH:23][C:21]([CH3:22])([CH2:20][CH:14]1[CH2:15][CH:16]2[CH2:19][CH:13]1[CH:18]=[CH:17]2)[CH2:2][C:1]([O:4][C:5]1([CH2:11][CH3:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:3]
Reactant: CCC1(OC(C)=O)CCCCC1
Reactant: CC(=O)CC1CC2C=CC1C2
Product: CCC1(OC(=O)CC(C)(O)CC2CC3C=CC2C3)CCCCC1
Yield: 92 %

Procedure:
The procedure of Synthesis Example 1 was repeated except that 1-ethylcyclohexyl acetate was used instead of 1-ethylcyclopentyl acetate, and 3-(5-norbornen-2-yl)acetone was used instead of 5-norbornene-2-carbaldehyde. There was obtained 1-ethylcyclohexyl 3-hydroxy-3-methyl-4-(5-norbornen-2-yl)butyrate. Yield 92%.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[NH2:48][CH:49]1[CH2:55][CH2:54][S:53][CH:52]2[CH2:56][CH2:57][CH2:58][CH:59]([CH2:60][CH3:61])[N:51]2[C:50]1=[O:62]>>[CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])[C:19]1=[O:33])=[O:16])[C:9]([NH:48][C@H:49]1[CH2:55][CH2:54][S:53][C@H:52]2[CH2:56][CH2:57][CH2:58][C@@H:59]([CH2:60][CH3:61])[N:51]2[C:50]1=[O:62])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC1CCCC2SCCC(N)C(=O)N12
Reactant: COc1ccccc1N1CCCC[C@H](NC(=O)[C@H](CC[C@H](Cc2ccccc2)C(=O)O)Cc2ccccc2)C1=O
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCCCN(c4ccccc4OC)C3=O)Cc3ccccc3)C(=O)N12

Procedure:
(2R,5R)-2,5-Dibenzyl-N1-((4S,7R,10aS)-7-ethyl-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-yl)-N6-((S)-1-(2-methoxyphenyl)-2-oxoazepan-3-yl)hexanediamide was synthesized as described in General Procedure H using Intermediate 70 (36 mg, 0.067 mmol) and Intermediate 74 (23 mg, 0.067 mmol) to give a white solid (25 mg, 49% yield). Anal. Calcd. for C44H56N4O5S m/z 752.7. found: 753.6 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.41-7.07 (m, 11H), 7.07-6.87 (m, 3H), 5.24 (s, 1H), 5.00-4.84 (m, 1H), 4.81-4.69 (m, 1H), 4.38-4.26 (m, 1H), 4.09-3.83 (m, 1H), 3.79 (d, J=3.5 Hz, 3H), 3.47-3.27 (m, 1H), 3.22-3.03 (m, 1H), 2.90-2.54 (m, 5H), 2.45-2.28 (m, 2H), 2.23-1.94 (m, 11H), 1.93-1.76 (m, 3H), 1.77-1.59 (m, 4H), 1.50 (d, J=29.0 Hz, 3H), 1.39-1.22 (m, 1H), 0.97-0.82 (m, 3H).
Reaction SMILES: [CH3:1][C:2]([O:4][C:5]([CH3:7])=O)=[O:3].[N+:8]([C:11]1[CH:12]=[CH:13][C:14]([O:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[O:24][CH:23]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)CC3O)=[N:15][CH:16]=1)([O-:10])=[O:9]>N1C=CC=CC=1>[N+:8]([C:11]1[CH:12]=[CH:13][C:14]([O:17][C:18]2[CH:27]=[C:26]3[C:25](=[CH:20][CH:19]=2)[O:24][CH:23]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:7][CH:5]3[O:4][C:2](=[O:3])[CH3:1])=[N:15][CH:16]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)C(O)CC(c2ccccc2)O3)nc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC1CC(c2ccccc2)Oc2ccc(Oc3ccc([N+](=O)[O-])cn3)cc21
Temperature: 0 °C

Procedure:
Acetanhydride (0.26 ml) was added dropwise into a solution of 100 mg of 6-(5-nitropyridin-2-yloxy)-2-phenylchroman-4-ol (Example 8(b)) in dry pyridine. The reaction mixture was refluxed for 1½ hours. It was then poured in ice-water and extracted with ethyl acetate. The organic phase was washed with 1 M HCl-solution, water and saturated NaCl-solution. It was then dried with MgSO4 and evaporated to dryness. 1H NMR (400 MHz, d6-DMSO) δ: 9.05 (d, 1H, J 2.8 Hz), 8.61 (dd, 1H, J 9.1, 2.8 Hz), 7.52-7.35 (m, 5H), 7.23 (d, 1H, J 9.1 Hz), 7.14-7.10 (m, 2H), 6.98 (d, 1H, J 8.5 Hz), 6.18 (dd, 1H, J 10.1, 6.4 Hz), 5.44(dd, 1H, J 11.4, 1.4Hz), 2.51 (m, 1H), 2.15 (m, 1H), 2.05 (s, 3H).
Reaction SMILES: [OH-].[K+].O.Cl[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][N+:6]=1[O-:12].[CH2:13]([SH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([S:20][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N+:6]([O-:12])[CH:7]=1
Reactant: [O-][n+]1cc(Cl)ccc1Cl
Reactant: SCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: [O-][n+]1cc(Cl)ccc1SCc1ccccc1
Temperature: 25 °C
Yield: 59.6 %

Procedure:
A solution consisting of 1.1 g (0.016 mole) of 85% KOH pellets, 50 ml of ethanol, and 0.5 ml of water was prepared. To this solution was added slowly, with stirring at room temperature, a mixture of 3.3 g (0.02 mole) of 2,5-dichloropyridine-N-oxide and 2.5 g (0.02 mole) of benzylmercaptan dissolved in 25 ml of ethanol. The reaction mixture was heated to about 60° C. for 2 hours and then evaporated to dryness. The residue was taken up in water and chloroform, the phases separated and the chloroform phase was dried over Na2SO4. The Na2SO4 was filtered off and the chloroform evaporated to leave a solid. The solid was recrystallized from ethanol to give 3.0 g of material, having a melting point of 130-133° C. Recovery was 2.2 g. The structure was confirmed by its IR spectrum.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][NH2+:13][CH3:14])[CH:6]=[CH:5]2.[Br-].C(=O)(O)[O-].[Na+]>O>[CH3:14][NH:13][CH2:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([OH:1])[CH:11]=[CH:10]2
Reactant: C[NH2+]Cc1ccc2cc(O)ccc2c1
Agent: O=C([O-])O
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: CNCc1ccc2cc(O)ccc2c1
Yield: 80 %

Procedure:
(6-Hydroxy-naphthalene-2-ylmethyl)-methyl-ammonium; bromide (9 g, 33.56 mmol), prepared in step 3 of Example 31, was taken up in 300 mL of water and made basic by the addition of with 5% sodium bicarbonate. Some solid remained in the solution, which was removed by filtration. The filtrate was extracted with ethyl acetate multiple times. The organic extracts were combined, dried (MgSO4) and the solvent removed under reduced pressure to give 6-methylaminomethyl-naphthalene-2-ol (5 g, 80%) as a tan solid, mp 168-169° C.
Reaction SMILES: C([O:3][CH3:4])=O.[CH3:5][C:6]1([C:13](=O)[CH3:14])[CH2:9][C:8]2([CH2:12][CH2:11][CH2:10]2)[CH2:7]1.[H-].[Na+]>CCOCC.CO>[CH3:5][C:6]1([CH:13]([CH:14]=[CH:4][OH:3])[CH2:14][CH2:13][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:9][C:8]2([CH2:12][CH2:11][CH2:10]2)[CH2:7]1
Reactant: COC=O
Reactant: CC(=O)C1(C)CC2(CCC2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: CCCCCCC(C=CO)C1(C)CC2(CCC2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.6 %

Procedure:
A solution of 7.8 g (130.0 mmol) methyl formate and 4.91 g (32.4 mmol) of 2-methyl-2-acetylspiro[3.3]heptane in 8.0 ml of dry ether was dropped into a slurry of 1.2 g of sodium hydride in 180 ml of ether. A few drops of MeOH were added and the reaction mixture stirred for 1.5 hr at 25° C. The reaction mixture was cooled to -10° C and the reaction quenched by slow addition of water. The layers were separated and the aqueous layer extracted twice with ether. The combined organic extracts were washed with water and 1 N NaOH. The combined aqueous layers were acidified with 6 N HCl and extracted with ether. The ether extracts were washed with brine, then dried (MgSO4), filtered and evaporated in vacuo to yield 4.0 g of (2-methylspiro[3.3]hept-2-yl)(2-hydroxyvinyl)heptane as a yellow oil (69.5%).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].Br[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][N:14]([C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=1[CH3:30])[C:23]([O:25][CH3:26])=[O:24])[C:13]2=[O:31]>>[CH3:30][C:29]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][C:20]=1[N:14]1[C:13](=[O:31])[C:12]2[C:17](=[CH:18][CH:19]=[C:10]([N:6]3[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5]3)[CH:11]=2)[N:16]=[CH:15]1
Reactant: CCN1CCNCC1
Reactant: COC(=O)c1ccc(C)c(-n2cnc3ccc(Br)cc3c2=O)c1
Product: CCN1CCN(c2ccc3ncn(-c4cc(C(=O)OC)ccc4C)c(=O)c3c2)CC1

Procedure:
Using an analogous procedure to that described paragraph (B) in the portion of Example 1 which is concerned with the preparation of starting material N-ethylpiperazine was reacted with methyl 3-(6-bromo-4-oxoquinazolin-3(4H)-yl)-4-methylbenzoate to give methyl 4-methyl-3-[6-(4-ethylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]benzoate; NMR Spectrum: (DMSOd6) 1.05 (t, 3H), 2.17 (s, 3H), 2.40 (m, 2H), 2.53 (m, 4H), 3.29 (m, 4H), 3.87 (s, 3H), 7.48 (s, 1H), 7.63 (m, 3H), 7.97 (s, 1H), 8.02 (d, 1H), 8.10 (d, 1H); Mass Spectrum: M+H+ 407.
Reaction SMILES: [OH:1][CH2:2]/[CH:3]=[C:4](/[CH2:6][CH2:7]/[CH:8]=[C:9](/[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])\[CH3:10])\[CH3:5].[N+](=[CH:19][P:20](=[O:25])([O:23][CH3:24])[O:21][CH3:22])=[N-]>>[CH3:5]/[C:4](/[CH2:6][CH2:7]/[CH:8]=[C:9](\[CH3:10])/[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])=[CH:3]\[CH2:2][O:1][CH2:19][P:20](=[O:25])([O:23][CH3:24])[O:21][CH3:22]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CO
Reactant: COP(=O)(C=[N+]=[N-])OC
Product: COP(=O)(COC/C=C(\C)CC/C=C(\C)CCC=C(C)C)OC
Temperature: 25 °C
Yield: 36.4 %

Procedure:
(E,E)-Farnesol, (5.0 mmol, 1.11 g, 1.26 ml) was stirred under argon in 10 ml of dry deoxygenated benzene (10 ml) and treated in one portion with ##STR87## (1.0 mmol, 0.442 g). The dark blue/green solution was stirred at room temperature and a solution of (1.5 g, 10.0 mmol) of dimethyl diazomethylphosphonate (prepared according to D. Seyferth et al, J. Org. Chem., 1971, vol. 36, No. 10, pages 1379 to 1386) in 20 ml of dry, deoxygenated benzene was added dropwise over 4 hours via syringe pump. After addition, the reaction mixture was stirred an additional 45 minutes. The reaction mixture was stripped of solvent and applied as a 75% ethyl acetate/Hexane solution to a flash chromatography column (50 mm diameter, 6" of silica gel) eluted with 75% ethyl acetate/hexane to afford 0.627 g, (36% yield), of the ether as a dark blue/green oil.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=O.Cl.[CH3:12][NH:13][C@@H:14]([CH2:19][CH2:20][CH:21]=[CH2:22])[C:15]([O:17][CH3:18])=[O:16]>>[F:9][C:2]([F:1])([F:10])[CH2:3][CH2:4][CH2:5][C:6]([N:13]([C@@H:14]([CH2:19][CH2:20][CH:21]=[CH2:22])[C:15]([O:17][CH3:18])=[O:16])[CH3:12])=[O:8]
Reactant: C=CCC[C@H](NC)C(=O)OC
Reactant: O=C(O)CCCC(F)(F)F
Agent: Cl
Product: C=CCC[C@@H](C(=O)OC)N(C)C(=O)CCCC(F)(F)F
Yield: 65 %

Procedure:
Step L (1): 5,5,5-Trifluoropentanoic acid and (S)-methyl 2-(methylamino)hex-5-enoate hydrochloride from Step K (2) were coupled according to the conditions described in Step A (1). The crude reaction products were purified by silica-gel column chromatography to give 276 mg (65% yield) of (S)-methyl 2-(5,5,5-trifluoro-N-methylpentanamido)hex-5-enoate. LC-MS (M+H)+=296.3; 1H NMR (500 MHz, CDCl3) δ ppm 1.73-1.83 (m, 1H) 1.84-2.25 (m, 7H) 2.37-2.52 (m, 2H) 2.78-2.96 (m, 3H) 3.66-3.75 (m, 3H) 4.94-5.09 (m, 2H) 5.17 (dd, J=10.53, 4.73 Hz, 1H) 5.70-5.84 (m, J=6.71 Hz, 1H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9])[CH:2]1[O:4][CH2:3]1.S(=O)(=O)(O)[OH:12]>CC(C)=O>[CH3:9][CH:8]([CH3:10])[CH2:7][CH2:6][O:5][CH:1]([OH:12])[CH:2]([OH:4])[CH3:3]
Reactant: CC(C)CCOCC1CO1
Reactant: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CC(C)CCOC(O)C(C)O

Procedure:
The thus obtained 3-methylbutyl glycidyl ether (100 g), acetone (200 ml) and a 3% sulfuric acid aqueous solution (100 ml) were refluxed for 2 hours. Then, after concentration at 50° C./26 hPa, toluene (200 ml) was added to the residue and the resulting mixture was washed with a 3% sodium hydroxide aqueous solution (170 g). The mixture was further washed with saturated brine (150 g) three times and concentrated, and the concentrate was purified by distillation to give 3-methylbutoxypropane-1,2-diol (63 g) (bp: 115–116° C./2.6 hPa).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.[C:13]1([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:22]3[CH2:23][CH2:24][CH:19]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:20][CH2:21]3)[N:10]=2)[CH:7]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: ClCc1cn2cc(Cl)ccc2n1
Solvent: C1CCOC1
Product: Clc1ccc2nc(CN3CCC(c4ccccc4)CC3)cn2c1
Yield: 34 %

Procedure:
Following the general procedure of Example 39, Step 2 and making non-critical variations, 6-chloro-2-(chloromethyl)imidazo[1,2-α]pyridine (Example 4, Step 1; 0.307 g), 4-phenylpiperidine (Aldrich or Chart J; 0.2955 g), and THF (2 mL) are converted to product, which is chromatographed on silica gel using methanol/dichlormethane (4/96), followed by crystallization from ethyl acetate, to give 0.169 g of the title compound; mp 132-133° C.; MS m/z 325; IR (mineral oil) 1073, 801, 696, 1324, 1501 cm-1 ; 1H NMR (CDCl3) δ1.83, 2.20, 2.51, 3.14, 3.75, 7.11, 7.24, 7.52, 7.54, 8.13.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([NH:10][C:11]3[O:12][CH2:13][C:14]4[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1.[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH:1]1([C:4]2[CH:5]=[C:6]([NH:10][C:11]3[O:12][CH2:13][C:14]4[CH:20]=[C:19]([NH:21][S:28]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)(=[O:30])=[O:29])[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1ccc2c(c1)COC(Nc1cccc(C3CC3)c1)=N2
Product: O=S(=O)(Nc1ccc2c(c1)COC(Nc1cccc(C3CC3)c1)=N2)c1ccccc1
Yield: 57.6 %

Procedure:
Prepared from N2-(3-Cyclopropyl-phenyl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 119) (200 mg, 0.72 mmol) and benzenesulfonyl chloride (139 mg, 0.78 mmol) according to the procedure described for Example 27. Obtained the title compound as an off-white foam (174 mg, 58%), MS (ISP) m/e=420.3 [(M+H)+].
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[I:12]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C>[CH3:11][O:10][C:8]([C:3]1[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([I:12])[N:4]=1)=[O:9]
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)c1nccnc1N
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1nc(I)cnc1N
Temperature: 70 °C
Reaction time: 15 h
Yield: 61.5 %

Procedure:
Methyl 3-amino-2-pyrazinecarboxylate (10 g, 65.3 mmol) and N-iodosuccinimide (24 g, 106.7 mmol) were dissolved in anhydrous DMF (150 mL) and the mixture was stirred at 70° C. for 15 hours under a nitrogen atmosphere. The mixture was then cooled to room temperature and a saturated aqueous solution of sodium thiosulfate (400 mL) was added. The suspension was sonicated for 15 minutes, concentrated under vacuum and dispersed in water. The crude product was filtered off and washed with cold ethanol. The residue was crystallized from ethanol, using decolorizing charcoal to afford 3-amino-6-iodo-pyrazine-2-carboxylic acid methyl ester (11.2 g, 61% yield) as orange needles. 1H-NMR (d6-DMSO) δ: 8.57 [1H] s, 7.59 [2H] s, br, 3.93 [3H] s. MS: m/z 280 [MH+].