Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)=[N:18]4)=[CH:13][CH:12]=3)=[CH:9][N:8]([C@H:27]3[CH2:30][C@H:29]([CH2:31]OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:28]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[NH:43]1[CH2:46][CH2:45][CH2:44]1>C1COCC1>[N:43]1([CH2:31][C@H:29]2[CH2:30][C@H:27]([N:8]3[C:4]4[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=4[C:10]([C:11]4[CH:20]=[C:19]5[C:14]([CH:15]=[CH:16][C:17]([C:21]6[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=6)=[N:18]5)=[CH:13][CH:12]=4)=[CH:9]3)[CH2:28]2)[CH2:46][CH2:45][CH2:44]1
Reactant: C1CNC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C[C@H](n3cc(-c4ccc5ccc(-c6ccccc6)nc5c4)c4c(N)ncnc43)C2)cc1
Solvent: C1CCOC1
Product: Nc1ncnc2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)cn2[C@H]1C[C@H](CN2CCC2)C1
Reaction time: 8 h

Procedure:
A solution of toluene-4-sulfonic acid trans-3-[4-amino-5-(2-phenylquinolin-7-yl)pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl ester and azetidine (0.30 mL, 254 mg, 4.5 mmol) in THF (4 mL) was heated in a sealed tube to 50° C. overnight. More azetidine (0.30 mL, 254 mg, 4.5 mmol) was added, and heating was continued overnight. THF was evaporated, water and saturated NaHCO3 solution were added, the mixture was extracted with CH2Cl2 (5×20 mL), and the combined CH2Cl2 extracts were washed with water and brine and dried over MgSO4. The crude material was purified by chromatography on silica gel [Jones Flashmaster, 5 g/25 mL cartridge, eluting with CH2Cl2 (1-9)→5% MeOH in CH2Cl2 (10-31)→6.6% MeOH in CH2Cl2 (32-55)→6.6% MeOH in CH2Cl2+NH3 (0.05 M) (56-86)], yielding the title compound as a highly viscous yellow oil. This oil was dissolved in CDCl3 (0.7 mL), tBuOMe was added, and the off-white precipitate was filtered off and dried in vacuo yielding the desired product. 1H NMR (CDCl3, 400 MHz) δ 2.15 (quint, J=7.2 Hz, 2H), 2.33-2.54 (m, 4H), 2.57-2.70 (m, 3H), 2.73 (d, J=7.4 Hz, 2H), 3.33 (t, J=7.2 Hz, 4H), 5.26 (brs, 2H), 5.44 (quint, J=8.1 Hz, 1H), 7.37 (s, 1H), 7.46-7.52 (m, 1H), 7.52-7.58 (m, 2H), 7.70 (dd, J=1.7, 8.3 Hz, 1H), 7.91 (d, J=8.5 Hz, 1H), 7.93 (d, J=7.2 Hz, 1H), 8.17-8.22 (m, 2H), 8.26 (d, J=8.6 Hz, 1H), 8.28-8.31 (m, 1H), 8.35 (s, 1H). 13C NMR (CDCl3, 100.6 MHz, DEPT135) δ 17.73 (−), 27.06 (+), 33.60 (2C, −), 46.72 (+), 55.51 (2C, −), 63.99 (−), 101.05 (Cquart), 116.12 (Cquart), 118.85 (+), 120.57 (+), 125.86 (Cquart), 127.29 (+), 127.45 (2C, +), 128.18 (+), 128.34 (+), 128.76 (2C, +), 129.41 (+), 136.31 (Cquart), 136.46 (+), 139.30 (Cquart), 148.38 (Cquart), 150.73 (Cquart), 151.83 (+), 157.07 (Cquart), 157.95 (Cquart). MS (ES+): m/z 461.2 (11) [MH+], 338.2 (14) [MH+—C4H5CH2azetidine]. HPLC: tR=2.0 min (OpenLynx, polar 5 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][C:12]3[O:13][CH2:14][O:15][C:11]=3[C:10]=2[C:18]([O:20]C)=[O:19])=[CH:5][CH:4]=1.[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:17]=[CH:16][C:12]3[O:13][CH2:14][O:15][C:11]=3[C:10]=2[C:18]([OH:20])=[O:19])=[CH:7][CH:8]=1
Reactant: COC(=O)c1c(-c2ccc(OC)cc2)ccc2c1OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-c2ccc3c(c2C(=O)O)OCO3)cc1

Procedure:
The crude 5-(4-methoxyphenyl)-(1,3)-benzodioxole-4-carboxylic acid, methyl ester was hydrolyzed with 1 N sodium hydroxide (2 mL) in refluxing ethanol (10 mL) until TLC analysis indicated the completion of the reaction. The cooled reaction mixture was extracted with methylene chloride and then the aqueous layer was acidified with 1 N hydrochloric acid. The acidic solution was extracted with methylene chloride and the organic layers were dried and concentrated by rotary evaporation to give the crude acid.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[NH:11][CH:10]=[N:9][C:8]=2[CH:7]=[CH:6][C:5]=1[CH3:13])([O-:3])=[O:2].[H-].[Na+].[C:16]1([C@@H:22]([NH:24][C:25]2[N:30]=[C:29](Cl)[CH:28]=[CH:27][N:26]=2)[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C>[C:16]1([C@@H:22]([NH:24][C:25]2[N:26]=[C:27]([N:9]3[C:8]4[CH:7]=[CH:6][C:5]([CH3:13])=[C:4]([N+:1]([O-:3])=[O:2])[C:12]=4[N:11]=[CH:10]3)[CH:28]=[CH:29][N:30]=2)[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C[C@H](Nc1nccc(Cl)n1)c1ccccc1
Reactant: Cc1ccc2nc[nH]c2c1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(ncn2-c2ccnc(N[C@@H](C)c3ccccc3)n2)c1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 8 h
Yield: 36.8 %

Procedure:
To a stirred solution of 4-nitro-5-methyl-benzimidazole (50 mg, 0.28 mmol, 1.1 eq) in DMF was added NaH (60% dispersion in oil, 11.4 mg, 0.28 mmol, 1.1 eq). After gas evolution ceased, 2-[(S)-1-phenylethylamino]-4-chloro-pyrimidine (60 mg, 0.26 mmol, 1 eq) was added and the mixture was warmed to 80° C. and stirred overnight. The reaction was cooled and the DMF was removed under reduced pressure. The products were purified by preparative thin layer chromatography to afford 35.8 mg of the title compound. Mass spectrum (ESI) 375 (M+).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.Br[CH:19]1[CH2:24][CH2:23][CH2:22][CH:21]=[CH:20]1>C1COCC1.[Ag]=O>[CH:24]1([O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:6][CH2:7]2)[CH2:23][CH2:22][CH2:21][CH:20]=[CH:19]1
Reactant: O=C(OCc1ccccc1)N1CCC(O)CC1
Reactant: BrC1C=CCCC1
Agent: O=[Ag]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(OC2C=CCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-hydroxy-N-(benzyloxycarbonyl)piperidine (5.0 g) in THF (50 ml) were added 3-bromocyclohexene (3.67 ml) and silver oxide (7.4 g). The mixture was stirred at ambient temperature overnight. To the solution were added 3-bromocyclohexene (4.0 ml) and silver oxide (5.0 g), and the mixture was stirred at 40° C. for 6 hours. The reaction mixture was filtered, and the filtrate was evaporated in vacuo. The resulting residue was chromatographed on silica gel (300 ml) eluting with a mixture of n-hexane and ethyl acetate (5:1 v/v). The fractions containing the desired compound were collected and evaporated under reduced pressure to give 4-(2-cyclohexenyloxy)-N-(benzyloxycarbonyl)piperidine (3.83 g).
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:11]=[C:10]([CH:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[C:9]([F:19])=[CH:8][C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:22])=O>>[ClH:22].[F:2][C:3]1[CH:11]=[C:10]([CH:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[C:9]([F:19])=[CH:8][C:4]=1[C:5]([Cl:1])=[O:6]
Reactant: CN1CCC(c2cc(F)c(C(=O)O)cc2F)CC1
Reactant: O=S(Cl)Cl
Agent: Cl
Product: CN1CCC(c2cc(F)c(C(=O)Cl)cc2F)CC1

Procedure:
2.91 g (10 mmoles) of 2,5-difluoro-4-(1-methyl-4-piperidinyl)benzoic acid hydrochloride was refluxed with thionyl chloride and evaporated to afford the title compound.
Reaction SMILES: [CH:1](=[C:8]1[C:13](=[O:14])[O:12][C:11]([CH3:16])([CH3:15])[O:10][C:9]1=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:18]#[N:19].[K+]>>[CH3:16][C:11]1([CH3:15])[O:10][C:9](=[O:17])[CH:8]([CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:18]#[N:19])[C:13](=[O:14])[O:12]1
Reactant: [C-]#N
Reactant: CC1(C)OC(=O)C(=Cc2ccccc2)C(=O)O1
Agent: [K+]
Product: CC1(C)OC(=O)C(C(C#N)c2ccccc2)C(=O)O1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 120, Step 2 starting from 5-benzylidene-2,2-dimethyl-1,3-dioxane-4,6-dione and potassium cyanide.
Reaction SMILES: [CH:1]1[C:13]2[C:4]([C:5](=O)[N:6]=[C:7]3[C:12]=2[CH:11]=[CH:10][CH:9]=[CH:8]3)=[N:3][N:2]=1.C1(P([N:29]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>>[C:1]1([NH2:29])[NH:2][N:3]=[C:4]2[C:13]=1[C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:6]=[CH:5]2
Reactant: O=C1N=c2ccccc2=C2C=NN=C12
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Product: Nc1[nH]nc2cnc3ccccc3c12

Procedure:
In step (2) of Reaction Scheme III, a pyrazolo[3,4-c]quinolin-4-one of Formula XXIII is treated with diphenyl phosphoryl azide to provide a pyrazolo[3,4-c]quinolin-1-amine of Formula XXIII.
Reaction SMILES: C([O:8][C:9]([C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:21])[NH:17][CH:18]([CH3:20])[CH3:19])=[O:10])C1C=CC=CC=1.O.[OH-].[Li+]>C1COCC1.O.C(OCC)(=O)C>[CH:18]([NH:17][C:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@H:11]1[C:9]([OH:10])=[O:8])=[O:21])([CH3:20])[CH3:19]
Reactant: CC(C)NC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)NC(=O)N1CCC[C@H]1C(=O)O
Yield: 40.7 %

Procedure:
(2S)-1-(Isopropylcarbamoyl)pyrrolidine-2-carboxylic acid benzyl ester (528 mg, 1.82 mmol) was dissolved in THF/H2O (9:1, 10 ml). Lithium hydroxide monohydrate (229 mg, 5.46 mmol) was added. After 18 h at room temperature the reaction mixture was diluted with ethyl acetate (50 ml). This solution was washed with 1M KHSO4, water and brine, dried (Na2SO4) and evaporated in vacuo to give a colourless oil identified as the title compound (148 mg, 0.74 mmol, 41%).
Reaction SMILES: [F:1][CH:2]([F:44])[C:3]1[C:7](C=O)=[C:6]([N:10]2[CH2:42][CH2:41][C:13]3[N:14]=[C:15]([C:20]4[C:28]([CH3:29])=[CH:27][CH:26]=[C:25]5[C:21]=4[C:22]([CH3:40])=[N:23][N:24]5S(C4C=CC(C)=CC=4)(=O)=O)[N:16]=[C:17]([O:18]C)[C:12]=3[CH2:11]2)[N:5]([CH3:43])[N:4]=1.Cl.C(=O)(O)[O-].[Na+]>C(O)C>[F:44][CH:2]([F:1])[C:3]1[CH:7]=[C:6]([N:10]2[CH2:42][CH2:41][C:13]3[N:14]=[C:15]([C:20]4[C:28]([CH3:29])=[CH:27][CH:26]=[C:25]5[C:21]=4[C:22]([CH3:40])=[N:23][NH:24]5)[N:16]=[C:17]([OH:18])[C:12]=3[CH2:11]2)[N:5]([CH3:43])[N:4]=1
Reactant: COc1nc(-c2c(C)ccc3c2c(C)nn3S(=O)(=O)c2ccc(C)cc2)nc2c1CN(c1c(C=O)c(C(F)F)nn1C)CC2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc2[nH]nc(C)c2c1-c1nc(O)c2c(n1)CCN(c1cc(C(F)F)nn1C)C2
Temperature: 0 °C

Procedure:
To a solution of 3-(difluoromethyl)-5-(2-(3,5-dimethyl-1-tosyl-1H-indazol-4-yl)-4-methoxy-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-1-methyl-1H-pyrazole-4-carbaldehyde (0.8 g, 1.287 mmol) in ethanol (10.7 mL) was added concentrated HCl (2.1 mL). The microwave vessel was sealed and the mixture was irradiated at 125° C. for 1 h 20 min. The reaction mixture was then cooled to 0° C. and poured into ice water. Solid sodium bicarbonate was slowly added to neutralize the reaction mixture to pH=7, then the crude product was extracted with DCM (3×) and the combined organic layers were dried over sodium sulfate to provide 6-(3-(difluoromethyl)-1-methyl-1H-pyrazol-5-yl)-2-(3,5-dimethyl-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ol, MS (ESI+) m/z 426.4 (M+H)+.
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:21]=[CH:20][C:9]([CH2:10][NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18]C)[CH:13]=2)=[CH:8][CH:7]=1>ClCCl>[Cl:5][C:6]1[CH:21]=[CH:20][C:9]([CH2:10][NH:11][C:12]2[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:7]=1
Reactant: COc1cccc(NCc2ccc(Cl)cc2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cccc(NCc2ccc(Cl)cc2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.4 %

Procedure:
Boron tribromide (2.59 ml, 27.4 mmol) was added drop wise to a cool stirred solution of (4-chloro-benzyl)-(3-methoxy-phenyl)-amine (2.37 g, 9.6 mmol) in anhydrous dichloromethane (90 ml) and the mixture was stirred at 0° C. for 1 hour then ambient for 15 hours. The reaction was cooled to 0° C. and quenched with the addition of saturated sodium bicarbonate solution (aq) (100 ml). The aqueous layer was collected and extracted further with dichloromethane (2×100 ml) and combined organic extracts were concentrated in vacuo to obtain crude product. The crude residue was purified by flash chromatography (SiO2) eluting with 5% ethyl acetate/dichloromethane to yield a cream solid (1.58 g, 71% yield). HPLC retention time 4.55 min Mass spectrum (ES+) m/z 234 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].[CH2:19]([NH:22][CH2:23][CH2:24][CH3:25])[CH2:20][CH3:21].C>C(O)C>[CH2:19]([N:22]([CH2:23][CH2:24][CH3:25])[C:6]1[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]([C:15]([F:18])([F:17])[F:16])=[C:2]([Cl:1])[C:7]=1[N+:8]([O-:10])=[O:9])[CH2:20][CH3:21]
Reactant: CCCNCCC
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c1Cl
Solvent: CCO
Product: CCCN(CCC)c1c([N+](=O)[O-])cc(C(F)(F)F)c(Cl)c1[N+](=O)[O-]
Yield: 79.6 %

Procedure:
A heavy walled glass reaction tube of approximately 50 ml. capacity was charged with 7.0 grams (0.023 mole) of 2,4-dichloro-3,5-dinitrobenzotrifluoride, 4.64 grams (0.0458 mole) of di-n-propylamine and 40 ml. of absolute ethanol. The tube was sealed and heated in an oil bath at 94°-99° C. for 98 hours. The cooled reaction mixture was then evaporated to dryness to give an oily residue which was extracted with boiling diethyl ether. The insoluble di-n-propylamine hydrochloride was removed by filtration and washed with additional ether. The combined ether filtrates were evaporated to give an oily orange residue which was dissolved in 100 ml. of absolute ethanol and decolorized with activated charcoal. The ethanol and volatiles were removed by evaporation under reduced pressure to give the product (6.77 grams) as a viscous reddish oil.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([C:15]1[N:23]=[C:22]2[C:18]([N:19]=[CH:20][N:21]2[C@@H:24]2[CH2:28][C@H:27]([N:29]3[CH:33]=[C:32]([CH2:34][OH:35])[CH:31]=[N:30]3)[C@@H:26]([OH:36])[C@H:25]2[OH:37])=[C:17]([NH:38][CH2:39][CH:40]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[N:16]=1)=[O:14].FC(F)(F)C(O)=O.C(NC(=O)NCCCNC(C1N=[C:78]2C(N=[CH:76][N:77]2[C@@H:80]2C[C@H](N3C=C(CO)C=N3)[C@@H](O)[C@H:81]2[OH:93])=C(NCC(C2C=CC=CC=2)C2C=CC=CC=2)N=1)=O)C.Cl.CC(C)(N)C(Cl)=O>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:76][N:77]([CH3:78])[CH2:80][C:81]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([C:15]1[N:23]=[C:22]2[C:18]([N:19]=[CH:20][N:21]2[C@@H:24]2[CH2:28][C@H:27]([N:29]3[CH:33]=[C:32]([CH2:34][OH:35])[CH:31]=[N:30]3)[C@@H:26]([OH:36])[C@H:25]2[OH:37])=[C:17]([NH:38][CH2:39][CH:40]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[N:16]=1)=[O:14])=[O:93]
Reactant: CCNC(=O)NCCCNC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3C[C@H](n4cc(CO)cn4)[C@@H](O)[C@H]3O)c2n1
Reactant: NCCCNC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3C[C@H](n4cc(CO)cn4)[C@@H](O)[C@H]3O)c2n1
Agent: CC(C)(N)C(=O)Cl
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CC(=O)NCCCNC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3C[C@H](n4cc(CO)cn4)[C@@H](O)[C@H]3O)c2n1

Procedure:
This compound is prepared from 9-[(1R,2S,3R,4S)-2,3-dihydroxy-4-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid (3-amino-propyl)-amide trifluoroacetate (Example 63) using a procedure analogous to that of 9-[(1R,2S,3R,4S)-2,3-dihydroxy-4-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid [3-(3-ethyl-ureido)-propyl]-amide trifluoroacetate (Example 87) replacing ethyl isocyanate with dimethyl-amino-acetyl chloride hydrochloride.
Reaction SMILES: C[O:2][C:3]1(OC)[C:9]2([CH3:11])[O:10][C:6]([CH3:12])([CH:7]=[CH:8]2)[C:5](=[O:13])[CH2:4]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.CCCCCC.C(OCC)(=O)C>CC(C)=O.O>[CH3:11][C:9]12[O:10][C:6]([CH3:12])([CH:7]=[CH:8]1)[C:5](=[O:13])[CH2:4][C:3]2=[O:2]
Reactant: COC1(OC)CC(=O)C2(C)C=CC1(C)O2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O
Product: CC12C=CC(C)(O1)C(=O)CC2=O

Procedure:
1.61 g (7.59 mmol) of 4,4-dimethoxy-1,5-dimethyl-8-oxa-bicyclo[3.2.1]oct-6-en-2-one and 0.432 g (2.28 mmol) of p-toluenesulfonic acid are dissolved in a 2:1 mixture of acetone and water and heated for 50 minutes at a temperature of 70° C. (TLC monitoring: hexane/ethyl acetate 9:1). The acetone is then removed under reduced pressure. The aqueous phase is then adjusted to pH 9 with saturated sodium hydrogen carbonate solution and extracted three times with ethyl acetate to remove neutral components. The aqueous phase is then adjusted to pH 5 with dilute hydrochloric acid and extracted three times with fresh ethyl acetate. The organic phase is dried over sodium sulfate and concentrated by evaporation under reduced pressure, there being obtained 1.04 g (82.5%) of technically pure 1,5-dimethyl-8-oxa-bicyclo[3.2.1]oct-6-ene-2,4-dione in the form of a yellowish product, which can be used without further purification in the next reaction step to form compounds of formula I.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].IC.[BH4-].[Li+]>CN(C)C=O.O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][OH:11])=[CH:13][CH:14]=1
Reactant: COCCOc1ccc(C(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COCCOc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.6 %

Procedure:
To a solution of 4-(2-methoxyethoxy)benzoic acid (100 mg, 0.51 mmol) in N,N-dimethylformamide (2 mL) were added potassium carbonate (282 mg, 2.04 mmol) and iodomethane (79 μL, 1.27 mmol) at room temperature. The mixture was stirred at the same temperature overnight, and then to the reaction solution was added water. The mixture was extracted with ethyl acetate twice. The organic layer was combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was dissolved in tetrahydrofuran (3 mL), and then thereto was added lithium borohydride (53 mg, 2.45 mmol) at 0° C. The reaction solution was slowly warmed to room temperature, and stirred for 3 days. To the reaction solution was added water, and the mixture was extracted with ethyl acetate twice. The organic layer was combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give [4-(2-methoxyethoxy)phenyl]methanol (61 mg, 68%) as a colorless and clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24].C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][CH2:37][CH2:38][OH:39]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:36][CH2:37][CH2:38][OH:39])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24]
Reactant: OCCCBr
Reactant: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(O)c(OC)cc23)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OCCCO)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
N-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl)oxy]phenyl}-N′-propylurea (55 mg), potassium carbonate (20 mg), and 3-bromo-1-propanol (62 μl) were dissolved in N,N-dimethylformamide (4 ml), and the solution was stirred at room temperature for 3 hr. The solvent was removed by distillation under the reduced pressure. Water was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with chloroform/methanol to give 25 mg (yield 40%) of the title compound.
Reaction SMILES: O[CH2:2][CH2:3][CH:4]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[OH:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH:4]12[CH2:3][CH2:2][O:16][CH:5]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2
Reactant: OCCC1CCCCCCCCCCC1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C1CCCCCC2OCCC2CCCC1
Yield: 64.5 %

Procedure:
The toluene solution of the diol from step 5 (approximately 0.59 mol) was mixed with 12 gm of p-toluenesulfonic acid and heated with agitation for approximately 4 hours under a water separator. After the reaction was complete, the mixture was neutralized with 5% sodium hydroxide solution, the aqueous phase was separated, and the toluene phase was evaporated. Approximately 80 gm of 13-oxabicyclo[10.3.0]pentadecane (65% yield) were isolated by vacuum distillation at 90° to 95° C./0.25 mbar.
Reaction SMILES: [C:1]([C:3]1[C:4]([S:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[N:5][CH:6]=[C:7]([CH3:9])[CH:8]=1)#[N:2].[Br:20]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1C=CC=CC=1>[C:1]([C:3]1[C:4]([S:10][C:11]2[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)=[N:5][CH:6]=[C:7]([CH2:9][Br:20])[CH:8]=1)#[N:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cnc(Sc2ccc([N+](=O)[O-])cc2)c(C#N)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: N#Cc1cc(CBr)cnc1Sc1ccc([N+](=O)[O-])cc1

Procedure:
A mixture of 60.00 g (0.221 mol) of 3-cyano-2-(4-nitrophenylthio)-5-methylpyridine, 39.37 g (0.221 mol) of N-bromosuccinimide, 3.0 g of benzoyl peroxide and 60 mL of benzene was refluxed for 16 hours while being irradiated with a 275-W sunlamp. The solvent was removed under reduced pressure and the residue was shaken with a mixture of 1 L of water and 1 L of methylene chloride. The organic layer was separated, washed with 1 L of water, dried over anhydrous magnesium sulfate, and filtered. Removal of the solvent by evaporation under reduced pressure yielded 3-cyano-2-(4-nitrophenylthio)-5-bromomethylpyridine which can be used in the following step without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C@H:21]([OH:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:4]([O:13][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15])[C:5]2[C:10]([C:11]=1[CH3:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl(O)(=O)(=O)=O>C(OC(C)(C)C)(=O)C>[C:2]([O:27][C@@H:21]([C:3]1[C:2]([CH3:1])=[C:11]([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[O:13][S:14]([C:17]([F:19])([F:20])[F:18])(=[O:15])=[O:16])[C:22]([O:24][CH2:25][CH3:26])=[O:23])([CH3:3])([CH3:11])[CH3:1]
Reactant: CCOC(=O)[C@@H](O)c1c(C)c(C)c2ccccc2c1OS(=O)(=O)C(F)(F)F
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)c(C)c2ccccc2c1OS(=O)(=O)C(F)(F)F
Reaction time: 5 h

Procedure:
To a solution of (S)-ethyl 2-(3,4-dimethyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate (3.80 g, 9.35 mmol) in tert-butyl acetate (94 mL) was added 70% perchloric acid (0.160 mL, 1.37 mmol). The reaction mixture was stirred for 5 h and quenched with solid sodium bicarbonate. The mixture was stirred for 5 minutes and saturated sodium bicarbonate solution was carefully added until pH 7, then diluted with water and extracted with ethyl acetate (2×). The combined organic layer was washed with saturated sodium bicarbonate solution and dried (MgSO4), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 25% ethyl acetate/hexanes) to give the desired product. 1H NMR (400 MHz, CDCl3) δ 8.08 (dd, J=8.7, 8.7 Hz, 2H), 7.63-7.55 (m, 2H), 5.75 (s, 1H), 4.3-4.1 (m, 2H), 2.63 (s, 3H), 2.47 (s, 3H), 1.20 (s, 3H), 1.17 (t, J=7.4 Hz, 3H).