Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[CH2:10]([SH:24])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[H-].[Na+].C(O)(=O)C>CN(C)C=O>[CH2:10]([S:24][C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCCCCCS
Reactant: O=C(O)c1ccc(Br)o1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCSc1ccc(C(=O)O)o1

Procedure:
A mixture of 20.1 g (0.011 mole) of 5-bromofuroic acid, 24.2 g (0.011 mole) of tetradecanethiol in 800 ml of dimethylformamide and 8.5 g (0.021 mole) of sodium hydride is heated on a steam bath overnight then refluxed for one-half hour. The mixture is then cooled, acidified with acetic acid and extracted with ether-water. The ether layer is washed with water and salt water, dried over sodium sulfate and filtered. The filtrate is evaporated to dryness, and the remaining solid is recrystallized from hexane and from methanol to give 5-tetradecylthio-2-furoic acid, M.P. 84°-86° C.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.[C:18]1([SH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CC(C)([O-])C.[Na+]>O1CCOCC1.CO.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:18]1([S:24][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]4[CH2:17][CH2:16]4)=[O:14])[N:8]=[CH:9]3)=[CH:4][CH:3]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Nc1cc2ccc(Br)cc2cn1)C1CC1
Reactant: Sc1ccccc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CO
Solvent: C1COCCO1
Product: O=C(Nc1cc2ccc(Sc3ccccc3)cc2cn1)C1CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 26.5 %

Procedure:
A mixture of N-(7-bromoisoquinolin-3-yl)cyclopropanecarboxamide (145 mg, 0.5 mmol), benzenethiol (55 mg, 0.50 mmol), 1,1′-bis(diphenylphosphino)ferrocene (41.8 mg, 0.10 mmol), palladium(II) acetate (22.4 mg, 0.10 mmol) and sodium tert-butoxide (96 mg, 1.0 mmol) in dioxane (15 mL) were stirred at 100° C. overnight under nitrogen. The mixture was diluted with methanol and filtered through a pad of Celite. The pad was washed with methanol. The combined filtrates were concentrated to dryness and purify by Prep-HPLC to give the product (42.5 mg, 26%). LCMS (ESI): RT (min)=1.202, M+H+=320.9, method=A. 1H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 9.06 (s, 1H), 8.41 (s, 1H), 8.02 (t, J=0.8 Hz, 1H), 7.84 (d, J=8.8 Hz, 1H), 7.53 (dd, J=1.6, 8.4 Hz, 1H), 7.38-7.31 (m, 5H), 2.09-1.99 (m, 1H), 0.83-0.79 (m, 4H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:11]([S:16]([OH:19])(=O)=[O:17])=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].CN(C=O)C.C1(C)C=CC=CC=1.S(Cl)([Cl:34])=O>>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:11]([S:16]([Cl:34])(=[O:19])=[O:17])=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(-c2ccccc2S(=O)(=O)O)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cccc(-c2ccccc2S(=O)(=O)Cl)c1

Procedure:
3′-Nitrobiphenyl sulfonic acid (2 g) was refluxed in thionyl chloride (30 mL) with a catalytic quantity of DMF (0.5 mL) for 4 hours. Toluene was added and the solvents evaporated under vacuum. The residue was recrystallised from ethyl acetate/petrol to give the title compound as white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:12])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+].[CH3:24][C:25]([CH3:27])=O>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[O:12][C:25]([CH3:27])([CH3:24])[O:10][C:9]2=[O:11])=[CH:6][CH:7]=1
Reactant: CC(C)=O
Reactant: O=C(O)C(O)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC1(C)OC(=O)C(c2ccc(Br)cc2)O1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
(4-Bromo-phenyl)-hydroxy-acetic acid (97 g, 0.42 mol) is dissolved in 200 ml of acetone and cooled to −10° C. At this temperature 23 ml of concentrated sulfuric acid are added dropwise. After the addition is complete, the reaction mixture is stirred at −10° C. for further 30 minutes and is subsequently poured into a cooled (0° C.) solution of sodium carbonate (86 g, mol) in 800 ml of water. The crystalline 5-(4-bromo-phenyl)-2,2-dimethyl-[1,3]dioxolan-4-one is filtered, washed with ice-cold water and dried in the high-vacuum. 1H-NMR (300 MHz, CDCl3): 1.72 (s, 3H, CH3), 1.76 (s, 3H, CH3), 5.37 (s, 1H, CHO), 7.37 (d, 2H, CH arom.), 7.56 (d, 2H, CH arom.).
Reaction SMILES: [C:1]([CH2:4][CH:5]1[C:9]2[C:10]([C:16]([NH:18][C:19]3[C:24]([Cl:25])=[CH:23][N:22]=[CH:21][C:20]=3[Cl:26])=[O:17])=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:8]=2[O:7][CH2:6]1)([OH:3])=O.[NH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1>>[Cl:26][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([Cl:25])[C:19]=1[NH:18][C:16]([C:10]1[C:9]2[CH:5]([CH2:4][C:1]([NH:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)=[O:3])[CH2:6][O:7][C:8]=2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=1)=[O:17]
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1OCC2CC(=O)O
Reactant: Nc1cccnc1
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1OCC2CC(=O)Nc1cccnc1
Yield: 51 %

Procedure:
Substantially the same procedure as in Example 13 was repeated using Compound 9 (0.30 g) obtained in Example 9 and 3-aminopyridine to give Compound 19 (0.18 g, 51%) as a white solid.
Reaction SMILES: [C:1]12([C:11](Cl)=O)CC3CC(CC(C3)[CH2:2]1)C2.FC(F)(F)S(OC)(=O)=O.C1(NC(=S)NN)C=CC=CC=1.C(N(CC)CC)C.[C:41]12([C:51]([NH:53][NH:54][C:55]([NH:57][C:58]3[CH:63]=CC=C[CH:59]=3)=S)=O)[CH2:50][CH:45]3[CH2:46][CH:47]([CH2:49][CH:43]([CH2:44]3)[CH2:42]1)[CH2:48]2>C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:41]12([C:51]3[N:57]([CH:58]4[CH2:59][CH2:63]4)[C:55]([CH:11]4[CH2:1][CH2:2]4)=[N:54][N:53]=3)[CH2:48][CH:47]3[CH2:49][CH:43]([CH2:44][CH:45]([CH2:46]3)[CH2:50]1)[CH2:42]2
Reactant: O=C(NNC(=S)Nc1ccccc1)C12CC3CC(CC(C3)C1)C2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Agent: COS(=O)(=O)C(F)(F)F
Agent: NNC(=S)Nc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C1C2CC3CC1CC(c1nnc(C4CC4)n1C1CC1)(C2)C3
Reaction time: 0.33 h
Yield: 92.8 %

Procedure:
A mixture of N-(cyclopropyl)cyclopropanecarboxamide (A) (2.08 g, 16.6 mmol) and methyl trifluoromethanesulfonate (1.88 mL, 16.6 mmol) was warmed at 65° in a nitrogen atmosphere. After a few minutes a clear melt was obtained. After 20 min, the melt was cooled and formation of the imino ether triflate salt (B) confirmed by an NMR spectrum. Toluene (26 mL), triethylamine (3.86 mL, 27.7 mmol) and adamantane-1-carbohydrazide (C) (2.15 g, 11.1 mmol) were added, and the two-phase mixture was stirred at 65° for 5 h. The mixture was heated at 110° for 3 h. The cooled reaction was diluted with ethyl acetate (75 mL), washed with water (75 mL) and saturated brine (30 mL), and dried (MgSO4). The ethyl acetate was evaporated in vacuo to give 2.92 g of a yellow syrup. Flash chromatography on silica gel with ethyl acetate eluted the oxadiazole D. Elution with 7% methanol in chloroform and evaporation in vacuo gave crude 4-77. Recrystallization from isopropyl ether afforded pure 3-(1-adamantyl)-4,5-dicyclopropyl-4H-1,2,4-triazole) (4-77). MS: 284 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][C:11]=1[F:17])(=[O:9])=[O:8].[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:23]2[CH:24]=[CH:25][C:20]([C:19]([F:30])([F:29])[F:18])=[CH:21][CH:22]=2)=[CH:12][C:11]=1[F:17])(=[O:9])=[O:8]
Reactant: O=S(=O)(NCCCCO)c1ccc(Br)cc1F
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: O=S(=O)(NCCCCO)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1F

Procedure:
Using a method analogous to that described in Example 40, 4-bromo-2-fluorophenyl-sulfonic acid-(4-hydroxybutyl)-amide and 4-trifluoromethylphenyl boronic acid were reacted to give the title compound as a white solid. δC (DMSO, 62.9 MHz): 26.4, 29.5, 43.2, 62.2, 115.4 (d, J 25.4), 123.2, 125.7, 129.4, 130.8 (d, J 22.2), 131.6, 137.6, 141.5 (d, J 6.8) and 159.3 (d, J 253.9).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C@H:7]([C:9]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]1)[CH3:8])=[O:5].Cl>O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C@H:7]([C:9]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:12][NH:11][CH2:10]1)[CH3:8])=[O:5]
Reactant: C[C@H](NC(=O)c1ccc(Cl)cc1Cl)C1(c2ccccn2)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H](NC(=O)c1ccc(Cl)cc1Cl)C1(c2ccccn2)CNC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 227.6 %

Procedure:
A sample of tert-butyl 3-{(1S)-1-[(2,4-dichlorobenzoyl)amino]ethyl}-3-pyridin-2-ylazetidine-1-carboxylate (I-4, 1.35 g, 3.5 mmol) was treated with HCl (40 mL of a 4.0 M solution in dioxane) and stirred at room temperature for 2 h before being concentrated under reduced pressure to afford 2,4-dichloro-N-[(1S)-1-(3-pyridin-2-ylazetidin-3-yl)ethyl]benzamide hydrochloride (1.54 g, 86%) which was used without further purification. A suspension of 2,4-dichloro-N-[(1S)-1-(3-pyridin-2-ylazetidin-3-yl)ethyl]benzamide hydrochloride (1.54 g, 4.4 mmol) in CH2Cl2 (45 mL) at 0° C. was treated with i-Pr2NEt (3.1 mL, 18 mmol) and n-PrSO2Cl (0.75 mL, 6.6 mmol) dropwise. After 3 h, the reaction was quenched with the addition of 1 M aqueous NaOH (50 mL) and stirred 1 h before being extracted with CH2Cl2 (3×50 mL). The combined organic extracts were dried (Na2SO4), concentrated under reduced pressure, and purified by reverse phase HPLC to afford 2,4-Dichloro-N-{(1S)-1-[1-(propylsulfonyl)-3-pyridin-2-ylazetidin-3-yl]ethyl}benzamide (I-5) as a white amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:22])[C@@H:10]([OH:21])[CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17].Cl[C:24]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>CN(C)C=O.ClCCl>[OH:21][C@H:10]([C:9]([NH:8][C:3]1[CH:4]=[N:5][N:6]([CH3:7])[C:2]=1[NH:1][C:24]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:22])[CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:19])[CH3:17]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1ncc(NC(=O)[C@@H](O)CCNC(=O)OC(C)(C)C)c1N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1ncc(NC(=O)[C@@H](O)CCNC(=O)OC(C)(C)C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 52.7 %

Procedure:
To a solution of tert-butyl {(3S)-4-[(5-amino-1-methyl-1H-pyrazol-4-yl)amino]-3-hydroxy-4-oxobutyl}carbamate (68.51 g) in N,N-dimethylformamide (350 ml) was added chlorotriphenylmethane (67 g). To the mixture was dropwise added triethylamine (67 ml). The mixture was stirred at room temperature for 12 hours. The reaction mixture was dissolved in dichloromethane (2 L). The solution was washed successively with water and brine. The extract was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was triturated with acetonitrile and dried in vacuo to give tert-butyl ((3S)-3-hydroxy-4-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-4-oxobutyl)carbamate (64 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:19]([CH3:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:7]([CH:18]=1)[NH:8][C:9](=O)[CH:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1.N1CCC(C(NC2C=CC=CC=2)=O)CC1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.P(Cl)(Cl)(Cl)=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:19]([CH3:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:9]([CH:10]3[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)=[N:8][C:7]=2[CH:18]=1
Reactant: COc1ccc(N(C)c2ccccc2)c(NC(=O)C2CCN(C)CC2)c1
Agent: O=C(Nc1ccccc1)C1CCNCC1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(c1)N=C(C1CCN(C)CC1)c1ccccc1N2C

Procedure:
The general procedures of Examples 1 and 2 are repeated. The compound 4-methoxy-N-methyl-2-nitrodiphenylamine is prepared and reduced to the corresponding 2-amino derivative which is converted to 5'-methoxy-1-methyl-2'-(N-methylanilino)isonipecotanilide. This isonipecotanilide base is treated with phosphorus pentoxide/phosphorus oxychloride, the cyclized product is isolated and purified and 8-methoxy-5-methyl-11-(1-methyl-4-piperidyl)-5H-dibenzo[b,e]-[1,4]diazepine is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+]>CN(C)C=O>[CH2:14]([O:13][C:11](=[O:12])[CH:10]([CH2:1][CH:2]([CH3:7])[CH3:3])[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(CC(=O)OCc1ccccc1)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)CC(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 1.5 h
Yield: 699.3 %

Procedure:
A total of 334. 75 g of malonic acid dibenzyl ester was dissolved in 1310 ml of dimethylformamide and treated in portions with 51.5 g of 55% sodium hydride which has been previously decanted once with anhydrous benzene. The mixture was stirred for 1.5 hours and then 241 g of isobutyl iodide added dropwise. After stirring for 65 hours, the mixture was evaporated under reduced pressure and the residue stirred with diethyl ether. After filtration of undissolved material, the diethyl ether solution was washed three times with water, dried over magnesium sulfate and evaporated under reduced pressure. The oily residue obtained was distilled twice in a high vacuum, which yields 314 g of pure isobutylmalonic acid dibenzyl ester as a light-yellow oil, boiling point 185°-188°/0.6 mm Hg.
Reaction SMILES: [Na].[C:2]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)#[N:3].C(O)(=O)C.N[C:15]1[CH:16]=[C:17]([CH:22]([CH3:26])[C:23]([OH:25])=[O:24])[CH:18]=[CH:19][C:20]=1[OH:21]>CO.O>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:2]2[O:21][C:20]3[CH:19]=[CH:18][C:17]([CH:22]([CH3:26])[C:23]([OH:25])=[O:24])=[CH:16][C:15]=3[N:3]=2)[CH:5]=1
Reactant: N#Cc1cccnc1
Reactant: CC(C(=O)O)c1ccc(O)c(N)c1
Agent: [Na]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: CC(C(=O)O)c1ccc2oc(-c3cccnc3)nc2c1

Procedure:
Sodium (0.115 g.) was dissolved carefully in methanol (45 ml.) and 3-cyanopyridine (5.2 g.) was added. Next day, acetic acid (0.3 g.) was added followed by 2-(3-amino-4-hydroxyphenyl)propionic acid (9.05 g.). The stirred mixture was heated under reflux for 5 hours. The solid dissolved completely during this time. An equal volume of water was added to the hot solution. On cooling, cream crystals separated which were filtered off and re-crystallised from dimethylformamide-ethanol to yield the desired acid, m.p. 197°- 200°C.
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.COC(=O)C1C=CC(OC[C:36]2[C:37]([C:42]3[CH:47]=CC=CC=3F)=[N:38][O:39][C:40]=2C)=NC=1.NC1CCOCC1>>[CH3:17][C:16]1[O:15][N:14]=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[C:12]=1[CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([NH:38][CH:37]2[CH2:42][CH2:47][O:39][CH2:40][CH2:36]2)=[O:24])=[CH:5][N:6]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccn3)noc2C)nc1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3F)noc2C)nc1
Agent: NC1CCOCC1
Product: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)NC2CCOCC2)cn1
Yield: 79 %

Procedure:
As described for example 84f, 6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (97.6 mg, 0.3 mmol) was converted, instead of [6-[3-(2-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester, using 4-aminotetrahydropyran instead of 2,2,2-trifluoroethylamine, to the title compound (93 mg, 79%) which was obtained as a white solid. MS: m/e=395.0 [M+H]+.
Reaction SMILES: [CH:1]([CH:3]1[N:6]([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([O:10][CH3:11])=[O:9])[C:5](=[O:18])[CH:4]1[N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29])=[O:2].[O:30]1CCCC1>[Ag]=O.O>[C:1]([CH:3]1[N:6]([CH:7]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:8]([O:10][CH3:11])=[O:9])[C:5](=[O:18])[CH:4]1[N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29])([OH:30])=[O:2]
Reactant: COC(=O)C(c1ccccc1)N1C(=O)C(N2C(=O)c3ccccc3C2=O)C1C=O
Reactant: C1CCOC1
Agent: O=[Ag]
Solvent: O
Product: COC(=O)C(c1ccccc1)N1C(=O)C(N2C(=O)c3ccccc3C2=O)C1C(=O)O
Temperature: 25 °C
Reaction time: 40 h

Procedure:
A mixture of methyl 2-(4-formyl-2-oxo-3-phthalimido-1-azetidinyl)-2-phenylacetate (0.38 g.), silver oxide(0.92 g), tetra-hydrofuran (9 ml.) and water (1 ml.) was stirred at ambient temperature for 40 hours. The insoluble materials were filtered off from the reaction mixture and the tetrahydrofuran was removed by distillation from the filtrate under reduced pressure. Water was added to the resultant residue and adjusted to pH 2 with 10% hydrochloric acid, whereafter the mixture was extracted with ethyl acetate. The extract was washed with 1% Aqueous sodium bicarbonate, and the washings were adjusted to pH 2 with 10% hydrochloric acid. The aqueous solution was extracted with ethyl acetate, whereafter this extract and the above-obtained extract were combined, washed with water and then dried over magnesium sulfate. The solvent was removed by distillation from the solution under reduced pressure to give methyl 2-(4-carboxy-2-oxo-3-phthalimido-1-azetidinyl)-2-phenylacetate [a mixture of two cis isomers (a) and (b) at the third and fourth positions of the azetidine ring, (200 mg.)].
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]2[N:6]=[C:7]([C@@H:9]3[CH2:12][C@H:11]([OH:13])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[N:16]1[NH:17][C:18](=[O:22])[CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].CNCCNC>N1C=CC=CC=1.O.[Cu].[Cu]I>[OH:13][CH:11]1[CH2:12][CH:9]([C:7]2[S:8][C:4]3[CH:3]=[C:2]([N:17]4[C:18](=[O:22])[CH:19]=[CH:20][CH:21]=[N:16]4)[CH:15]=[CH:14][C:5]=3[N:6]=2)[CH2:10]1
Reactant: O[C@H]1C[C@@H](c2nc3ccc(Br)cc3s2)C1
Reactant: O=c1cccn[nH]1
Agent: [Cu]
Agent: [Cu]I
Agent: CNCCNC
Solvent: c1ccncc1
Solvent: O
Product: O=c1cccnn1-c1ccc2nc(C3CC(O)C3)sc2c1
Reaction time: 0.25 h

Procedure:
The product of Example 1D (cis-3-(6-Bromo-benzothiazol-2-yl)-cyclobutanol) (2.25 g, 7.93 mmole), 3(2H)-pyridazinone (CAS # 504-30-3) (1.52 g, 15.83 mmole), copper (500 mg, 7.93 mmole), potassium carbonate (3.28 g, 23.77 mmole), and copper(I) iodide (211 mg, 1.11 mmole) were mixed in degassed pyridine (50 ml) and placed under vacuum for 15 minutes then refilled with nitrogen. N,N′-dimethylethylene diamine (240 μl, 196 mg, 2.22 mmole) was added and the mixture was heated at reflux overnight. The mixture was diluted with water and extracted three times with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product which was purified by column chromatography (0.4% ammonium hydroxide and 4% methanol in dichloromethane) to provide the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 8.15 (d, J=2.15 Hz, 1H) 8.04 (d, J=8.90 Hz, 1H) 7.92 (dd, J=3.68, 1.53 Hz, 1H) 7.70 (dd, J=8.59, 2.15 Hz, 1H) 7.24-7.30 (m, 1H) 7.04-7.11 (m, 1H) 4.68-4.81 (m, 0.3H) 4.31-4.43 (m, 0.7H) 3.87-3.98 (m, 0.3H) 3.39-3.51 (m, 0.7H) 2.90-3.01 (m, 1.4H) 2.77-2.87 (m, 0.6H) 2.51-2.62 (m, 0.6H) 2.33-2.45 (m, 2.1H) 2.07 (d, J=5.22 Hz, 0.3H). MS: (M+H)+=300.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[C:26]3[O:25][C:24]([F:28])([F:27])[O:23][C:22]=3[CH:21]=[CH:20][CH:19]=2)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.O1CCOCC1.CO.O>CO.C(Cl)Cl>[F:28][C:24]1([F:27])[O:23][C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([C:16]([NH:15][C:6]3([C:4]([OH:5])=[O:3])[CH2:7][C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH2:14]3)=[O:17])[C:26]=2[O:25]1
Reactant: CCOC(=O)C1(NC(=O)c2cccc3c2OC(F)(F)O3)Cc2ccccc2C1
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: O=C(NC1(C(=O)O)Cc2ccccc2C1)c1cccc2c1OC(F)(F)O2
Reaction time: 70 h
Yield: 93.2 %

Procedure:
A 100 mL flask containing 2-[(2,2-difluoro-1,3-benzodioxole-4-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (0.38 g, 0.98 mmol) is charged with 1,4-dioxane (6 mL) and MeOH (6 mL). A stirring bar is added and stirring is initiated. After dissolution, water (3 mL) is added followed by the LiOH monohydrate (103 mg, 2.46 mmol). After 70 h, tlc analysis (silica, 10% MeOH/DCM) indicates that the starting material is completely consumed. The pH of the reaction mixture is carefully adjusted to pH 2 by slowly adding dilute aqueous HCl (3%, ˜6 mL). The contents of the flask are poured into a separatory funnel which contains EtOAc (30 mL). The layers are separated. The aqueous layer is extracted with EtOAc (20 mL). The combined organic extracts are washed with water (20 mL) and brine (20 mL), dried over MgSO4, filtered and concentrated by pumping to constant weight to give off white solid (0.33 g, 94%).
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].[CH3:6][C:7]([CH3:18])=[CH:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH3:6][C:7]([CH3:18])=[CH:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:2][C:3](=[O:5])[CH3:4])=[CH:15][CH:16]=1
Reactant: CC(C)=CCOc1ccc(O)cc1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)COc1ccc(OCC=C(C)C)cc1
Temperature: 25 °C

Procedure:
Chloroacetone (0.89 ml, 1.04 g, 11.2 mmol) is added to a mixture of 4-(3-methyl-2-butenoxy)phenol (2.0 g, 11.2 mmol), potassium carbonate (25 g) and potassium iodide (2.5 g) in 125 ml of anhydrous acetone. The mixture is heated under reflux for 4.5 hours and then is allowed to cool to RT to give 4-(3-methyl-2-butenoxy)phenoxyacetone.
Reaction SMILES: [CH3:1][Si:2]([CH3:16])([CH3:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]Br.[NH2:17][C:18]1[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=1>>[CH3:1][Si:2]([CH3:16])([CH3:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:27][CH:28]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: C[Si](C)(C)CCCCCCCCCCCBr
Product: CCOC(=O)c1ccc(NCCCCCCCCCCC[Si](C)(C)C)cc1

Procedure:
In the manner of example 3, 11-(trimethylsilyl)undecyl bromide was reacted with ethyl 4-aminobenzoate to yield ethyl 4-[11-(trimethylsilyl)undecylamino]benzoate, m.p. 66°-68° C.
Reaction SMILES: [O:1]=[C:2]1[N:7]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([C@H:15]([NH:19]C(=O)OC(C)(C)C)[CH2:16][C:17]#[CH:18])=[N:5][C:4]2[CH:27]=[CH:28][CH:29]=[N:30][C:3]1=2.Cl>CO>[NH2:19][C@@H:15]([C:6]1[N:7]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:2](=[O:1])[C:3]2[N:30]=[CH:29][CH:28]=[CH:27][C:4]=2[N:5]=1)[CH2:16][C:17]#[CH:18]
Reactant: C#CC[C@@H](NC(=O)OC(C)(C)C)c1nc2cccnc2c(=O)n1Nc1ccccc1
Agent: Cl
Solvent: CO
Product: C#CC[C@@H](N)c1nc2cccnc2c(=O)n1Nc1ccccc1
Reaction time: 18 h
Yield: 121.7 %

Procedure:
To a solution of (R)-tert-butyl 1-(4-oxo-3-(phenylamino)-3,4-dihydropyrido[3,2-d]pyrimidin-2-yl)but-3-ynylcarbamate (1.20 g, 2.96 mmol) in methanol (15 ml) was added 4.5 ml of HCl (4.0 M in 1,4-dioxane). The reaction was carried out at room temperature for 18 hours. The solvent was removed under reduced pressure to afford (R)-2-(1-aminobut-3-ynyl)-3-(phenylamino)pyrido[3,2-d]pyrimidin-4(3H)-one (1.1 g) as a light brown solid, M.p. 206-208° C. LCMS: m/e 306 [M+H]. 1H NMR (400 MHz) (DMSO-d6): δ 9.34 (s, 1H), 8.85 (s, 1H), 8.20 (d, J=8 Hz, 1H), 7.94 (dd, J=8.0 Hz and 3.2 Hz, 1H), 7.22 (t, J=7.6 Hz, 2H), 6.91 (t, J=7.6 Hz, 1H), 6.80 (s, J=8 Hz, 1H), 4.98 (m, 3H), 4.53 (s, 1H), 3.11 (m, 2H).