Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][C:17]1([CH3:33])[C@@H:19]([C:20]#[C:21][C:22]([O:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:23])[C@H:18]1[C:30]([OH:32])=[O:31].[C:34]([C@@H:36](O)[C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([O:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:38]=1)#[N:35]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:16][C:17]1([CH3:33])[C@@H:19]([C:20]#[C:21][C:22]([O:24][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)=[O:23])[C@H:18]1[C:30]([O:32][C@H:36]([C:34]#[N:35])[C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([O:43][C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:38]=1)=[O:31]
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1C#CC(=O)OC1CCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1C#CC(=O)OC1CCCC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 68.4 %

Procedure:
2.96 g of dicyclohexylcarbodiimide were added at 0° C. to a stirred mixture of 3.6 g of the product of Step B, 30 ml of methylene chloride and 30 mg of 4-dimethylaminopyridine followed by the addition of a solution of 3.3 g of (S)α-cyano-3-phenoxy-benzyl alcohol in 10 ml of methylene chloride. The mixture was stirred at 0° C. for 5 minutes and at 20°-25° C. for 3 hours and was filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with a cyclohexane-ethyl acetate mixture yielded 4.5 g of (S)α-cyano-3-phenoxybenzyl(1R,cis)2,2-dimethyl-3-[2-(cyclopentyloxycarbonyl)ethynyl]-cyclopropane-carboxylate with a melting point of =72° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:10]([CH2:11][CH:12]=O)=[C:4]2[CH:3]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:10]([CH2:11][CH2:12][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[C:4]2[CH:3]=1
Reactant: C1CCNCC1
Reactant: COc1ccc(-c2nn3ccc(Br)cc3c2CC=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccc(-c2nn3ccc(Br)cc3c2CCN2CCCCC2)cc1
Temperature: 20 °C
Reaction time: 17 h

Procedure:
To a solution of 2-(5-bromo-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl)acetaldehyde (40 mg, 0.12 mmol) and piperidine (23 μl, 0.23 mmol) in 1,2-dichloroethane (3.5 ml) was added sodium triacetoxyborohydride (49 m, 0.23 mmol). The reaction mixture was stirred at 20° C. for 17 h. The reaction mixture was diluted with dichloromethane (10 mL) and washed with a 5% sodium bicarbonate solution (6 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give a residue that was purified by automated ISCO chromatography (methanol/dichloromethane; 5/95). The title compound was obtained as a white solid (28 mg, 58%). LCMS m/z 414.1, 416.1 (M+H)+, ret. time=1.76 min.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:14][C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([C:15]([F:18])([F:17])[F:16])[O:12][N:11]=2)=[CH:6][CH:5]=1.[OH-].[K+].Cl>CO.O>[Cl:26][C:21]1[CH:20]=[C:19]([C:13]2([C:15]([F:17])([F:16])[F:18])[O:12][N:11]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:27])=[O:2])=[CH:9][CH:8]=3)[CH2:14]2)[CH:24]=[C:23]([Cl:25])[CH:22]=1
Reactant: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 100.4 %

Procedure:
In a solution of 3.99 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl] benzoic acid methyl ester in 50 ml of methanol, a solution of 2.00 g of potassium hydroxide in 25 ml of water was added, stirred at room temperature for 3 days and then at 40° C. for 5 hours. After the completion of the reaction, the reaction mixture was cooled with ice, and poured in 200 ml of water, and adjusted to pH 1-2 with concentrated hydrochloric acid, and then extracted with ethyl acetate (50 ml×2), the organic phase was washed with water, dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 3.87 g of the aimed product as pale yellow crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]([O:18][CH3:19])([CH3:17])[CH3:16])[C:6]([O:8]C)=[O:7].[OH-].[Na+]>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]([O:18][CH3:19])([CH3:16])[CH3:17])[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1ccc(OCC(C)(C)OC)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1cc(C(=O)O)ccc1OCC(C)(C)OC
Temperature: 80 °C
Yield: 77.5 %

Procedure:
Methyl 3-methoxy-4-(2-methoxy-2-methyl-propoxy)benzoate (177 mg, 0.66 mmol), dioxane (1.9 mL) and NaOH (1.8 mL of 1 M, 1.80 mmol) were combined and the reaction mixture was heated at 80° C. for 15 minutes. The reaction mixture was concentrated in vacuo and the crude mixture was dissolved in water. The mixture was washed with EtOAc (3×). The aqueous layer was acidified with 1N HCl then washed with EtOAc (3×). The combined organic layers was dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to yield 3-methoxy-4-(2-methoxy-2-methyl-propoxy)benzoic acid (130 mg, 77%). ESI-MS m/z calc. 254.1. found 255.5 (M+1)+; Retention time: 1.14 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 12.61 (s, 1H), 7.54 (dd, J=8.4, 1.9 Hz, 1H), 7.45 (d, J=1.8 Hz, 1H), 7.07 (d, J=8.5 Hz, 1H), 3.89 (s, 2H), 3.81 (s, 3H), 3.17 (s, 3H), 1.22 (s, 6H).
Reaction SMILES: Cl.[NH2:2][OH:3].CC(C)([O-])C.[Na+].[CH2:10]([C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH3:23])[C:21]#[N:22])=[CH:16][CH:15]=1)[CH:11]([CH3:13])[CH3:12]>C(O)C>[CH2:10]([C:14]1[CH:15]=[CH:16][C:17]([CH:20]([CH3:23])[C:21]([NH:2][OH:3])=[NH:22])=[CH:18][CH:19]=1)[CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)Cc1ccc(C(C)C#N)cc1
Reactant: NO
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)Cc1ccc(C(C)C(=N)NO)cc1
Temperature: 25 °C
Yield: 70 %

Procedure:
A mixture of hydroxylamine hydrochloride (0.38 g, 5.32 mmol) and sodium tert-butoxide (0.5 g, 5.28 mmol) in ethyl alcohol (10 mL) is stirred at r.t. for 15′; the precipitate is filtered off and the mother liquors are added dropwise to a solution of 2-(4-isobutylphenyl)propionitrile (0.11 g, 0.49 mmol) in absolute ethyl alcohol (3 mL). The resulting solution is refluxed 18 h. After cooling at r.t. the solvents are evaporated under reduced pressure and the crude residue is diluted in trichloromethane (25 mL), washed with 5% solution of citric acid (2×15 mL), then with a saturated solution of NaCl (2×15 mL), dried over Na2SO4 and evaporated under vacuum to give 2-(4-isobutylphenyl)-N-hydroxy-propionamidine isolated as white solid after crystallisation from n-hexane (0.075 g, 0.34 mmol). Yield 70%. m.p. 75-78° C. 1H-NMR (CDCl3): δ 7.25 (d, 2H, J=7 Hz); 7.12 (d, 2H, J=7 Hz); 5.030 (bs, 1H, NH); 4.35 (bs, 2H, NH—OH); 3.58 (q, 1H, J=8 Hz); 2.48 (d, 2H, J=8 Hz); 1.87 (m, 1H); 1.50 (d, 3H, J=8 Hz); 0.92 (d, 6H, J=8 Hz).
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:12]=[CH:11][C:10](Br)=[CH:9][N:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[OH:14][C:15]1[CH:16]=[C:17]([CH:22]=[C:23]([O:25][C@@H:26]([CH3:30])[CH2:27][O:28][CH3:29])[CH:24]=1)[C:18]([O:20]C)=[O:19]>>[N:1]1([C:5]([C:7]2[N:8]=[CH:9][C:10]([O:14][C:15]3[CH:16]=[C:17]([CH:22]=[C:23]([O:25][C@@H:26]([CH3:30])[CH2:27][O:28][CH3:29])[CH:24]=3)[C:18]([OH:20])=[O:19])=[CH:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1ccc(Br)cn1)N1CCC1
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)OC)c1
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)N3CCC3)nc2)cc(C(=O)O)c1

Procedure:
3-{[6-(Azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzoic acid was prepared in an analogous fashion from 2-(azetidin-1-ylcarbonyl)-5-bromopyridine and methyl 3-hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]benzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([NH:9][C:10](=[NH:13])[O:11][CH3:12])[N:3]=1.[CH3:14][O-:15].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([O:15][CH3:14])[N:5]=[C:4]([NH:9][C:10](=[NH:13])[O:11][CH3:12])[N:3]=1
Reactant: C[O-]
Reactant: COC(=N)Nc1nc(Cl)cc(Cl)n1
Agent: [Na+]
Solvent: CO
Product: COC(=N)Nc1nc(Cl)cc(OC)n1
Reaction time: 12 h
Yield: 85.6 %

Procedure:
9.1 g (0.041 mol) of N-(4,6-dichloro-pyrimidin2-yl)-O-methyl-isourea are initially introduced in 80 ml of methanol. 2.2 g of sodium methoxide (0.041 mol), dissolved in 20 ml of methanol, are then added dropwise at 20° C. The mixture is subsequently stirred for 12 hours and concentrated, the residue is taken up in methylene chloride, and the solution is washed three times with water and concentrated again. 7.6 g (86% of theory) of N-(4-chloro-6-methoxy-pyrimidin-2-yl) -O-methyl-isourea are obtained in the form of white crystals of melting point 118°-120° C.
Reaction SMILES: [CH:1]1([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[SH:9][CH:10]([CH3:14])[C:11](O)=[O:12].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH:1]1([O:8][C:11](=[O:12])[CH:10]([SH:9])[CH3:14])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(S)C(=O)O
Reactant: OC1CCCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(S)C(=O)OC1CCCCCC1

Procedure:
Reaction: ##STR128## Into a 50 ml reaction flask equipped with stirrer, thermometer, reflux condenser and heating mantle are placed 11.4 grams cycloheptanol; 22 grams of 2-mercaptopropionic acid and 0.5 grams of paratoluene sulfonic acid. The reaction mass is heated to reflux and refluxed for a period of 10 hours. At the end of the 10 hour period, the reaction mass is distilled on a micro distillation apparatus to yield the compound having the structure: ##STR129##
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>>[OH:23][C:20]1[CH:19]=[CH:18][C:17]([C@H:14]2[CH2:13][CH2:12][C@H:11]([N:10]([CH2:9][CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:24](=[O:26])[CH3:25])[CH2:16][CH2:15]2)=[CH:22][CH:21]=1
Reactant: Oc1ccc([C@H]2CC[C@H](NCCCc3ccccc3)CC2)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N(CCCc1ccccc1)[C@H]1CC[C@H](c2ccc(O)cc2)CC1

Procedure:
In a manner similar to Example 16, trans-4-[4-(3-phenylpropylanino)cyclohexyl]phenol was allowed to react with acetic anhydride to give trans-N-[4-(4-hydroxyphenyl)cyclohexyl]-N-(3-phenylpropyl) acetamide. Yield (90 mg, 2%): mp 175-180° C.; IR (KBr): 3240, 2929, 1620, 1590 cm−1; 1H NMR (300 MHz, DMSO-d6) δ 9.11 (s, 1H), 7.30-7.17 (m, 5H), 7.00 (d, J=9 Hz, 2H), 6.69 (dd, J=9, 2 Hz, 2H), 3.37 (m, 1H), 3.25 (m, 4H), 2.61 (m, 2H), 2.41 (m, 1H), 2.10 (s, 3H), 1.87-1.75 (m, 4H), 1.72-1.46 (m, 4H); CI-MS (methane) (m/z): 352 [M+H]+; HRMS-API (m/z): [M+H]+ Calcd for C23H29NO2, 352.2276. found: 352.2278. HPLC: method A, 12.08 minutes (97.3%); method B, 16.36 minutes (98.9%); Anal. Calcd for C23H29NO2.0.75H2O: C, 75.67; H, 8.43; N, 3.84. Found: C, 75.40; H, 7.93; N, 3.78.
Reaction SMILES: ClC(Cl)(Cl)C(=N)O[CH:5]([C:7]1[CH:8]=[C:9]([C:24]([F:27])([F:26])[F:25])[CH:10]=[C:11]2[C:15]=1[N:14]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:13]=[CH:12]2)[CH3:6].[OH:31][CH2:32][C:33]1([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]1.C1CCCCC1>ClCCl>[C:46]1([C:33]2([CH2:32][O:31][CH:5]([C:7]3[CH:8]=[C:9]([C:24]([F:26])([F:27])[F:25])[CH:10]=[C:11]4[C:15]=3[N:14]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:21])([CH3:22])[CH3:23])[CH:13]=[CH:12]4)[CH3:6])[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:44])([CH3:45])[CH3:43])=[O:40])[CH2:35][CH2:34]2)[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Reactant: CC(OC(=N)C(Cl)(Cl)Cl)c1cc(C(F)(F)F)cc2ccn(COCC[Si](C)(C)C)c12
Solvent: C1CCCCC1
Solvent: ClCCl
Product: CC(OCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(C(F)(F)F)cc2ccn(COCC[Si](C)(C)C)c12
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 47.4 %

Procedure:
To a solution of (±)-1-(5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-7-yl)ethyl 2,2,2-trichloroacetimidate (290 mg, 0.576 mmol) and tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (184 mg, 0.633 mmol) in dichloromethane (2 mL) at 0° C. was added cyclohexane (2 ml) and fluoroboric acid diethyl ether complex (0.016 ml, 0.115 mmol). The reaction was stirred at 0° C. for 45 min and was judged complete by TLC. The reaction was quenched with aqueous sodium bicarbonate (5 mL) and extracted with ethyl acetate (3×5 mL). The combined organic layers were dried with magnesium sulfate and evaporated. The residue was purified by chromatography on silica gel with a gradient of ethyl acetate/hexanes from 12% to 100%. The product (173 mg, 0.273 mmol, 47.5% yield) was isolated as a clear oil. 1H-NMR (CDCl3, 400 MHz) δ 7.77 (m, 1H), 7.39 (m, 1H), 7.14-7.29 (m, 5H), 7.07 (m, 1H), 6.54 (m, 1H), 5.15 (m, 1H), 3.32 (m, 2H), 3.21 (m, 2H), 3.00 m, 2H), 2.11 (m, 2H), 1.88 (m, 2H), 1.45 (d, J=6.4 Hz, 3H), 1.42 (s, 9H), 0.75 (m, 2H), −0.09 (s, 9H); LC/MS (HPLC method 4): tR=4.36 min, 655.20(MNa)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.[OH:9][CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1.[H-].[Na+]>CN(C)C=O>[F:8][C:4]1[N:3]=[C:2]([O:9][CH2:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Fc1cccc(F)n1
Reactant: N#Cc1ccc(CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(COc2cccc(F)n2)cc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 60.5 %

Procedure:
To an N,N-dimethylformamide (50 mL) solution of 2,6-difluoropyridine (5 g, 43.4 mmol) and 4-(hydroxymethyl)benzonitrile (8.67 g, 65.1 mmol) was added sodium hydride (2.56 g, 65.1 mmol, 60% in oil) at room temperature. This mixture was stirred for 4 hours at 70° C. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH-silica gel column chromatography (heptane:ethyl acetate=10:1-4:1) to obtain the title compound (5.99 g, 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:23](=[O:35])[NH:24][CH2:25][C:26]2[C:31](=[O:32])[CH:30]=[C:29]([CH3:33])[NH:28][C:27]=2[CH3:34])[C:5]([CH3:22])=[C:6]([CH:21]=1)[O:7][CH:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1.Cl.O1CCOCC1>C(Cl)Cl>[Cl:1][C:2]1[CH:21]=[C:6]([O:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[C:5]([CH3:22])=[C:4]([CH:3]=1)[C:23]([NH:24][CH2:25][C:26]1[C:31](=[O:32])[CH:30]=[C:29]([CH3:33])[NH:28][C:27]=1[CH3:34])=[O:35]
Reactant: Cc1cc(=O)c(CNC(=O)c2cc(Cl)cc(OC3CCN(C(=O)OC(C)(C)C)CC3)c2C)c(C)[nH]1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cc(=O)c(CNC(=O)c2cc(Cl)cc(OC3CCNCC3)c2C)c(C)[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl 4-(5-chloro-3-(((2,6-dimethyl-4-oxo-1,4-dihydropyridin-3-yl)methyl)carbamoyl)-2-methylphenoxy)piperidine-1-carboxylate (80 mg, 158 mmol) in DCM (2 mL) was treated with 4 M HCl/dioxane (2 mL). The reaction stirred for 2 h at RT, then was concentrated in vacuo and triturated with EtOAc to give 5-chloro-N-((2,6-dimethyl-4-oxo-1,4-dihydropyridin-3-yl)methyl)-2-methyl-3-(piperidin-4-yloxy)benzamide as the hydrogen chloride salt (0.050 g, 113 mmol, 72% yield). 1H NMR (400 MHz, DMSO-d6) δ 1.74-1.90 (m, 2 H) 2.07 (s, 3 H) 2.11 (d, J=4.80 Hz, 2 H) 2.57 (s, 3 H) 2.72 (s, 3 H) 3.09 (br. s., 2 H) 3.17 (s, 2 H) 4.38 (d, J=4.80 Hz, 2 H) 4.60-4.87 (m, 1 H) 6.89 (s, 1 H) 7.12 (s, 1 H) 7.23 (d, J=1.77 Hz, 1 H) 8.69 (t, J=5.05 Hz, 1 H) 8.98 (br. s., 2 H) 14.42 (br. s., 1 H). MS(ES) [M+H]+ 404.3.
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([CH3:14])[O:7][C@H:6]1[N:15]1[CH:28]=[C:27]([F:29])[C:19]([NH:20][C:21]([O:23][CH2:24][CH2:25][CH3:26])=[O:22])=[N:18][C:16]1=[O:17])(=O)C.[OH-].[Na+].CO.Cl>C(Cl)Cl>[F:29][C:27]1[C:19]([NH:20][C:21]([O:23][CH2:24][CH2:25][CH3:26])=[O:22])=[N:18][C:16](=[O:17])[N:15]([CH:28]=1)[C@@H:6]1[O:7][C@H:8]([CH3:14])[C@@H:9]([OH:10])[C@H:5]1[OH:4]
Reactant: CCCOC(=O)Nc1nc(=O)n([C@@H]2O[C@H](C)[C@@H](OC(C)=O)[C@H]2OC(C)=O)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CCCOC(=O)Nc1nc(=O)n([C@@H]2O[C@H](C)[C@@H](O)[C@H]2O)cc1F

Procedure:
To a solution of 2',3'-di-O-acetyl-5'-deoxy-5-fluoro-N4 -(propoxycarbonyl)cytidine (2.5 g) in CH2Cl2 (17 ml) was added dropwise 1N NaOH (17 ml) with stirring and cooling with ice bath. After stirring for 1 hr at 0° C., MeOH (0.9 ml) was added to the mixture. And pH of the reaction mixture was adjusted to 6 by the addition of concentrated HCl and partitioned. The aqueous layer was extracted with a mixed solvent of CH2Cl2 /MeOH(95/5) successively (40 ml×10). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The solution was evaporated, and the residue was crystallized from ethyl acetate to give 5'-deoxy-5-fluoro-N4 -(propoxycarbonyl)cytidine as colorless crystals (1.6 g, y. 79.8%): mp. 125°-126.5° C.; EI-MS m/z 331 (M+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:3]=1.C1C(=O)N([Br:19])C(=O)C1>CC(N=NC(C#N)(C)C)(C#N)C.C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:3]=1
Reactant: Cc1cccc(C(C)(C)C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1cccc(CBr)c1
Yield: 101.8 %

Procedure:
To 1-methyl-3-tert-butyl-benzene (551 mg, 3.72 mmol), NBS (730 mg, 1.1 eq) and AIBN (14 mg, catalytic amount) was added CCl4 (8 mL), which was then refluxed for 2 h. The suspended particles were removed by filtration, and washed with CCl4. The organic layers were combined and concentrated under reduced pressure to give 860 mg of a yellow liquid (which was identified by NMR to contain about 15% dibromo derivative).
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:6]=[N:7][C:8]([C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=2[F:18])=[CH:9][CH:10]=1)=[N+]=[N-].[Cl:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1[N:26]=[C:27]=S>C1COCC1.CCOC(C)=O>[Cl:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1[NH:26][C:27]1[N:6]2[N:7]=[C:8]([C:11]3[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=3[F:18])[CH:9]=[CH:10][C:5]2=[CH:4][N:1]=1
Reactant: S=C=Nc1cnccc1Cl
Reactant: [N-]=[N+]=NCc1ccc(-c2c(F)cccc2F)nn1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Fc1cccc(F)c1-c1ccc2cnc(Nc3cnccc3Cl)n2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53.9 %

Procedure:
N-(4-chloro-3-pyridinyl)-2-(2,6-difluorophenyl)imidazo[1,5-b]pyridazin-7-amine PMe3 (0.62 mL of 1.0 M solution in THF, 0.62 mmol) was added dropwise to a solution of 3-(azidomethyl)-6-(2,6-difluorophenyl)pyridazine (Preparation I, 140 mg, 0.57 mmol) in THF (2.5 mL) at RT. The reaction turned purple and an evolution of gas was observed. It was stirred for 15 min at RT. A solution of 4-chloro-3-isothiocyanatopyridine (Preparation XXIV, 106 mg, 0.62 mmol) in THF (1 mL) was added. After 15 min at RT, the reaction was diluted with EtOAc (50 mL) and washed with H2O (10 mL). The aqueous phase was extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine (15 mL), dried over anh. Na2SO4, filtered and concentrated. The crude material was purified by silica gel chromatography (0-3% MeOH in CH2Cl2) to provide N-(4-chloro-3-pyridinyl)-2-(2,6-difluorophenyl)-imidazo[1,5-b]pyridazin-7-amine (110 mg, 54% yield) as an orange crystalline solid. MS (ESI, pos. ion) m/z: 350.8 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 9.90 (s, 1 H), 8.17 (d, J=5.09 Hz, 1 H), 7.79 (d, J=9.59 Hz, 1 H), 7.64 (s, 1 H), 7.40-7.51 (m, 1 H), 7.37 (s, 1 H), 7.32 (d, J=5.09 Hz, 1 H), 7.07 (m, 2 H), 6.57 (dt, J=9.44, 1.64 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([CH2:11][O:12][CH3:13])[C:3]=1[C:4]#[N:5].CO.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([CH2:11][O:12][CH3:13])[C:3]=1[CH2:4][NH2:5]
Reactant: COCc1cc(Cl)cc(Cl)c1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COCc1cc(Cl)cc(Cl)c1CN
Temperature: 60 °C

Procedure:
A soln. of BH3 (3.5 mL, 1M in THF) was added to a solution of 2,4-dichloro-6-(methoxymethyl)benzonitrile (0.88 mmol) in 3 mL THF. The reaction mixture was heated to 60° C. for 2 h. At 0° C., 3.5 mL MeOH was dropwise added and the mixture was stirred until gaz evolution was finished. An aq. soln. of 10% NaOH was added still under cooling. The solvent was removed under vacuo, the residue was diluted with water and extracted 3 times with EtOAc. The comb. org. layers were dried over MgSO4 and conc. in vacuo to give the desired product as orange oil.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][N:9]2C(=O)C3=CC=CC=C3C2=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.O.NN>CO>[N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1c2ccccc2C(=O)N1CCCN1CCCC1
Agent: NN
Solvent: CO
Solvent: O
Product: NCCCN1CCCC1
Yield: 59.7 %

Procedure:
N-[3-(1-Pyrrolidinyl) propyl] phthalimide (729 mg) and hydrazine monohydrate (284 mg) were dissolved in methanol (9 ml) and the resulting solution was refluxed with heating for 2 hours. After cooling, the reaction solution was concentrated under reduced pressure followed by addition of a 4N sodium hydroxide aqueous solution to the resulting residue and extraction thereof with chloroform. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (Reference Compound 2-1, 216 mg).
Reaction SMILES: [CH2:1]([O:5][CH:6]=[CH2:7])[CH2:2][CH2:3][CH3:4].[C:8]([OH:13])(=[O:12])[C:9]([CH3:11])=[CH2:10]>>[C:8]([O:13][CH:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH3:7])(=[O:12])[C:9]([CH3:11])=[CH2:10]
Reactant: C=COCCCC
Reactant: C=C(C)C(=O)O
Product: C=C(C)C(=O)OC(C)OCCCC

Procedure:
The reaction procedure of Example 1 was repeated using equimolar amounts of n-butylvinyl ether and methacrylic acid. The structure of the product, 1-n-butoxyethyl methacrylate (Compound C) was obtained in 88% yield. Compound C is an example of a mono-functional alpha-alkoxyalkyl(meth)acrylate which may optionally be included with multi-functional alpha-alkoxyalkyl(meth)acrylate compounds in compositions of the present invention. The structure of Compound C was confirmed by 1H NMR and infrared analysis.