Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:11]1[CH2:15][C:14](=[O:16])[N:13]=[C:12]1[NH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:28])([F:27])[F:26])=O)C1C=CC=CC=1.[CH:29]([C:31]1[N:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[N:37]=[CH:36][C:35]([C:41]#[N:42])=[C:34]2[O:43][CH:44]([CH3:46])[CH3:45])=O.N1CCCCC1>CC(O)C>[CH:44]([O:43][C:34]1[C:33]2[C:38](=[CH:39][CH:40]=[C:31]([CH:29]=[C:15]3[C:14](=[O:16])[N:13]=[C:12]([NH:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:26])([F:27])[F:28])[NH:11]3)[N:32]=2)[N:37]=[CH:36][C:35]=1[C:41]#[N:42])([CH3:46])[CH3:45]
Reactant: O=C1CN(C(=O)OCc2ccccc2)C(NCc2ccccc2C(F)(F)F)=N1
Reactant: CC(C)Oc1c(C#N)cnc2ccc(C=O)nc12
Solvent: C1CCNCC1
Solvent: CC(C)O
Product: CC(C)Oc1c(C#N)cnc2ccc(C=C3NC(NCc4ccccc4C(F)(F)F)=NC3=O)nc12
Temperature: 25 °C

Procedure:
To a mixture of 4-oxo-2-(2-trifluoromethyl-benzylamino)-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester (70.4 mg, 0.18 mmol) (prepared as described in C-H Kwon et al. J. Med. Chem. 1991, 34, 1845-1849), 6-formyl-4-isopropoxy-[1,5]naphthyridine-3-carbonitrile (56.5 mg, 0.23 mmol) (see Example 1) and iPrOH (5 mL) in a 25-mL round bottom flask was added piperidine (0.05 mL) and the suspension was then heated under refluxing for 5 h to give a brown solution. The reaction mixture was cooled to r.t. and concentrated to give a light yellow solid, 66.3 mg, which was purified by flash column purification to give 4-isopropoxy-6-[5-oxo-2-(2-trifluoromethyl-benzylamino)-3,5-dihydro-imidazol-4-ylidenemethyl]-[1,5]naphthyridine-3-carbonitrile, as a light yellow solid, 18.6 mg (21.5%). HR-ES (+) m/e calcd for C24H19F3N6O2 (M+H)+ 481.1595. found 481.1595.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:18](=[O:19])[N:9]2[CH2:10][CH2:11][C:12]3[C:17]([C:8]2=[CH:7][CH:6]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:4].[OH-].[Na+]>O1CCOCC1>[O:19]=[C:18]1[N:9]2[CH2:10][CH2:11][C:12]3[C:17]([C:8]2=[CH:7][CH:6]=[C:5]1[C:3]([OH:4])=[O:2])=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: COC(=O)c1ccc2n(c1=O)CCc1ccccc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1ccc2n(c1=O)CCc1ccccc1-2
Reaction time: 1 h
Yield: 87.8 %

Procedure:
To a solution of 4-oxo-6,7-dihydropyrido[2,1,a]isoquinoline-3-carboxylic acid methyl ester (3-101-02) (252 mg) in dioxane (2.0 mL) was 2 mol/L aqueous sodium hydroxide solution (2.0 mL) at room temperature. After the reaction mixture was stirred for 1 h, and washed with diethyl ether, adjusted to be acidic with conc. hydrochloric acid. To the reaction mixture were added water and ethyl acetate, and the organic layer was separated. The aqueous layer was extracted three times with ethyl acetate and the combined organic layers were washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to give 4-oxo-6,7-dihydropyrido[2,1,a]isoquinoline-3-carboxylic acid (3-101-03) (209 mg, 88%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][C:7]2[CH2:11][C:10]([CH2:14][OH:15])([CH2:12][OH:13])ON=2)=[CH:4][CH:3]=1.C(O)(=O)C.O>O1CCCC1.O.[Pt](=O)=O>[OH:13][CH2:12][C:10]1[CH:11]=[C:7]([CH2:6][C:5]2[CH:16]=[CH:17][C:2]([F:1])=[CH:3][CH:4]=2)[O:15][CH:14]=1
Reactant: OCC1(CO)CC(Cc2ccc(F)cc2)=NO1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: OCc1coc(Cc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 63.2 %

Procedure:
67.9 g of 3-(p-fluorobenzyl)-5,5-bis-(hydroxymethyl)-isoxazoline are taken up in 400 ml of tetrahydrofuran, 80 ml of glacial acetic acid and 40 ml of water, and 1.5 g of platinum(IV) oxide hydrate are added. Hydrogenation is carried out for 5-6 hours at 25°-30° C., a slightly exothermic reaction taking place (cooling). When the absorption of hydrogen is complete, the catalyst is filtered off, the filtrate is evaporated down and the residue is stirred in 400 ml of methylene chloride with 400 ml of 10% strength hydrochloric acid for 1 hour at room temperature. The organic phase is separated off, washed neutral, dried over sodium sulfate and evaporated down. Purification by column chromatography over silica gel with toluene/acetone 9/1 as the eluent gives 37 g of 3-hydroxymethyl-5-(p-fluorobenzyl)-furan of melting point 45°-47° C. ##STR13##
Reaction SMILES: [OH:1][CH:2]1[CH:18]2[CH:10]([CH2:11][CH:12]([OH:28])[C:13]3([CH3:27])[CH:17]2[CH2:16][CH2:15][CH:14]3[CH:19]([CH3:26])[CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:9]2([CH3:29])[CH:4]([CH2:5][CH:6]([O:30][CH2:31][CH2:32]O)[CH2:7][CH2:8]2)[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:53]1(=[O:63])[NH:57][C:56](=[O:58])[C:55]2=[CH:59][CH:60]=[CH:61][CH:62]=[C:54]12.C([O-])(O)=O.[Na+]>C1COCC1>[O:58]=[C:56]1[C:55]2[C:54](=[CH:62][CH:61]=[CH:60][CH:59]=2)[C:53](=[O:63])[N:57]1[CH2:32][CH2:31][O:30][CH:6]1[CH2:5][CH:4]2[C:9]([CH3:29])([CH:10]3[CH:18]([CH:2]([OH:1])[CH2:3]2)[CH:17]2[C:13]([CH3:27])([CH:14]([CH:19]([CH3:26])[CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH2:15][CH2:16]2)[CH:12]([OH:28])[CH2:11]3)[CH2:8][CH2:7]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COC(=O)CCC(C)C1CCC2C3C(O)CC4CC(OCCO)CCC4(C)C3CC(O)C12C
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)CCC(C)C1CCC2C3C(O)CC4CC(OCCN5C(=O)c6ccccc6C5=O)CCC4(C)C3CC(O)C12C
Temperature: 45 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
1.5 g of methyl 4-[7,12-Dihydroxy-3-(2-hydroxyethoxy)-10,13-dimethylhexadecahydrocyclopenta[a]phenanthren-17-yl]pentanoate, 950 mg of triphenylphosphine and 550 mg of phthalimide are warmed to 45° C. in 26 ml of THF and 1.14 ml of diethyl azodicarboxylates are added dropwise at this temperature. The reaction mixture is stirred at 45° C. for 2 hours, then poured into 200 ml of a semiconcentrated aqueous NaHCO3 solution and extracted 3 times using 200 ml of EA each time. The extract is dried over Na2SO4 and the solvent is removed in vacuo. Chromatography on silica gel using t-butyl methyl ether (MTB) yields 1.76 g of a viscous oil
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[O:23]1[CH:27]=[C:26]([CH2:28]O)[N:25]=[CH:24]1>>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:28][C:26]3[N:25]=[CH:24][O:23][CH:27]=3)[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: Clc1c(-c2ccccc2)nnc2[nH]nc(-c3ccccc3)c12
Reactant: OCc1cocn1
Product: Clc1c(-c2ccccc2)nnc2c1c(-c1ccccc1)nn2Cc1cocn1

Procedure:
Compound IIh was synthesized from 4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine and oxazol-4-ylmethanol following the general procedure for the Mitsunobu reaction as described above.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]2[O:16][CH2:15]2)=[CH:10][CH:9]=1)[CH:2]([CH3:4])[CH3:3].[NH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH2:30][CH2:31][C:32](=[O:35])[NH:33][N:34]=2)=[CH:25][C:24]=1[CH3:36]>>[CH2:1]([O:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:19][CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH2:30][CH2:31][C:32](=[O:35])[NH:33][N:34]=3)=[CH:25][C:24]=2[CH3:36])=[CH:10][CH:9]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: Cc1cc(C2=NNC(=O)CC2)ccc1OCCN
Reactant: CC(C)COCCc1ccc(OCC2CO2)cc1
Product: Cc1cc(C2=NNC(=O)CC2)ccc1OCCNCC(O)COc1ccc(CCOCC(C)C)cc1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-isobutoxy-ethyl)-phenoxy]-2,3-epoxypropane and 6-[4-(2-aminoethoxy)-3-methyl-phenyl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[OH-].[Na+].[CH2:27](Br)[CH2:28][CH2:29][CH2:30][CH3:31].[Br-].[NH4+]>C(Cl)Cl.O>[CH2:27]([O:1][C:2]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5])[CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCCc1ccc(O)c(C(=O)c2ccccc2)c1
Reactant: CCCCCBr
Agent: [Br-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCCc1ccc(OCCCCC)c(C(=O)c2ccccc2)c1
Yield: 82 %

Procedure:
A solution of 2-hydroxy-5-nonyl benzophenone, 15 g, in 100 mL methylene chloride was mixed with a solution of 9.25 g NaOH in 100 mL water. To this mixture was added 6.9 g n-pentyl bromide and 1.48 g tetra-n-butylv ammonium bromide. The whole mixture was then vigorously agitated overnight at 40° C. After cooling to room temperature with 50 mL CH2Cl2. The combined methylene chloride layers were concentrated to an oil, which was taken up in 100 mL petroleum ether and washed with 100 mL water. Finally, the organic layer was dried over anhydrous magnesium sulfate and the volatiles removed under vacuum to give 15 g (82% yield) of 2-n-pentoxy-5-nonyl benzophenone.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7](C(C3CCCN3)C)[NH:8]2)=[CH:4][CH:3]=1.B1([C:24]2[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=2)OCCCO1>>[NH:8]1[CH2:7][CH2:6][CH2:5][CH:9]1[CH:10]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([C:28]3[CH:27]=[N:26][CH:25]=[CH:24][CH:29]=3)[CH:10]=2)[CH:6]=[CH:7]1)[CH3:2]
Reactant: c1cncc(B2OCCCO2)c1
Reactant: CC(c1cc2ccc(Br)cc2[nH]1)C1CCCN1
Product: CC(C1CCCN1)n1ccc2ccc(-c3cccnc3)cc21

Procedure:
(9.3 mg, 49%); from 6-Bromo-1-(2-pyrrolidinyl)ethyl indole (19.0 mg, 0.065 mmol) and pyridine-3-boronic acid 1,3-propanediol cyclic ester (21.0 mg, 0.130 mmol).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([OH:34])([C:30]([F:33])([F:32])[F:31])[C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O>[Pd].CCO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([S:10]([N:13]2[CH2:14][CH2:15][N:16]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([OH:34])([C:26]([F:29])([F:28])[F:27])[C:30]([F:31])([F:32])[F:33])=[CH:23][CH:24]=3)[CH2:17][CH2:18]2)(=[O:11])=[O:12])=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)N2CCN(c3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)N2CCN(c3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Reaction time: 12 h
Yield: 53.1 %

Procedure:
A 100-mL round-bottomed flask was charged with 2-(4-(4-((4-nitrophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (180 mg) and EtOH (20 mL). The reaction was placed under an atmosphere of argon. 10% Pd/C (37.3 mg, 0.351 mmol, Sigma-Aldrich, St. Louis, Mo.) was added and the reaction stirred under a balloon atmosphere of H2 (0.707 mg, 0.351 mmol) for 12 h. The reaction was carefully filtered through a pad of Celite®(diatomaceous earth), rinsing with EtOH. The crude material was concentrated onto silica gel and purified via column chromatography (40 g silica gel, 0 to 10% MeOH in CH2Cl2) to give 2-(4-(4-((4-aminophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (90 mg). 1H NMR (400 MHz, CD3OD) δ=7.54 (d, J=8.8 Hz, 2H), 7.48 (d, J=8.6 Hz, 2H), 6.98 (d, J=9.0 Hz, 2H), 6.73 (d, J=8.6 Hz, 2H), 3.31-3.26 (m, 4H), 3.11-3.03 (m, 4H). m/z (ESI, +ve ion) 484.1 (M+H)+. GK-GKRP IC50 (Binding)=0.582 μM; GK-GKRP EC50 (LC MS/MS-2)=0.828 μM.
Reaction SMILES: FC(F)(F)C(O)=O.[Si]([O:25][CH2:26][C:27]1[NH:28][C:29](=[O:45])[N:30]([CH:32]2[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]2)[CH:31]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>ClCCl>[OH:25][CH2:26][C:27]1[NH:28][C:29](=[O:45])[N:30]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)[nH]c2=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1[nH]c(CO)cn1C1CCNCC1
Reaction time: 0.5 h

Procedure:
Trifluoroacetic acid (5 mL) was added to a solution of tert-butyl 4-[4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]piperidine-1-carboxylate (550 mg, 1.03 mmol) in dichloromethane (15 mL). After 30 min, the reaction was concentrated to give the title compound.
Reaction SMILES: [C:1]([O-:5])(=[O:4])[CH:2]=[CH2:3].[Na+].CC(=C)C(OCCC[CH2:15][CH2:16][CH2:17][O:18][C:19]([CH:21]1[CH2:26][CH2:25][CH:24]([CH:27]2[CH2:32][CH2:31][CH:30]([CH2:33][CH2:34][CH2:35]CC)[CH2:29][CH2:28]2)[CH2:23][CH2:22]1)=[O:20])=O.[I-].[Na+].O>CN(C)C=O>[C:1]([O:5][CH2:15][CH2:16][CH2:17][O:18][C:19]([CH:21]1[CH2:26][CH2:25][CH:24]([CH:27]2[CH2:28][CH2:29][CH:30]([CH2:33][CH2:34][CH3:35])[CH2:31][CH2:32]2)[CH2:23][CH2:22]1)=[O:20])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)[O-]
Reactant: C=C(C)C(=O)OCCCCCCOC(=O)C1CCC(C2CCC(CCCCC)CC2)CC1
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CC(=O)OCCCOC(=O)C1CCC(C2CCC(CCC)CC2)CC1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
A mixture of sodium acrylate (2.5 g, 13.4 mmol), 4′-propyl-bicyclohexyl-4-carboxylic acid 3-bromo-propyl ester (synthesis described for preferred example 1) (5.0 g, 13.4 mmol) and sodium iodide (2.5 g, 16.7 mmol) in dimethylformamide (150 ml) is stirred at 130° C. overnight. The mixture is cooled to room temperature, poured into water, and this is extracted twice with diethyl ether. The ethereal solution is washed with water and then dried over sodium sulphate. The solution is evaporated to dryness and purified by flash column chromatography using DCM/petrol (1/1) as eluant to give upon evaporation of the appropriate fractions a colourless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17]C)[CH:12]=3)[C:5]2=[N:6][CH:7]=1.N1C2C=CC=CC=2NC=1>Br.C(O)(=O)C.[OH-].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([C:11]3[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=3)[C:5]2=[N:6][CH:7]=1
Reactant: COc1cccc(-n2cnc3cc(Br)cnc32)c1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Oc1cccc(-n2cnc3cc(Br)cnc32)c1
Temperature: 100 °C
Yield: 100.5 %

Procedure:
A suspension of 6-bromo-3-(3-methoxyphenyl)-3H-imidazo[4,5-b]pyridine (10.7 g, 35 mmol) in hydrobromic acid (80 ml of a 30 wt. % solution in acetic acid) was heated at 100° C. for 20 hours. After cooling to ambient temperature the reaction mixture was slowly dissolved in excess 3N sodium hydroxide, keeping the temperature <20° C. (to prevent hydrolysis of the benzimidazole back to the bis-amine). The aqueous phase was extracted with ether (×2) then adjusted to pH 7 with concentrated hydrochloric acid. The resulting solid was collected by filtration, washed with water and dried under high vacuum to give 3-(6-bromoimidazo[4,5-b]pyridin-3-yl)phenol as a beige-coloured solid (10.2 g, 99%); δH (400 MHz, d6-DMSO) 6.88 (1H, ddd, J 8, 2 and 1), 7.28 (1H, ddd, J 8, 2 and 1), 7.35-7.41 (2H, m), 8.52 (2H, dd, J 11 and 2), 8.91 (1H, s), 9.96 (1H, br s); m/z (ES+) 290 and 292 (M++H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:17][CH2:18][CH3:19])[CH2:5][C:6]#[C:7][C:8]([NH:10][C:11]1[S:15][N:14]=[C:13]([CH3:16])[CH:12]=1)=[O:9])[CH3:2].ClC1C=CC=CC=1.[N:27]([CH:30]([C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[N:38]=[CH:37][C:36]([O:42][CH2:43][CH2:44][O:45][CH3:46])=[CH:35]2)[CH3:31])=[N+:28]=[N-:29]>>[CH2:18]([O:17][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][C:6]1[N:29]=[N:28][N:27]([CH:30]([C:32]2[CH:33]=[C:34]3[C:39](=[CH:40][CH:41]=2)[N:38]=[CH:37][C:36]([O:42][CH2:43][CH2:44][O:45][CH3:46])=[CH:35]3)[CH3:31])[C:7]=1[C:8]([NH:10][C:11]1[S:15][N:14]=[C:13]([CH3:16])[CH:12]=1)=[O:9])[CH3:19]
Reactant: CCOC(CC#CC(=O)Nc1cc(C)ns1)OCC
Reactant: COCCOc1cnc2ccc(C(C)N=[N+]=[N-])cc2c1
Solvent: Clc1ccccc1
Product: CCOC(Cc1nnn(C(C)c2ccc3ncc(OCCOC)cc3c2)c1C(=O)Nc1cc(C)ns1)OCC
Temperature: 100 °C

Procedure:
5,5-diethoxy-N-(3-methylisothiazol-5-yl)pent-2-ynamide (0.700 g, 2.5 mmol) was dissolved in chlorobenzene (2.5 mL, 2.5 mmol), and to the solution was added 6-(1-azidoethyl)-3-(2-methoxyethoxy)quinoline (0.68 g, 2.5 mmol). The mixture was heated to 100° C. overnight and then increased to 110° C. for 5.5 h. The reaction was concentrated in vacuo. The compound was purified via MPLC (eluting with 0-40% EtOAc in hexanes) to yield 5-(2,2-diethoxyethyl)-3-(1-(3-(2-methoxyethoxy)quinolin-6-yl)ethyl)-N-(3-methylisothiazol-5-yl)-3H-1,2,3-triazole-4-carboxamide.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:42])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][C:14]=2[CH2:28][N:29]2[C@@H:33]([CH3:34])[C@@H:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[O:31][C:30]2=[O:41])[CH:7]=1)[CH3:2].Br[C:44]1[N:45]=[C:46]([CH3:50])[N:47]([CH3:49])[CH:48]=1>>[CH2:1]([O:3][C:4](=[O:42])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:44]3[N:45]=[C:46]([CH3:50])[N:47]([CH3:49])[CH:48]=3)=[CH:15][C:14]=2[CH2:28][N:29]2[C@@H:33]([CH3:34])[C@@H:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[O:31][C:30]2=[O:41])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1
Reactant: Cc1nc(Br)cn1C
Product: CCOC(=O)Cc1cccc(Oc2ccc(-c3cn(C)c(C)n3)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 19, Step 3, using the following starting materials: {3-[2-((4S,5R)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-phenyl}-acetic acid ethyl ester and 4-bromo-1,2-dimethyl-1H-imidazole.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.Cl.[NH2:11][OH:12].[OH-].[Na+]>C(O)C.O>[F:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[N:11]\[OH:12])=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=Cc1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O/N=C\c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 279.1 %

Procedure:
To a suspension of 4-fluorobenzaldehyde (24.8 g, 200 mmol) (6.75 g, 54 mmol) and hydroxylamine hydrochloride (4.16 g, 60 mmol) in ethanol (4.3 mL) and water (13 mL) was added ice (25 g). Then a solution of sodium hydroxide (5.5 g, 138 mmol) in water (6.5 mL) was added dropwise within a 10 min period (temperature rises from −8° C. to +7° C.) whereupon most of the solid dissolves. After 30 min stirring at room temperature a white solid precipitated and the resulting mixture was then diluted with water and acidified with HCl (4 N). The white precipitate was then filtered off, washed with water and dried under high vacuum to afford the title compound (23.3 g, 84%) which was obtained as a white solid. MS: m/e=139.1 [M]+.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([Cl:23])=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].[CH3:25][C:26]1[S:30][CH:29]=[N:28][CH:27]=1>>[Cl:23][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:29]4[S:30][C:26]([CH3:25])=[CH:27][N:28]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: Cc1cncs1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3cccnc3Cl)c2)cn1
Product: Cc1cnc(C(=O)c2cn(-c3cccc(-c4cccnc4Cl)c3)cn2)s1

Procedure:
This compound is prepared by method C using compound 12l and 5-methylthiazole
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4]1([CH2:10][CH2:11][CH2:12][C:13]2[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=2[O:15][CH2:16][CH:17]2[CH2:19][O:18]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O1CCCC1>[CH3:1][N:2]([CH2:19][CH:17]([OH:18])[CH2:16][O:15][C:14]1[CH:20]=[CH:21][CH:22]=[CH:23][C:13]=1[CH2:12][CH2:11][CH2:10][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:3]
Reactant: c1ccc(CCCc2ccccc2OCC2CO2)cc1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)CC(O)COc1ccccc1CCCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 59 %

Procedure:
3 ml of 50% by volume aqueous dimethylamine were added to a solution of 0.45 g of 2-[2-(3-phenylpropyl)phenoxymethyl]oxirane [prepared as described in step (a) above] in 10 ml of tetrahydrofuran, and the mixture was stirred at room temperature for one day. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 20:1 by volume mixture of methylene chloride and methanol as the eluent, to give 0.31 g (yield 59%) of the title compound as a colorless oil.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([N:17]2[CH2:22][CH2:21][CH:20]([CH2:23]O)[CH2:19][CH2:18]2)=[O:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:25]N1C(=O)CCC1=O>C1C=CC=CC=1>[Br:25][CH2:23][CH:20]1[CH2:21][CH2:22][N:17]([C:15]([O:14][C:11]2[CH:12]=[CH:13][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:9][CH:10]=2)=[O:16])[CH2:18][CH2:19]1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(Oc1ccc(Oc2ccccc2)cc1)N1CCC(CO)CC1
Solvent: c1ccccc1
Product: O=C(Oc1ccc(Oc2ccccc2)cc1)N1CCC(CBr)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 210.1 %

Procedure:
The hydroxymethyl derivative produced in Example 30 (5.0 g, 15 mmol) and wiphenylphosphine (4.0 g, 15 mmol) were dissolved in 100 ml of benzene and the resulting solution put under a nitrogen atmosphere. N-Bromosuccinimide (2.7 g, 15 mmol) was added in portions to the above solution and the reaction stirred at room temperature overnight. The solvent was removed under reduced pressure to give 12.3 g of a brown oil. Purification of this oil by chromatography on 600 g of silica gel (230-400 mesh) using ethyl acetate-hexane as the eluent gave 4.52 g of a white solid. Recrystallization of this solid from diisopropyl ether gave the title compound as a white crystalline solid (4.12 g, 68%), mp 76°-78° C.
Reaction SMILES: C1C[N:4]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[Cl:34][C:35]1[CH:61]=[CH:60][C:38]2[N:39]([C:47]([C:49]3[CH:50]=[CH:51][C:52]4[O:57][CH2:56][C:55](=[O:58])[NH:54][C:53]=4[CH:59]=3)=[O:48])[C@@H:40]([CH2:43][C:44]([OH:46])=O)[CH2:41][O:42][C:37]=2[CH:36]=1.[NH4+].[Cl-].CCOC(C)=O>C(Cl)Cl>[Cl:34][C:35]1[CH:61]=[CH:60][C:38]2[N:39]([C:47]([C:49]3[CH:50]=[CH:51][C:52]4[O:57][CH2:56][C:55](=[O:58])[NH:54][C:53]=4[CH:59]=3)=[O:48])[C@@H:40]([CH2:43][C:44]([NH2:4])=[O:46])[CH2:41][O:42][C:37]=2[CH:36]=1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: O=C(O)C[C@H]1COc2cc(Cl)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: NC(=O)C[C@H]1COc2cc(Cl)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52.3 %

Procedure:
PyBOP (127 mg, 0.24 mmol) and TEA (0.141 mL, 1.02 mmol) was added to a solution of {(3S)-7-chloro-4-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl]-3,4-dihydro-2H-1,4-benzoxazin-3-yl}acetic acid (Intermediate 22a, 82 mg, 0.20 mmol) in DCM (2 mL). Thereafter, NH4Cl (43.6 mg, 0.81 mmol) was added and the mixture was stirred at rt for 1.5 h. EtOAc (30 mL) was added and the mixture was washed with sat. aq. Na2CO3 (30 mL), HCl (0.5M, 20 mL) and brine (20 mL). The product was purified by preparative HPLC (Phenomenex Luna Hilic column (5 μm 250×30 ID mm) using a gradient of 10 to 45% MeOH/DEA 100/0.5 in CO2, 120 bar, over 6 min at 40 OC) to give the title compound (42.0 mg, 51.3%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH2:10])(=[O:9])=[O:8])=[CH:4][CH:3]=1.[OH-].[Na+].[N+:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1)([O-:15])=[O:14].Cl>CC(C)=O>[Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C:20]([C:19]2[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:24][CH:23]=2)=[O:21])(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1ccc(Cl)s1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C(NS(=O)(=O)c1ccc(Cl)s1)c1ccc([N+](=O)[O-])cc1
Reaction time: 12 h
Yield: 80.5 %

Procedure:
A 85 mg portion (0.43 mmol) of 5-chlorothiophenesulfonamide dissolved in 2 mL of acetone was treated with 110 μL of 4N NaOH (0.43 mmol) followed by addition of 80 mg (0.43 mmol) of 4-nitrobenzoyl chloride. After stirring for 12 h, the solution was acidfied 1N HCl and the precipitate was collected by filtration and dried. Recrystallization from EtOAc/hexane afforded 120 mg (81%) of the titled compound. ES-MS (M+H)+=347 (Cl).