Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:17][CH2:18][C@H:19]([CH2:21][O:22][C:23]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH-].[K+].O>C1C=CC=CC=1>[CH2:1]([O:17][CH2:18][C@H:19]([CH2:21][O:22][C:23]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[O:20][CH2:1][CH2:2][CH:3]=[CH:4][CH2:5][CH3:6])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCOC[C@@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: CCC=CCCO[C@H](COCCCCCCCCCCCCCCCC)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 195.4 %

Procedure:
10.60 grams of (R)-1-hexadecyl-3-trityl-sn-glycerol was dissolved in a mixture of 50 ml benzene and 50 ml petroleum ether. 16.65 grams of powdered KOH was added, and the reaction mixture was heated to reflux under nitrogen. A solution of 10 ml 3-hexenyl-1-methane sulfonate in 50 ml benzene and 200 ml petroleum ether was added dropwise to the refluxing reaction mixture over the course of over 10 hours while removing the water formed in the reaction by azeotropic distillation. After completion of the addition, stirring was continued for 2 hours. The reaction mixture was cooled to room temperature and 200 ml water was added. The mixture was extracted thrice with 200 ml diethyl ether, the combined organic phase was washed thrice with 200 ml water, and the solvent was removed under reduced pressure, yielding 11.88 grams of crude (R)-1-hexadecyl-2-(3 hexenyl)-3-trityl-sn-glycerol. The 1-hexadecyl-2-(3-hexenyl)-3-trityl-glycerol was dissolved in 100 ml methanol, 4 ml concentrated HCl was added, and the resulting solution was refluxed for 4 hours. 100 ml water was added and the mixture extracted four times with 100 ml diethyl ether. The combined organic phase was washed with 100 ml water and dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. The obtained residue was dissolved in hexane and stored at 4° C. overnight. Filtration of the precipitate and removal of the solvent under reduced pressure yielded 10.08 grams of crude product. This product was purified by chromatography on silica gel (95.91 grams). 3.71 grams of the product, (S)-1-hexadecyl-2-(3′-hexenyl)-sn-glycerol, was eluted with a 1:1 (v/v) mixture of hexane and chloroform, followed by chloroform and then chloroform with 2% acetone.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[CH:18]=[N:19][C:20]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:21][CH:22]=2)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:31][Si](C)(C)[N-][Si](C)(C)C.[Na+].CI>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[CH:18]=[N:19][C:20]([N:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH3:31])=[CH:21][CH:22]=2)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)cn1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CN(C(=O)OC(C)(C)C)c1ccc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)cn1

Procedure:
The above prepared 4-[(6-tert-butoxycarbonylamino-pyridine-3-carbonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (0.720 g, 1.71 mmol) was dissolved in 30 ml of abs. THF and treated at 0° C. with sodium hexamethyldisilazide-solution (1M in THF, 1.05 eq.) and, after 15 Min., 50 eq. of methyl iodide (5.33 ml). The mixture was allowed to react for six days! Pouring onto crashed ice/NH4Cl, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (silica gel, hexane/AcOEt=55/45) yielded eventually 0.497 g of the title compound as white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([CH3:12])=[CH:5]2.[N+:13]([O-])([O-:15])=[O:14].[K+].N.ClCCl.CCCCC>OS(O)(=O)=O>[Cl:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([CH3:12])=[CH:5]2
Reactant: Cc1cc2cc(Cl)ccc2cn1
Reactant: O=[N+]([O-])[O-]
Agent: N
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: ClCCl
Solvent: CCCCC
Product: Cc1cc2c([N+](=O)[O-])c(Cl)ccc2cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
To a solution of 6-chloro-3-methylisoquinoline (10.0 g, 57.5 mmol) in concentrated H2SO4 (100 mL) was added dropwise during 10 min. a solution of KNO3 (6.05 g, 60 mmol) in concentrated H2SO4 (50 mL) at 5° C. Care was taken that the temperature of the reaction mixture did not rise above 10° C. The reaction mixture was stirred for 3 h at room temperature, poured onto ice (200 g) and rendered basic (pH=10) with a 33% aqueous ammonia solution. A dark yellow precipitate was formed, which was filtered off, thoroughly rinsed with water and taken up in dichloromethane. The organic phase was washed with water and brine, dried over Na2SO4, filtered and dried in vacuo to afford a pale brown solid. Re-crystallization from dichloromethane/pentane afforded the title compound as pale brown crystals (9.2, 41.4 mmol, 72%). MS (ES+): 223 (M(C10H735ClN2O2)+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[CH:10][C:5]2[N:6]=[C:7]([SH:9])[NH:8][C:4]=2[CH:3]=1.Cl.Cl[CH2:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18]>>[CH3:12][C:11]1[C:2]([CH3:1])=[CH:3][C:4]2[NH:8][C:7]([S:9][CH2:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[NH2:18])=[N:6][C:5]=2[CH:10]=1
Reactant: Nc1ccccc1CCl
Reactant: Cc1cc2nc(S)[nH]c2cc1C
Agent: Cl
Product: Cc1cc2nc(SCc3ccccc3N)[nH]c2cc1C

Procedure:
The title compound was prepared by the method of Example 1 using 2.56 g of 5,6-dimethyl-2-mercaptobenzimidazole instead of 2-mercaptobenzimidazole and 2.56 g of 2-(chloromethyl) aniline hydrochloride instead of 2-(chloromethyl)-N,N-dimethylaniline. Instead of using sodium carbonate in an extraction, the crude precipitate was neutralized with triethylamine in methanol. Trituration of the resultant crude title compound with methanol and diethyl ether gave 2.0 g of analytically pure title compound. Anal. Calc'd. for C15H15N3S: C, 67.81; H, 6.05; N,14.83; S, 11.31. Found: C, 67.21; H, 6.16; N, 14.50; S, 11.06.
Reaction SMILES: [F:1][C:2]1([F:52])[C:6]2[N:7]([CH2:14][C:15]([NH:17][C@H:18]([C:28]3[C:33]([C:34]4[CH:35]=[CH:36][CH:37]=[C:38]5[C:42]=4[N:41]([CH3:43])[N:40]=[C:39]5[NH:44][S:45]([CH3:48])(=[O:47])=[O:46])=[CH:32][N:31]=[C:30](SC)[N:29]=3)[CH2:19][C:20]3[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=3)=[O:16])[N:8]=[C:9]([C:10]([F:13])([F:12])[F:11])[C:5]=2[C@H:4]2[CH2:51][C@@H:3]12.C1C=C(Cl)C=C(C(OO)=O)C=1.C(N(CC)C(C)C)(C)C.Cl.[CH3:74][C:75]1([OH:79])[CH2:78][NH:77][CH2:76]1>C(Cl)Cl>[F:1][C:2]1([F:52])[C:6]2[N:7]([CH2:14][C:15]([NH:17][C@H:18]([C:28]3[C:33]([C:34]4[CH:35]=[CH:36][CH:37]=[C:38]5[C:42]=4[N:41]([CH3:43])[N:40]=[C:39]5[NH:44][S:45]([CH3:48])(=[O:47])=[O:46])=[CH:32][N:31]=[C:30]([N:77]4[CH2:78][C:75]([OH:79])([CH3:74])[CH2:76]4)[N:29]=3)[CH2:19][C:20]3[CH:21]=[C:22]([F:27])[CH:23]=[C:24]([F:26])[CH:25]=3)=[O:16])[N:8]=[C:9]([C:10]([F:11])([F:13])[F:12])[C:5]=2[C@H:4]2[CH2:51][C@@H:3]12
Reactant: CSc1ncc(-c2cccc3c(NS(C)(=O)=O)nn(C)c23)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2C(F)(F)[C@@H]2C[C@H]32)n1
Reactant: CC1(O)CNC1
Agent: Cl
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1nc(NS(C)(=O)=O)c2cccc(-c3cnc(N4CC(C)(O)C4)nc3[C@H](Cc3cc(F)cc(F)c3)NC(=O)Cn3nc(C(F)(F)F)c4c3C(F)(F)[C@@H]3C[C@H]43)c21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Compound 36B (30 mg, 0.039 mmol) was dissolved in 3 mL of CH2Cl2 and to it was added m-CPBA (17.5 mg, 77%, 0.078 mmol). The reaction mixture was allowed to stir at rt for 20 min. To the reaction mixture was added N,N-diisopropylethylamine (0.2 mL, 0.017 mmol) and 3-methylazetidin-3-ol hydrochloride (34 mg, 0.39 mmol). The reaction mixture was allowed to stir at room temperature for 30 min and then partitioned between EtOAc and brine. The organic layer was separated, washed with brine and dried over Na2SO4 and concentrated. The residue was purified by RP-HPLC eluting with acetonitrile/H2O (with 0.1% TFA) to afford the title product. 1H NMR (400 MHz, methanol-d4) δ 8.53 (dd, 1H), 8.25 (d, 1H), 7.83 (m, 1H), 7.36-6.52 (m, 3H), 6.47-6.22 (m, 2H), 4.85 (m, 3H), 4.40-3.94 (m, 4H), 3.75-2.67 (m, 8H), 2.51 (m, 2H), 1.60 (s, 3H), 1.51-1.23 (m, 1H), 1.18-0.88 (m, 1H). MS (m/z): 808.01 [M+H]+.
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][OH:10]>C(O)C>[OH:10]/[N:9]=[C:1](\[NH2:8])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: N#Cc1ccccc1
Solvent: CCO
Product: N/C(=N\O)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of ethanol (5.0 mL), benzonitrile (203 mg, 1.97 mmol) and hydroxylamine (520 mg, 7.87 mmol) were refluxed for 1 hour. The reaction was then cooled to room temperature and concentrated in vacuo to give the a clear oil which was taken to the next step without further purification (268 mg, 100%). 1H NMR (500 MHz, CDCL3) δ(ppm): 4.92 (2H, bs), 7.38-7.44 (3H, m), 7.62-7.65 (2H, m). 13C NMR (125 MHz, CDCL3) δ(ppm): 126.1 (CH), 128.9 (CH), 130.2 (CH), 132.6, 152.8. MS (FAB+): 137 (MH+). HRMS for C7H8N2O (MH+): calculated: 137.0715; found 137.0718.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]1[C:7]([CH3:22])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1.Br[CH2:24][C:25]1[CH:37]=[CH:36][C:28]([O:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:27]([CH3:38])[CH:26]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:24][C:25]1[CH:37]=[CH:36][C:28]([O:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:27]([CH3:38])[CH:26]=1)[C:6]1[C:7]([CH3:22])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: COCCNc1cccc(-c2ccc(C(F)(F)F)cc2)c1C
Reactant: CCOC(=O)COc1ccc(CBr)cc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)COc1ccc(CN(CCOC)c2cccc(-c3ccc(C(F)(F)F)cc3)c2C)cc1C
Yield: 60.2 %

Procedure:
To a solution of N-(2-methoxyethyl)-2-methyl-4′-(trifluoromethyl)-1,1′-biphenyl-3-amine (500 mg, 1.62 mmol) in acetonitrile (30 mL) was added ethyl [4-(bromomethyl)-2-methylphenoxy]acetate (488 mg, 1.7 mmol) and N,N-diisopropylethylamine (295 μl, 1.7 mmol). The resultant mixture was heated for 4.5 h at 80° C. On cooling the solvents were removed in vacuo, the residue diluted with water and extracted with CH2Cl2. The organic solution was passed through a hydrophobic frit and the solvent removed in vacuo. Purification by Biotage™ chromatography (silica, 40 g) eluted with 5% EtOAc/cyclohexane afforded the title compound as a colourless oil (503 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.Cl.[N+:26]([C:29]1[CH:30]=[C:31]([C@H:35]([NH2:37])[CH3:36])[CH:32]=[CH:33][CH:34]=1)([O-:28])=[O:27].O>C(#N)C>[N+:26]([C:29]1[CH:30]=[C:31]([C@H:35]([NH:37][C:2]2[C:11]3[C:6](=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH3:36])[CH:32]=[CH:33][CH:34]=1)([O-:28])=[O:27]
Reactant: C[C@@H](N)c1cccc([N+](=O)[O-])c1
Reactant: COC(=O)c1cccc2c(Cl)ncnc12
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1cccc2c(N[C@H](C)c3cccc([N+](=O)[O-])c3)ncnc12
Temperature: 45 °C
Reaction time: 4 h

Procedure:
A suspension of methyl 4-chloroquinazoline-8-carboxylate (7.18 g, 32.25 mmol) in acetonitrile (70 mL), was treated with N,N-diisopropylethylamine (21.69 g, 167.81 mmol, 5 eq), followed by (1R)-1-(3-nitrophenyl)ethanamine hydrochloride (6.80 g, 33.56 mmol). The suspension was warmed to 45° C. and stirred for 4 h. The reaction mixture was slowly added to water (1000 mL) to precipitate an off-white solid. The solid was filtered to get 8.52 g (24.18 mmol, 75%). LCMS: (M+1) 353.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)C.Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27]>C1(C)C=CC=CC=1>[C:26]([N:2]([CH2:4][CH:5]([CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:10][CH:9]=1)[CH3:1])([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)Cl
Reactant: CN(C)CC(COc1ccc(C(F)(F)F)cc1)Cc1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)N(C)CC(COc1ccc(C(F)(F)F)cc1)Cc1ccccc1
Temperature: 25 °C

Procedure:
A solution of N,N-dimethyl-2-benzyl-3-(4-trifluoromethylphenoxy)propylamine (22.0 g) and ethyl chloroformate (34.1 g, 30.0 ml) in dry toluene (200 ml) is refluxed for 72 hours. The reaction mixture is cooled to room temperature, and the solvent removed under reduced pressure. Water (200 ml) is added, and the mixture extracted with dichloromethane (2×150 ml). The combined dichloromethane extracts are washed with 2N hydrochloric acid (200 ml) and water (200 ml), and dried over magnesium sulfate. The solvent is removed under reduced pressure to give N-carbethoxy-N-methyl-2-benzyl-3-(4-trifluoromethylphenoxy)propylamine as an oil, which is used without purification for the next synthetic step above.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:7])=[CH:4][CH:3]=1.C([Li])(C)(C)C.[CH3:27][O:28][C:29]1[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[CH:33][C:30]=1[CH:31]=[O:32]>C1COCC1>[CH:14]1([N:8]([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6](=[O:7])[C:5]2[CH:20]=[CH:21][C:2]([CH:31]([OH:32])[C:30]3[CH:33]=[C:34]([O:39][CH3:40])[C:35]([O:37][CH3:38])=[CH:36][C:29]=3[O:28][CH3:27])=[CH:3][CH:4]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COc1cc(OC)c(OC)cc1C=O
Reactant: O=C(c1ccc(Br)cc1)N(C1CCCCC1)C1CCCC1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1cc(OC)c(C(O)c2ccc(C(=O)N(C3CCCCC3)C3CCCC3)cc2)cc1OC
Reaction time: 0.33 h

Procedure:
To a cold (-70° C.), stirred solution of 4-bromo-N-cyclohexyl-N-cyclopentylbenzamide (1.5 g, 4.3 mmol) in THF (20 ml) was added slowly a solution of tertbutyllithium (5 ml of 1.7 M solution in pentane) under an Argon atmosphere. The reaction was stirred at -70° to -75° for 20 min. and a solution of 2,4,5-trimethoxybenzaldehyde (843 mg, 4.3 mmol) in THF (10 ml) was added dropwise over 30 min. The reaction was stirred at -70° to -75° for 30 min. and at room temperature for 1 hr. The reaction was quenched by the addition of water and the aqueous layer extracted three times with ethyl acetate. The combined organic layers were washed with water and dried (Na2SO4). The drying agent was filtered and the filtrate concentrated in vacuo to give the crude product. Purification was effected by chromatography on silica gel using mixtures of ethyl acetate and hexane. The product was isolated as a glass.
Reaction SMILES: [Li].CCC(=O)CC(=O)CC.C([O:18][C:19]1[CH:20]=[C:21]([CH2:33][CH2:34][CH:35]=[CH:36][CH2:37][CH2:38][CH:39]([C:44](=[O:47])[CH2:45][CH3:46])[C:40](=[O:43])[CH2:41][CH3:42])[CH:22]=[CH:23][C:24]=1[O:25]CC1C=CC=CC=1)C1C=CC=CC=1>>[OH:18][C:19]1[CH:20]=[C:21]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH:39]([C:40](=[O:43])[CH2:41][CH3:42])[C:44](=[O:47])[CH2:45][CH3:46])[CH:22]=[CH:23][C:24]=1[OH:25]
Reactant: CCC(=O)C(CCC=CCCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)C(=O)CC
Agent: CCC(=O)CC(=O)CC
Agent: [Li]
Product: CCC(=O)C(CCCCCCc1ccc(O)c(O)c1)C(=O)CC

Procedure:
[I; Ar is 3,4-(HO)2C6H3, R0 is H, R' and R" are CH3CH2CO, Y is CH2CH2CH2CH2 ] was prepared from the compound of Preparation D17 and the lithium salt of 3,5-heptanedione, followed by catalytic hydrogenation of the resulting 4-[6-(3,4-dibenzyloxyphenyl)-3-hexenyl]-3,5-heptanedione. It was obtained as an amber oil after chromatography.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:23]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[CH:22][N:21]([CH2:30][CH2:31][OH:32])[N:20]=2)=[CH:15][CH:14]=1.N1C=CC=CC=1.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH3:39][S:40]([O:32][CH2:31][CH2:30][N:21]1[CH:22]=[C:23]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[C:19]([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][N:6]=4)[N:1]=3)=[CH:18][CH:17]=2)=[N:20]1)(=[O:42])=[O:41]
Reactant: CS(=O)(=O)Cl
Reactant: OCCn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ncccc4n3)cc2)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ncccc4n3)cc2)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A stirred solution of Intermediate 5B, 2-(3-(4-((1,5-naphthyridin-2-yl)methoxy)phenyl)-4-(pyridin-4-yl)-1H-pyrazol-1-yl)ethanol in DCM is cooled at 0° C. Pyridine (12 equivalents) and methanesulfonyl chloride (8 equivalents) are added and the reaction mixture is stirred at 0° C. for 1 h. The mixture is quenched with water and extracted with more DCM. The organic solvent is separated, dried (MgSO4), and concentrated under reduced pressure. The crude residue is purified by silica gel column chromatography. The desired fractions are collected and concentrated under reduced pressure to yield 2-(3-(4-((1,5-naphthyridin-2-yl)methoxy)phenyl)-4-(pyridin-4-yl)-1H-pyrazol-1-yl)ethyl methanesulfonate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[CH:7]([N:12]=[C:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:8][CH2:9][CH:10]=[CH2:11])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl-].C([Al+]CC)C.[CH:43](=[O:46])[CH2:44][CH3:45]>C1COCC1>[C:1]([O:5][C:6]([C:7]1([CH2:8][CH2:9][CH:10]=[CH2:11])[CH:43]([CH2:44][CH3:45])[O:46][C:13]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:12]1)=[O:26])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC=O
Reactant: C=CCCC(N=C(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Agent: CC[Al+]CC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Solvent: C1CCOC1
Product: C=CCCC1(C(=O)OC(C)(C)C)NC(c2ccccc2)(c2ccccc2)OC1CC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
While under a nitrogen atmosphere, a stirred solution of 2-(benzhydrylidene-amino)-hex-5-enoic acid tert-butyl ester (350 mg, 1 mmol) in THF (5 mL, 0.2 M) was cooled to −78° C. and carefully treated with sodium bis(trimethylsilyl)amide (2 mL, 1 M, 2 equiv). After stirring 30 min, diethyl aluminum chloride (2.4 mL, 1 M, 2.4 equiv) was added and the reaction mixture was stirred an additional 30 min. Propionaldehyde (94 μl, 1.25 mmol, 1.25 eq) was added to the solution and the cooling bath was removed. After stirring overnight the reaction mixture was cooled to 0° C. and quenched with saturated NH4Cl. The resulting solution was diluted with ethyl acetate and washed successively with water and saturated potassium sodium tartrate, dried over MgSO4, filtered and concentrated. Purification by MPLC (1-40% ethyl acetate in heptane) gave 4-but-3-enyl-5-ethyl-2,2-diphenyl-oxazolidine-4-carboxylic acid tert-butyl ester (349 mg, 0.86 mmol, 86%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][CH2:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH2:3][CH2:2]1.Cl.[NH2:18][OH:19].C(N(CC)CC)C>C(O)C>[OH:19][N:18]=[C:13]([C:12]1[CH:11]=[CH:10][C:9]([CH2:8][O:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[CH:16][CH:15]=1)[NH2:14]
Reactant: NO
Reactant: N#Cc1ccc(COC2CCOCC2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: NC(=NO)c1ccc(COC2CCOCC2)cc1
Temperature: 25 °C

Procedure:
A solution of 4-[(tetrahydro-2H-pyran-4-yloxy)methyl]benzonitrile (Step 1, 1.50 g, 6.90 mmol), hydroxylamine hydrochloride (1.06 g, 15.2 mmol) and triethylamine (2.11 mL, 15.2 mmol) in ethanol (35 mL) was stirred and heated at reflux for 1 h. After being cooled to rt, the reaction mixture was evaporated to dryness. The resulting material was treated with ethyl acetate, and the solid was filtered off. The ethyl acetate solution was washed with water and saturated sodium chloride solution, dried with anhydrous magnesium sulfate and filtered. After evaporation of the solvent, the title compound was obtained (556 mg, 32%): 1H NMR (400 MHz, CDCl3) δ 7.62 (d, 2H), 7.38 (d, 2H), 4.85 (broad s, 2H), 4.60 (s, 2H), 4.00-3.92 (m, 2H), 3.62-3.55 (m, 1H), 3.49-3.40 (m, 2H), 1.96-1.90 (m, 2H), 1.72-1.60 (m, 2H); ES-MS m/z 251, HPLC RT (Method K) 0.34 min.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].[CH3:12][C:13]1[O:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>CCO.O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]2[O:10][C:17]([C:16]3[O:19][C:13]([CH3:12])=[CH:14][CH:15]=3)=[N:11][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: Cc1ccc(C=O)o1
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: O
Solvent: CCO
Product: Cc1ccc(-c2nc3cc([N+](=O)[O-])ccc3o2)o1
Reaction time: 0.08 h
Yield: 50 %

Procedure:
7.70 g (0.05 mole) of 4-nitro-2-aminophenol and 5.50 g (0.05 mole) of 5-methylfurfural are dissolved in 400 ml of 95% EtOH and refluxed overnight. The ethanol is removed and the resulting dark red oil is recrystallized from CH3CN yielding golden plates of the Schiff Base, mp 190°-193°. This material is then dissolved in CH3CN (200 ml) by heating and 22.2 g (0.05 mole) of lead tetraacetate added. Heating is continued for 5 min and then solution is diluted with an equal volume of water. The dark brown precipitate is collected, washed with water and recrystallized from CH2Cl2 and Darco G-60 yielding 6.1 g of product (50%), mp 182°-184°.
Reaction SMILES: C([NH:5][S:6]([C:9]1[C:10]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:22]3[C:31]4[C:26](=[C:27]([CH2:34][CH3:35])[N:28]=[C:29]([CH2:32][CH3:33])[CH:30]=4)[CH:25]=[CH:24][C:23]3=[O:36])=[CH:17][CH:16]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[CH2:34]([C:27]1[N:28]=[C:29]([CH2:32][CH3:33])[CH:30]=[C:31]2[C:26]=1[CH:25]=[CH:24][C:23](=[O:36])[N:22]2[CH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:10]2[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:16][CH:17]=1)[CH3:35]
Reactant: CCc1cc2c(ccc(=O)n2Cc2ccc(-c3ccccc3S(=O)(=O)NC(C)(C)C)cc2)c(CC)n1
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc2c(ccc(=O)n2Cc2ccc(-c3ccccc3S(N)(=O)=O)cc2)c(CC)n1
Yield: 77.1 %

Procedure:
A solution of N-tert-butyl-4'-[(5,7-diethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-1-yl)methyl]biphenyl-2-sulphonamide (200 mg) in trifluoroacetic acid (5 ml) was heated at reflux for 3 hours. Volatile material was removed by evaporation and water was added to the residue. The resultant solution was basified by the addition of solid potassium carbonate and then extracted twice with ethyl acetate. The combined extracts were washed with water, saturated sodium chloride solution and then dried (MgSO4). The solvent was removed by evaporation to give 4'-[(5,7-diethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-1-yl)methyl]biphenyl-2-sulphonamide as a solid (137 mg); m.p. 199°-200° C.; NMR (d6 -DMSO): 1.18(t, 3H), 1.26(t, 3H), 2.73(q, 2H), 3.07(q, 2H), 5.54(s, 2H), 6.72(d, 1H), 7.1-7.7(m, 10H), 8.01(dd, 1H), 8.23(d, 1H); mass spectrum (+ve FAB, methanol/NBA): 448 (M+H)+ ; microanalysis, found: C, 67.0; H, 5.5; N, 9.2%; C25H25N3O3S requires: C, 67.1; H, 5.6; N, 9.4%.