Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[I-].[CH2:45]([N+:49]1[N:53]=[C:52]([CH3:54])[S:51][C:50]=1[CH3:55])[CH2:46][CH2:47][CH3:48]>>[CH2:45]([N:49]1[N:53]=[C:52]([CH3:54])[S:51]/[C:50]/1=[CH:55]\[C:5]([C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=1)=[O:7])[CH2:46][CH2:47][CH3:48]
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: CCCC[n+]1nc(C)sc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 3-chlorobenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-D6/D2O) δ ppm 0.92 (t, 3 H) 1.27-1.40 (m, 2 H) 1.72-1.80 (m, 2 H) 2.47-2.50 (m, 3 H) 4.27 (t, 2 H) 6.76 (s, 1 H) 7.46-7.53 (m, 1 H) 7.52-7.57 (m, 1 H) 7.94-7.99 (m, 1 H) 8.01-8.05 (m, 1 H); MS (ESI) m/z 309 (M+H)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][CH2:12][CH2:13][OH:14])[CH:4]=[CH:3][CH:2]=1.[S:15](Cl)(=[O:18])(=[O:17])[NH2:16].Cl>C(#N)C.C(O)(C)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][CH2:12][CH2:13][O:14][S:15](=[O:18])(=[O:17])[NH2:16])[CH:4]=[CH:3][CH:2]=1
Reactant: NS(=O)(=O)Cl
Reactant: OCCOc1cccc2cccnc12
Agent: Cl
Solvent: CC(C)O
Solvent: CC#N
Product: NS(=O)(=O)OCCOc1cccc2cccnc12

Procedure:
Using the procedure of Example 54, 5.4 g (0.029 mole) of 2-(8-quinolinyloxy)ethanol was reacted with sulfamoyl chloride. During work-up of the reaction, quite a bit of light-yellow material deposited out from the organic-aqueous system. 1H NMR of this material suggested that it might be a quaternary salt. The oily product obtained at the end of the work-up procedure weighed 2.7 g. This oil was dissolved in acetonitrile-isopropyl alcohol and acidified with 37% hydrochloric acid. The mixture was evaporated to almost dryness and then redissolved in methanol. To the solution was added ethyl acetate and most of the methanol was evaporated carefully. The light-yellow solid was collected and dried at 40° C. in vacuum overnight to give 2.4 g solid monohydrochloride, mp 138°-140° C.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([C:16]3[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=3[CH3:23])[C:6]3[C:11]([N:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[C:24]([NH:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([C:16]3[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=3[CH3:23])[C:6]3[C:11]([N:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1ccc(C)c(-c2c3ccccc3nc3ccc(N)cc23)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Product: Cc1ccc(C)c(-c2c3ccccc3nc3ccc(NC(=O)c4ccccc4)cc23)c1
Reaction time: 8 h

Procedure:
2.98 pbw of 2-amino-9-(2,5-dimethylphenyl)acridine (compound 1d) were dissolved in 75 pbv of methylene chloride at 23° C. and 2.1 pbw of benzoyl chloride were gradually added while stirring. The temperature rose to 27°-28° C. during this process. The solution was stirred for 4 hours and, after standing overnight, extracted by shaking with sodium hydroxide solution, and the organic phase was distilled off after drying over anhydrous sodium sulfate. Yield: 3.96 pbw (98% of theory), yellowish green crystals. Mp.: 253°-255° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(C(C)=O)C>[CH2:20]([O:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:3][C:2]=1[Cl:1])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)Cc1ccc(O)c(Cl)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)Cc1ccc(OCc2ccccc2)c(Cl)c1

Procedure:
A mixture of 8.7 g (43.4 mmoles) of methyl 3-chloro-4-hydroxyphenylacetate, 6.2 g (44.8 mmoles) of powdered anhydrous potassium carbonate, 7.6 g (44.6 mmoles) of benzyl bromide, and 25 ml of methyl ethyl ketone was refluxed for six hours.
Reaction SMILES: [Cl-].[CH3:2][C:3]1[S:7][C:6]([CH3:8])=[C:5]([CH3:9])[C:4]=1[CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[F:35]/[C:36](=[C:42](/[CH:44]=O)\[CH3:43])/[C:37]([O:39][CH2:40][CH3:41])=[O:38].CCOCC>O1CCCC1.O>[F:35]/[C:36](=[C:42](\[CH3:44])/[CH:43]=[CH:10]/[C:4]1[C:5]([CH3:9])=[C:6]([CH3:8])[S:7][C:3]=1[CH3:2])/[C:37]([O:39][CH2:40][CH3:41])=[O:38]
Reactant: CCOC(=O)/C(F)=C(/C)C=O
Reactant: Cc1sc(C)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C(F)=C(C)\C=C\c1c(C)sc(C)c1C
Temperature: -60 °C
Yield: 58 %

Procedure:
A suspension of 21.0 g. (48 mmol) of (2,4,5-trimethyl-3-thenyl)-triphenylphosphonium chloride in tetrahydrofuran was stirred under argon while being cooled to -60° C. The ylide was formed by adding 1.1 equivalents of n-butyllithium and warming to -35° C. for 15 minutes. A solution of 7.7 g. (48 mmol) of ethyl 2E-2-fluoro-3-formyl-2-butenoate in 50 ml. of anhydrous ether was added slowly. This mixture was warmed to 0° C., poured into water, extracted with hexane, washed twice with 60% methanol/water, water, saturated sodium chloride solution, dried and evaporated. Purification by silica gel chromatography gave 8.8 g. (58% yield) of ethyl (2E,4E)-2-fluoro-3-methyl-5-(2,4,5-trimethyl-3-thienyl)-2,4-pentadienoate.
Reaction SMILES: Br[C:2]1[CH:40]=[CH:39][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:28][C:29]2([C:34]([O:36]CC)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:4][CH:3]=1.[CH3:41][O:42][C:43]1[N:48]=[CH:47][C:46](B(O)O)=[CH:45][N:44]=1>>[CH3:41][O:42][C:43]1[N:48]=[CH:47][C:46]([C:2]2[CH:3]=[CH:4][C:5]([CH2:6][N:7]3[C:11]4[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]5[CH:27]=[CH:26][C:25]6[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=6)[N:19]=5)=[CH:15][C:10]=4[N:9]=[C:8]3[CH2:28][C:29]3([C:34]([OH:36])=[O:35])[CH2:30][CH2:31][CH2:32][CH2:33]3)=[CH:39][CH:40]=2)=[CH:45][N:44]=1
Reactant: CCOC(=O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(Br)cc2)CCCC1
Reactant: COc1ncc(B(O)O)cn1
Product: COc1ncc(-c2ccc(Cn3c(CC4(C(=O)O)CCCC4)nc4cc(OCc5ccc6ccccc6n5)ccc43)cc2)cn1

Procedure:
The title compound was prepared using similar methods to those in Example 110 using ethyl 1-((1-(4-bromobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzo[d]imidazol-2-yl)methyl)cyclopentanecarboxylate and 2-methoxypyrimidine-5-boronic acid in Step A. MS (ESI): mass calcd. for C36H33N5O4, 599.25; m/z found, 600.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.64 (s, 2H), 8.21-8.16 (m, 1H), 8.09-8.04 (m, 1H), 7.83-7.79 (m, 1H), 7.74-7.69 (m, 1H), 7.69-7.64 (m, 1H), 7.56-7.51 (m, 1H), 7.48-7.41 (m, 3H), 7.18-7.13 (m, 1H), 7.13-7.08 (m, 2H), 7.08-7.03 (m, 1H), 5.40 (s, 2H), 5.38 (s, 2H), 4.05 (s, 3H), 3.25-3.18 (m, 1H), 2.31-2.21 (m, 2H), 1.84-1.79 (m, 2H), 1.54-1.42 (m, 5H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:11]([F:14])([F:13])[F:12])=[N:8][O:9][CH:10]=1)=[O:5])C.Cl.O>C(O)(=O)C>[F:14][C:11]([F:12])([F:13])[C:7]1[C:6]([C:4]([OH:5])=[O:3])=[CH:10][O:9][N:8]=1
Reactant: CCOC(=O)c1conc1C(F)(F)F
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1conc1C(F)(F)F
Temperature: 70 °C
Reaction time: 2 h
Yield: 8.1 %

Procedure:
3-Trifluoromethyl-isoxazole-4-carboxylic acid ethyl ester (Preparation 47, 1.00 g, 4.78 mmol), glacial acetic acid (4 ml), concentrated hydrochloric acid (2 ml, 20 mmol) and water (2 ml, 200 mmol) were heated together with stirring at 70° C. for 2 hours. Solvents were removed by evaporation in vacuo and the residue was left to stand at room temperature for 16 hours. Water (40 ml) and t-butylmethyl ether (80 ml) was added and the layers separated. The organic layer was washed with dilute hydrochloric acid (20 ml), then dried over anhydrous Na2SO4 (s), filtered and evaporated in vacuo to afford the title compound as a brown gum (70 mg, 8%). Material was taken on with no further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:36])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]3[S:29][C:30]([C:33](O)=[O:34])=[CH:31][N:32]=3)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.Cl.[CH3:38][NH:39][CH3:40].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C.O>[CH3:1][O:2][CH2:3][C@H:4]([CH3:36])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]3[S:29][C:30]([C:33]([N:39]([CH3:40])[CH3:38])=[O:34])=[CH:31][N:32]=3)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=2)[CH:11]=1
Reactant: CNC
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(-c3ncc(C(=O)O)s3)[nH]2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(-c3ncc(C(=O)N(C)C)s3)[nH]2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 90.4 %

Procedure:
2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-1,3-thiazole-5-carboxylic acid (62.8 mg, 0.119 mmol) synthesized in Example (5d) was dissolved in N,N-dimethylformamide (5 mL), and dimethylamine hydrochloride (27.0 mg, 0.331 mmol), HATU (68.2 mg, 0.179 mmol) and N,N-diisopropylethylamine (80 μL, 0.46 mmol) were added, followed by stirring at room temperature for 20 hours under nitrogen atmosphere. Water (20 mL) was added to the reaction solution, and extraction was carried out with ethyl acetate (20 mL). The organic layer was washed with saturated brine, and subsequently dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=60%-90%) to afford the desired compound (59.8 mg, yield 90%) as a yellow solid.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[C:14]([O:18][C:19](=[O:30])[NH:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27]Br)=[C:23]([CH3:29])[N:22]=1)([CH3:17])([CH3:16])[CH3:15].CCOC(C)=O>CN(C=O)C>[CH2:10]([O:9][C:1](=[O:8])[CH:2]([CH2:27][C:24]1[C:23]([CH3:29])=[N:22][C:21]([NH:20][C:19]([O:18][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:30])=[CH:26][CH:25]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:11]
Reactant: Cc1nc(NC(=O)OC(C)(C)C)ccc1CBr
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1C)C(=O)OCC
Reaction time: 0.75 h
Yield: 74 %

Procedure:
A solution of diethyl malonate (1.21 mL, 7.97 mmol) in DMF (2 mL) was added dropwise to a suspention of NaH (348 mg, 7.97 mmol, 55% in mineral oil) in DMF (5 mL) at 0 ° C. under argon. The reaction mixture was stirred for 45 min and a solution of (5-bromomethyl-6-methyl-pyridin-2-yl)-carbamic acid tert-butyl ester (2.0 g, 6.64 mmol) in DMF (5 mL) was added dropwise. The mixture was stirred over night (0° C.→20° C.). EtOAc was added and the solution was washed with water and brine, dried and concentrated under reduced pressure. Flash chromatography (heptane/EtOAc, 4:1) gave 2-(6tert-butoxycarbonylamino-2-methyl-pyridin-3-ylmethyl)-malonic acid diethyl ester (1.87 g, 74%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1.[H][H]>C(O)C.Cl.[Pt]=O>[CH3:1][O:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1
Reactant: [H][H]
Reactant: COCCc1ccncc1
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Product: COCCC1CCNCC1

Procedure:
4-(2-Methoxyethyl)pyridine (9.6 g), in a mixture of ethanol (100 ml) and 2 N hydrochloric acid (30 ml) was hydrogenated over platinum oxide at 50°/50 p.s.i. until uptake of hydrogen ceased. The catalyst was removed by filtration and the solution evaporated in vacuo. The residue was then dissolved in water (50 ml), basified to pH 8 with dilute sodium hydroxide, and extracted with chloroform. The aqueous phase was evaporated in vacuo to give an oil which solidified on cooling. The solid was triturated with ether (60 ml), collected by filtration and dissolved in the minimum quantity of boiling ethyl acetate. The hot solution was filtered and on cooling deposited hygroscopic crystals of 4-(2-methoxyethyl)piperidine (9.9 g), m.p. 108°-110°. The structure was verified by i.r. and n.m.r. spectroscopy.
Reaction SMILES: [CH3:1][N:2]([C:7]([C:9]1[C:10]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:11][C:12]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:13]([CH:18]=1)[C:14]([O:16]C)=[O:15])=[O:8])[CH2:3][CH2:4][CH2:5][CH3:6].[OH-].[Li+].Cl>C1COCC1.O.CO.C(OCC)C>[CH3:1][N:2]([C:7]([C:9]1[C:10]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:11][C:12]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[C:13]([CH:18]=1)[C:14]([OH:16])=[O:15])=[O:8])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCN(C)C(=O)c1cc(C(=O)OC)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCCCN(C)C(=O)c1cc(C(=O)O)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 22 °C
Reaction time: 12 h

Procedure:
59 g (127.8 mmol) of methyl 5-[(N-methyl-N-butylamino)carbonyl]-2,4-bisbenzyloxybenzoate are dissolved in 200 ml of THF and added to a solution of 100 g (4.2 mol) of lithium hydroxide in 300 ml of water and 150 ml of methanol. The mixture is stirred for 12 h at 22° C., diluted with 250 ml of diethyl ether and acidified using 1N hydrochloric acid. The organic phase is separated off and washed a further three times with 100 ml of N hydrochloric acid each time, dried over sodium sulfate and evaporated. The crude product obtained in this way (80 g) is crystallised from ethyl acetate: 33 g (57.7%) of 5-[(N-methyl-N-butylamino)carbonyl]-2,4-bisbenzyloxybenzoic acid (white crystals); MW 447.5;
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:16][O:17][C:18](=[O:32])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:26]2[CH:30]=[N:29][C:28]([NH2:31])=[N:27]2)[CH:20]=1>>[CH3:16][O:17][C:18](=[O:32])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:26]2[CH:30]=[N:29][C:28]([NH:31][C:2]3[CH:3]=[CH:4][C:5]([N:10]4[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]4)=[C:6]([C:7]#[N:8])[CH:9]=3)=[N:27]2)[CH:20]=1
Reactant: COC(=O)c1cccc(Cn2cnc(N)n2)c1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Product: COC(=O)c1cccc(Cn2cnc(Nc3ccc(-n4cnc(C)c4)c(C#N)c3)n2)c1

Procedure:
Prepared in analogy to example 1b) starting with 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile and 3-(3-amino-[1,2,4]triazol-1-ylmethyl)-benzoic acid methyl ester. The title compound was obtained as a colorless solid (Yield=40%). MS ISP (m/e): 414.3 (100) [(M+H)+].
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14])=[O:7].[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1>>[Cl:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1
Reactant: CCC(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=C(CCCCCl)c1ccccc1Cl
Product: CCC(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3Cl)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 using 5-chloro-1-(2-chlorophenyl)-1-pentanone and N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 427.1 (M+H)+.
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl[CH2:7][C:8]1[C:9]([CH3:14])=[N:10][O:11][C:12]=1[CH3:13].[NH2:15][CH2:16][CH2:17][C:18]1[CH:33]=[CH:32][C:21]([O:22][C:23]2[CH:31]=[CH:30][C:26]([C:27]([NH2:29])=[O:28])=[CH:25][N:24]=2)=[CH:20][CH:19]=1.[OH-].[Na+]>CN(C)C=O>[CH3:14][C:9]1[C:8]([CH2:7][NH:15][CH2:16][CH2:17][C:18]2[CH:33]=[CH:32][C:21]([O:22][C:23]3[CH:31]=[CH:30][C:26]([C:27]([NH2:29])=[O:28])=[CH:25][N:24]=3)=[CH:20][CH:19]=2)=[C:12]([CH3:13])[O:11][N:10]=1
Reactant: NCCc1ccc(Oc2ccc(C(N)=O)cn2)cc1
Reactant: Cc1noc(C)c1CCl
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1noc(C)c1CNCCc1ccc(Oc2ccc(C(N)=O)cn2)cc1
Temperature: 25 °C
Yield: 59 %

Procedure:
Add sodium bicarbonate (0.0481 g, 0.573 mmol) to a stirred solution of 4-(chloromethyl)-3,5-dimethylisoxazole (0.054 mL, 0.435 mmol), and 6-[4-(2-amino-ethyl)-phenoxy]-nicotinamide (0.1004 g, 0.390 mmol) in dimethylformamide (4 mL). Heat the reaction to reflux under nitrogen for 4 h. Cool to room temperature, pour the reaction mixture into 1 N sodium hydroxide (50 mL), extract with diethyl ether (3×50 mL), dry the extracts over magnesium sulfate, filter, and concentrate on a rotary evaporator to give the crude product. The crude product is purified by flash chromatography on silica gel eluting with 0.8% concentrated ammonium hydroxide/8% ethanol/chloroform to yield 0.0843 g (59%) of 6-(4-{2-[(3,5-dimethyl-isoxazol-4-ylmethyl)-amino]-ethyl}-phenoxy)-nicotinamide: mass spectrum (ion spray): m/z=367.1 (M+1); 1H NMR (CDCl3): 8.57 (dd, 1H), 8.16 (dd, 1H), 7.26-7.22 (m, 4H), 7.09-7.05 (m, 2H), 6.96 (d, 1H), 3.54 (s, 2H), 2.88-2.79 (m, 4H), 2.33 (s, 3H), 2.20 (s, 3H), 1.50 (br s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-])=O)([CH3:4])([CH3:3])[CH3:2].O.O.Cl[Sn]Cl>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:17])([F:18])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1N

Procedure:
The title compound was prepared from (5-chloro-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example A1) (7.00 g, 20.5 mmol) by reduction with SnCl2.2H2O according to the general procedure J (method b). Obtained as a yellow solid (3.13 g, 49%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([S:8]([N:11]2[C:16]3[CH:17]=[C:18]([C:21]([OH:23])=O)[CH:19]=[CH:20][C:15]=3[O:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:7]=1.C(N(CC)CC)C.N1C(Cl)=NC(Cl)=NC=1Cl.[CH2:42]([O:44][C:45](=[O:53])[C:46]1[CH:51]=[CH:50][C:49]([NH2:52])=[CH:48][CH:47]=1)[CH3:43]>CC(C)=O.O1CCCC1>[CH2:42]([O:44][C:45](=[O:53])[C:46]1[CH:51]=[CH:50][C:49]([NH:52][C:21]([C:18]2[CH:19]=[CH:20][C:15]3[O:14][CH2:13][CH2:12][N:11]([S:8]([C:6]4[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[O:24][CH3:25])(=[O:9])=[O:10])[C:16]=3[CH:17]=2)=[O:23])=[CH:48][CH:47]=1)[CH3:43]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCOc2ccc(C(=O)O)cc21
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CCO3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid (1.0 g, 2.6 mmol) in acetone (130 mL) and tetrahydrofuran (30 mL) was treated with triethylamine (0.5 g, 0.68 mL, 1.9 equiv.) and stirred at room temperature overnight. A solution of cyanuric chloride (596 mg, 3.2 mmol, 1.24 equiv.) in acetone (20 mL) was added dropwise over a period of 1 hour. The reaction mixture was stirred at room temperature for 4 hours, 4-amino-benzoic acid ethyl ester (775 mg, 4.7 mmol, 1.8 equiv.) was then added. The reaction mixture was stirred at room temperature overnight, the solvents were then removed. The residue was purified by flash chromatography, to yield 4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid ethyl ester as a white solid, 0.91 g (66%). δH (300 MHz; CDCl3) 8.10 (1H, d), 8.03-8.07 (3H, m), 7.92 (1H, bs), 7.73 (2H, d), 7.70 (1H, d), 7.67 (1H, d), 7.53 (1H, d), 7.50 (1H, d), 4.37 (2H, q), 4.03 (2H, m), 3.88 (2H, m), 3.56 (3H, s), 1.40 (3H, t).
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=O.[CH:12]1([NH2:15])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][NH:15][CH:12]1[CH2:14][CH2:13]1
Reactant: NC1CC1
Reactant: O=C(O)c1cccc(F)c1Cl
Product: Fc1cccc(CNC2CC2)c1Cl

Procedure:
Prepared from 2-chloro-3-fluorobenzoic acid (2.00 g, 11.5 mmol) and cyclopropylamine according to above-described procedures C and E, and purified over amberlyst A15 (1.86 g, 81% over 2 steps). LC-MS (2-chloro-N-cyclopropyl-3-fluorobenzamide): tR=0.76 min, ES+: 214.10; LC-MS (title compound): tR=0.60 min, ES+: 200.12.
Reaction SMILES: [CH:1]1[CH:5]=[C:4]([CH:6]=O)[O:3][CH:2]=1.[NH2:8][CH2:9][CH2:10][OH:11].C[C@H](NC([C@H]1N(C([C@@H](NC([C@@H](N)CC2C=CC(O)=CC=2)=O)CC(O)=O)=O)CCC1)=O)C(N1[C@H](C(N2[C@H](C(N3[C@H](C(N4[C@H](C(N5[C@H](C(N6[C@H](C(O)=O)CCC6)=O)CCC5)=O)CCC4)=O)CCC3)=O)CCC2)=O)CCC1)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[O:3]1[CH:2]=[CH:1][CH:5]=[C:4]1[CH2:6][NH:8][CH2:9][CH2:10][OH:11]
Reactant: O=Cc1ccco1
Reactant: NCCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](CC(=O)O)NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Agent: [Na+]
Solvent: ClCCCl
Product: OCCNCc1ccco1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
An aldehyde, e.g., 2-furfuraldehyde (2 g, 20.82 mmol), and an amine, e.g., 2-aminoethanol, (1.65 g, 27.06 mmol) were poured together in a mixture 1:1 TMOF:DCE (50 ml) and the reaction mixture was cooled down to zero degree. The reducing agent NaBH(OAc)3 (6.18 g, 29.14 mmol) was added in 4 subsequent portions over a 5 min period, the reaction mixture was allowed to gradually warm to room temperature and stirred for 16 hours. The solvents was removed from the reaction in vacuo and the residue was partitioned between dichloromethane (150 ml) and saturated bicarbonate solution (50 ml). After separation, the organic layer was washed with saturated bicarbonate solution (50 ml) and brine (50 ml). The combined organic layers were then dried over sodium sulphate, filtered and the solvent removed in vacuo. The desired secondary amines, e.g., 2-[(2-furylmethyl)amino]ethanol, were obtained as a yellowish oil (1.82 g, 62%).
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[CH:6]([C:9]1[O:13][N:12]=[C:11]([CH3:14])[CH:10]=1)[O:7][CH3:8].CN(C)C=O.[CH3:24][CH:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[H-].[Na+]>CCOCC>[CH3:8][O:7][CH:6]([C:9]1[O:13][N:12]=[C:11]([CH3:14])[CH:10]=1)[C:5]1[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=1[CH:3]=[N:2][O:1][CH:25]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:24]
Reactant: COC(c1cc(C)no1)c1ccccc1C=NO
Reactant: CC(Br)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(c1cc(C)no1)c1ccccc1C=NOC(C)c1ccccc1
Reaction time: 3 h
Yield: 91.3 %

Procedure:
To a mixture of 0.25 g (1 mmol) of 5-(2-hydroxyiminomethyl-α-methoxybenzyl)-3-methylisoxazole, 3 ml of N,N-dimethylformamide and 0.24 g (1.3 mmol) of α-methylbenzyl bromide was added 0.05 g (1.3 mmol) of 60% sodium hydride under ice-cooling and stirred at the same temperature for 3 hours. After completion of the reaction, 100 ml of ether was added and washed twice with 80 ml of brine. The ether layer was dried over anhydrous magnesium and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane) to give 5-[α-methoxy-2-(4-phenyl-2-aza-3-oxa-1-pentenyl)benzyl]-3-methylisoxazole (0.32 g, 91.3%) as colorless oil.