Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:8]([O:10][CH3:11])=[O:9])(=[O:4])=[O:3].C(N(C(C)C)CC)(C)C.[CH3:26][NH:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>C(Cl)Cl>[CH3:11][O:10][C:8](=[O:9])[C:7]1[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:5]([S:2](=[O:4])(=[O:3])[N:27]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH3:26])[CH:6]=1
Reactant: CNC1CCCCC1
Reactant: COC(=O)c1ccc(OC)c(S(=O)(=O)Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(OC)c(S(=O)(=O)N(C)C2CCCCC2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of methyl 3-(chlorosulfonyl)-4-methoxybenzoate (2.0 g, 7.56 mmol) and diisopropylethylamine (1.94 ml, 11.34 mmol) in DCM (50 ml) is treated with N-methyl cyclohexylamine (0.70 ml, 9.07 mmol) at 0° C. The solution is stirred at room temperature for 3 hours and N-methyl cyclohexylamine (0.70 ml, 9.07 mmol) is added. The solution is partitioned between DCM (250 ml) and 0.5 N HCl (100 ml). The organic layer is washed with 0.5 N HCl (2×100 ml), sat. aq. NaHCO3 (2×100 ml) and water (100 ml), dried over MgSO4, and the solvent removed in vacuo to yield a yellow oil. Crystallisation (iPr2O/EtOAc) yields 3-(Cyclohexyl-methyl-sulfamoyl)-4-m ethoxy-benzoic acid methyl ester as yellow crystals; [M+H] 342.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[CH2:16]([NH:18][CH2:19][CH3:20])[CH3:17]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:18]([CH2:19][CH3:20])[CH2:16][CH3:17])=[O:15])=[CH:6][CH:7]=1
Reactant: CCNCC
Reactant: O=C(O)c1cnoc1-c1ccc(Br)cc1
Product: CCN(CC)C(=O)c1cnoc1-c1ccc(Br)cc1

Procedure:
The title compound was prepared from 5-(4-bromophenyl)isoxazole-4-carboxylic acid (13.4 mg, 0.050 mmol) and diethylamine (4.4 mg, 0.060 mmol) as described in synthetic method A and thereafter purified by preparative HPLC method A to give a solid (3.8 mg). MS (pos) m/z 323.0 and 325.0.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][NH:6][C:7]1[C:12]([NH:13][C:14](=O)[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:11][CH:10]=[C:9]([Cl:23])[N:8]=1)C.O.[OH-].[K+].Cl>C(O)CO>[Cl:23][C:9]1[N:8]=[C:7]2[N:6]([CH2:5][C:4]([OH:3])=[O:24])[C:14]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[N:13][C:12]2=[CH:11][CH:10]=1
Reactant: CCOC(=O)CNc1nc(Cl)ccc1NC(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2ccc(Cl)nc21
Temperature: 25 °C
Yield: 26.9 %

Procedure:
A solution of N-[6-chloro-3-[(4-chlorobenzoyl)amino]-2-pyridinyl]glycine ethyl ester (1.7 g, 0.00462 mole) in ethylene glycol (25 ml) was refluxed under nitrogen for two hours. To one-half of the solution (0.0023 mole) was added water (2 ml) and solid potassium hydroxide (0.20 g, 0.003515 mole) and the mixture was refluxed for an additional 15 minutes, poured into ice water (100 ml) and acidified with 3N hydrochloric acid solution. The resulting solid was collected by filtration, rinsed with water, dissolved in hot methanol and filtered hot. Addition of water to the cloud point and cooling to room temperature gave a solid which was collected by filtration, washed with water, and dried at 60° C. under high vacuum to give 0.4 g (54% yield) of title compound, mp>250° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[C:23]([CH:28]=O)=[CH:24][CH:25]=[CH:26][CH:27]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][N:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:10][CH2:11]1
Reactant: O=Cc1ccccc1-c1ccccc1Cl
Reactant: COc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: COc1ccccc1N1CCN(Cc2ccccc2-c2ccccc2Cl)CC1

Procedure:
69 mg of the target compound (0.18 mmol, 21.7%) was obtained using 1-(2-methoxyphenyl)piperazine (311 mg, 1.62 mmol), 2′-chlorobiphenyl-2-carbaldehyde (175 mg, 0.81 mmol) and NaBH(OAc)3 (523 mg, 2.43 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[NH2:10][C:11]1[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: Clc1cc(Cl)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(Nc2cc(Cl)nc(Cl)n2)n[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.3 %

Procedure:
A mixture of 2,4,6-trichloropyrimidine (1.0 g, 5.4 mmol), 3-amino-5-methyl-1H-pyrazole (0.53 g, 5.4 mmol), and sodium carbonate (0.57 g, 5.4 mmol) in ethanol (25 ml) was stirred at ambient temperature for 18 hours. Water was added and the resulting precipitate was collected by filtration washed with water and a small amount of methanol, and dried to give the title compound (1.15 g, 88%) as a colourless crystalline solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.[OH-].C([P+](CCCC)(CCCC)CCCC)CCC.Cl[CH2:32][C:33]1[CH:34]=[C:35]([C:42]2[CH:47]=[C:46]([O:48][CH3:49])[CH:45]=[CH:44][C:43]=2[F:50])[C:36]([CH:39]2[CH2:41][CH2:40]2)=[CH:37][CH:38]=1>C1COCC1>[CH:39]1([C:36]2[C:35]([C:42]3[CH:47]=[C:46]([O:48][CH3:49])[CH:45]=[CH:44][C:43]=3[F:50])=[CH:34][C:33]([CH2:32][O:1][C:2]3[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=3)=[CH:38][CH:37]=2)[CH2:41][CH2:40]1
Reactant: O=C(O)CCc1cccc(O)c1
Reactant: COc1ccc(F)c(-c2cc(CCl)ccc2C2CC2)c1
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2cc(COc3cccc(CCC(=O)O)c3)ccc2C2CC2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 28 %

Procedure:
To a solution of 3-(3-hydroxyphenyl)-propionic acid (0.031 g, 0.186 mmol) (commercially available from Alfa, CAS No. 621-54-5) in THF (1 mL) was added tetrabutylphosphonium hydroxide (40 wt % solution in water) (0.27 g, 0.39 mmol). The mixture was then cooled in an ice bath to 0° C. After 10 minutes, 13.5 (0.055 g, 0.191 mmol) was added at 0° C. Upon complete addition, the reaction was allowed to warm to room temperature. After 44 hours, the solvent was removed under vacuum. The residue was diluted with water and acidified with 2M HCl to pH 2. The mixture was extracted with EtOAc. The layers were separated and the solvent was removed under vacuum to yield an oil that was purified by flash chromatography (SiO2 gel 60, eluted with 0 to 65% EtOAc in hexanes) to yield a colorless film 13 (0.023 g, 28% yield.) 1H NMR (400 MHz, CDCl3) δ ppm 7.39 (1H, dd, J=8.0, 1.8 Hz), 7.31 (1H, d, J=2.0 Hz), 7.23 (1H, t, J=8.0 Hz), 7.10 (1H, m), 6.99 (1H, d, J=7.8 Hz), 6.90 (5H, m), 5.04 (2H, s), 3.82 (3H, s), 2.95 (2H, t, J=7.8 Hz), 2.72 (2H, m), 1.85 (1H, m), 0.87 (2H, m), 0.68 (2H, m).
Reaction SMILES: Cl.[CH:2]([O:5][CH2:6][CH2:7][N:8]([C:13]1[CH:35]=[CH:34][C:16]([C:17]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[CH2:21][CH2:20]2)=[O:18])=[CH:15][CH:14]=1)[C:9](=[O:12])[CH2:10]Cl)([CH3:4])[CH3:3].[SH:36][CH2:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41]>>[CH:2]([O:5][CH2:6][CH2:7][N:8]([C:13]1[CH:35]=[CH:34][C:16]([C:17]([N:19]2[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=3)[CH2:23][CH2:24]2)=[O:18])=[CH:15][CH:14]=1)[C:9](=[O:12])[CH2:10][S:36][CH2:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])([CH3:3])[CH3:4]
Reactant: CC(C)OCCN(C(=O)CCl)c1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Reactant: O=C(O)CCCS
Agent: Cl
Product: CC(C)OCCN(C(=O)CSCCCC(=O)O)c1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1

Procedure:
Analogously to Example 1, 1-{4-[N-(2-isopropoxyethyl)-N-chloroacetylamino]-benzoyl}-4-[2-(4-chlorophenyl)-ethyl]-piperazine hydrochloride is reacted with 4-mercaptobutyric acid, yielding 1-{4-[N-(2-isopropoxyethyl)-N-(3-carboxy-propylmercapto-acetyl)-amino]-benzoyl}-4-[2-(4-chlorophenyl)-ethyl]-piperazine.
Reaction SMILES: CC(C)([O-])C.[K+].[NH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[CH:8]1.Br[CH:17]([CH3:31])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1)=[O:19]>O1CCOCC1.CN(C=O)C>[N:7]1([CH:17]([CH3:31])[C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=2)=[O:19])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[CH:8]1
Reactant: CC(Br)C(=O)Nc1cccc(C(F)(F)F)c1
Reactant: c1ccc2[nH]cnc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CC(C(=O)Nc1cccc(C(F)(F)F)c1)n1cnc2ccccc21
Reaction time: 4 h
Yield: 60 %

Procedure:
A solution of potassium tert-butoxide (0.25 mL of 1 M solution in THF, 0.25 mmol) was added to a solution of 1H-benzoimidazole (30 mg, 0.25 mmol) in anhydrous dioxane (10 mL) and anhydrous DMF (1 mL) under argon at ambient temperature. The mixture was stirred for 5 min before a solution of bromo-N-(3-trifluoromethyl-phenyl)-propionamide (59 mg, 0.2 mmol) in anhydrous dioxane (3 mL) was added. The mixture was stirred for 4 h, filtered and concentrated in vacuum. The crude product was purified on a preparative HPLC (XTerra C8 column 19×300 mm, 0.1 M aqueous NH4Ac/CH3CN). Product-containing fractions were pooled and lyophilized to afford 40 mg (60%) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 1.8 (d, J=7.1 Hz, 3H), 5.1 (q, J=7.4 Hz, 1 H), 7.2 (m, 4 H), 7.4 (d, J=7.1 Hz, 1H), 7.5 (m, 2H,) 7.7 (m, 1H), 7.9 (s, 1H), 1/02 (s, 1 H).
Reaction SMILES: [CH2:1]([S:5](Cl)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].Cl.[N:10]1[C:19]2[CH2:18][CH2:17][NH:16][CH2:15][C:14]=2[CH:13]=[CH:12][C:11]=1[C:20]([O:22][CH3:23])=[O:21]>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH2:1]([S:5]([N:16]1[CH2:17][CH2:18][C:19]2[N:10]=[C:11]([C:20]([O:22][CH3:23])=[O:21])[CH:12]=[CH:13][C:14]=2[CH2:15]1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)c1ccc2c(n1)CCNC2
Reactant: CCCCS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CCCCS(=O)(=O)N1CCc2nc(C(=O)OC)ccc2C1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
To a microwave vial containing n-butanesulfonyl chloride (0.0352 g, 0.225 mmol), was added methyl 5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxylate hydrochloride (0.0288 g, 0.15 mmol), TEA (0.167 mL, 1.2 mmol), DMAP (1.83 mg, 0.015 mmol), and DMF (2 mL). The mixture was shaken at rt for 13 h. The solvent was then completely evaporated to yield a solid. LC-MS: (FA) ES+ 313.
Reaction SMILES: O[CH:2]([CH2:15][O:16][CH3:17])[CH2:3][NH:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:18]1(=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](=[O:27])[NH:19]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[O:28]=[C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](=[O:27])[N:19]1[CH:2]([CH2:15][O:16][CH3:17])[CH2:3][NH:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COCC(O)CNC(=O)OCc1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCC(CNC(=O)OCc1ccccc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
12.10 g (38.4 mmol, 76%) rac-benzyl (2-hydroxy-3-methoxypropyl)carbamate (Example 132A), 6.79 g (46.1 mmol) of 1H-isoindole-1,3(2H)-dione and 15.12 g (57.7 mmol) triphenylphosphine were initially charged in THF (158 ml). 11.4 ml (57.7 mmol) of diisopropyl azodicarboxylate were added dropwise, and the mixture was then stirred at RT for 10 min. The mixture was then concentrated and the residue purified by silica gel chromatography (cyclohexane/ethyl acetate gradient: from 3:0 to 2:1). The product fractions were concentrated. This gave 14.84 g (97% of theory, purity 93%) of the target compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8](=[O:16])OC2C=CC=CC=2)=[CH:5][C:4]([C:17]([F:20])([F:19])[F:18])=[N:3]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[CH:28][N:27]=[C:26]2[O:35][C:36]1[CH:37]=[C:38]([CH:40]=[CH:41][CH:42]=1)[NH2:39].C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[CH:28][N:27]=[C:26]2[O:35][C:36]1[CH:37]=[C:38]([NH:39][C:8]([NH:7][C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:17]([F:18])([F:19])[F:20])[CH:5]=2)=[O:16])[CH:40]=[CH:41][CH:42]=1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: Cn1nc(C(F)(F)F)cc1NC(=O)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(F)(F)F)nn4C)c3)c2cc1OC
Temperature: 50 °C
Yield: 24 %

Procedure:
Using the procedure described in Example 159B, phenyl 1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate from the previous step (0.114 g, 0.4 mmol), 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (0.119 g, 0.4 mmol), and N,N-diisopropylethylamine (0.3 mL) in THF (6 mL) were heated at 50° C. for 3 hours, to afford 1-[3-(6,7-Dimethoxyquinazolin-4-yloxy)phenyl]-3-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea as solid (0.047 g, 24%). 1H NMR (300 MHz, CDCl3) δ 9.6 (br, 1H), 8.64 (s, 1H), 7.63 (m, 1H), 7.57 (s, 1H), 7.43 (t, 1H), 7.33 (m, 2H), 7.01 (d, 1H), 6.94 (s, 1H), 6.26 (s, 1H), 4.08 (s, 6H), 3.93 (s, 3H); LC-MS (ESI) m/z 489 (M+H)+.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:43]=[CH:42][C:20]([CH2:21][O:22]/[N:23]=[C:24](/[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[CH:19][CH:18]=1.CO.Cl>O1CCCC1>[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][O:22]/[N:23]=[C:24](/[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:42][CH:43]=1
Reactant: CCOC(=O)CCCCCC/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\CCCCCCC(=O)O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
A 1N aqueous saturated solution of sodium hydroxide (5 ml) was added to a solution of ethyl E-8-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-8-phenyloctanoate (660 mg) in tetrahydrofuran (10 ml)-methanol (5 ml) and stirred at room temperature for 1 hour. 1N hydrochloric acid (5.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-8-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-8-phenyloctanoic acid (580 mg, yield 92%) as colorless crystals. m.p. 116-117° C.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH:12]1([NH2:15])[CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>CC#N>[CH:12]1([NH:15][C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[CH2:14][CH2:13]1
Reactant: NC1CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(F)cc1NC1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
To a solution of 2,4-difluoro-1-nitrobenzene (0.7 mL, 6.3 mmol) in anhydrous CH3CN (10 mL) were added cyclopropylamine (0.4 mL, 6.3 mmol) and DIPEA (1.1 mL, 6.3 mmol). The reaction mixture was stirred at RT for 18 h then evaporated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% EtOAc in cyclohexane) to afford the title compound as a yellow solid (6.3 mmol, quantitative). 1H NMR (CDCl3, 300 MHz): δ 8.26-8.09 (2H, m), 6.95 (1H, dd, J=11.43, 2.68 Hz), 6.46-6.35 (1H, m), 2.60-2.50 (1H, m), 0.98-0.89 (2H, m), 0.71-0.63 (2H, m).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([N:30]([CH2:35][C:36]([OH:38])=[O:37])[CH2:31][C:32]([OH:34])=[O:33])[CH:8]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:10]=1)(=O)C.[OH-].[Na+].OC1C=C(NCC(O)=O)C=C(OCCCCCCCCCCCCCCCCCC)C=1>O1CCOCC1.CO>[C:32]([CH2:31][N:30]([C:7]1[CH:8]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:10]=[C:5]([OH:4])[CH:6]=1)[CH2:35][C:36]([OH:38])=[O:37])([OH:34])=[O:33]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(OC(C)=O)cc(N(CC(=O)O)CC(=O)O)c1
Agent: CCCCCCCCCCCCCCCCCCOc1cc(O)cc(NCC(=O)O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CCCCCCCCCCCCCCCCCCOc1cc(O)cc(N(CC(=O)O)CC(=O)O)c1
Reaction time: 60 h

Procedure:
To solution of 1.0 g (1.87 mmol) of N-[3-(acetyloxy)-5-(octadecyloxy)phenyl-N-(carboxymethyl)glycine in 30 ml of dioxane and 70 ml of methanol was added 1.6 mol (9.6 mmol) of 6N NaOH The solution was kept at room temperature for 60 hours. The solvent was removed at reduced pressure and the residue wa acidified with 3N HCl. The resultant solid was filtered to give 0.546 g, mp 143°-146°, of pure N-carboxymethyl)-N-[3-hydroxy-5-(octadecyloxy)phenyl]glycine.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:8][C:9](=[O:14])[CH2:10][C:11]([O-:13])=O)[CH3:7].[Br:15][C:16]1[C:24]([F:25])=[C:23]([F:26])[C:19](C(Cl)=O)=[C:18]([F:27])[C:17]=1[F:28].Cl>O1CCCC1.N1C=CC=CC=1C1C=CC=CN=1>[Br:15][C:16]1[C:17]([F:28])=[C:18]([F:27])[C:19]([C:11]([CH2:10][C:9]([O:8][CH2:6][CH3:7])=[O:14])=[O:13])=[C:23]([F:26])[C:24]=1[F:25]
Reactant: O=C(Cl)c1c(F)c(F)c(Br)c(F)c1F
Reactant: CCOC(=O)CC(=O)[O-]
Agent: Cl
Agent: [Li]CCCC
Agent: c1ccc(-c2ccccn2)nc1
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1c(F)c(F)c(Br)c(F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
n-Butyllithium (192 ml, 2.4M in hexane) was slowly added to a stirred solution of 30.24 g monoethylmalonate and 15 mg 2,2'-bipyridine in 500 ml tetrahydrofuran cooled to -60° to -70° C. under nitrogen. After about half of the butyllithium had been added, the temperature of the mixture was raised to -20° to -25° C. at which temperature the remainder of the butyllithium was added. The reaction mixture was then recooled to -60° to -70° C. and 33.41 g 4-bromo-2,3,5,6-tetrafluorobenzoyl chloride in 10 ml tetrahydrofuran was added. The reaction mixture was allowed to warm to room temperature, stirred overnight, and then poured into 460 ml 1M hydrochloric acid. The organic layer was separated, dried (magnesium sulfate) and concentrated. The residue was dissolved in ether, washed with aqueous potassium bicarbonate solution, dried (magnesium sulfate), concentrated and distilled to give 34.18 g ethyl 4-bromo-2,3,5,6-tetrafluorobenzoylacetate, b.p. 112°-117° C.(0.8 mm.).
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:11][C:12]1[N:20]2[C:15]([C:16](N3C=NC=N3)=[N:17][CH:18]=[N:19]2)=[C:14]([C:26]2[CH:27]=[N:28][N:29]([CH3:38])[C:30]=2[C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)[N:13]=1>CN(C)C=O.C(OCC)(=O)C>[N:1]1([C:16]2[C:15]3=[C:14]([C:26]4[CH:27]=[N:28][N:29]([CH3:38])[C:30]=4[C:31]4[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=4)[N:13]=[C:12]([CH3:11])[N:20]3[N:19]=[CH:18][N:17]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: C1CNC1
Reactant: Cc1ccc(-c2c(-c3nc(C)n4ncnc(-n5cncn5)c34)cnn2C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2c(-c3nc(C)n4ncnc(N5CCC5)c34)cnn2C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Azetidine (27.0 μL, 0.400 mmol) and cesium carbonate (97%, 202 mg, 0.601 mmol) were added to a solution of 7-methyl-5-[1-methyl-5-(4-methylphenyl)-1H-pyrazol-4-yl]-4-(1H-1,2,4-triazol-1-yl)imidazo[5,1-f][1,2,4]triazine (material from the previous reaction, ≦0.16 mmol) in N,N-dimethylformamide (3.0 mL), and the reaction mixture was stirred for 1 hour at room temperature. The reaction was diluted with ethyl acetate, washed with water, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification using silica gel chromatography (Gradient: 0% to 5% methanol in dichloromethane), followed by azeotroping with heptane, provided the product as a white solid. Yield: 35 mg, 0.097 mmol, 61% over 2 steps. LCMS m/z 360.2 (M+1). 1H NMR (400 MHz, CDCl3) δ 2.20-2.28 (m, 2H), 2.35 (s, 3H), 2.64 (s, 3H), 3.5-3.9 (v br m, 2H), 3.90 (s, 3H), 3.9-4.3 (v br m, 2H), 7.21 (AB quartet, JAB=8.1 Hz, ΔvAB=32.1 Hz, 4H), 7.64 (s, 1H), 7.78 (s, 1H).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH2:5]([NH:7][CH2:8][CH3:9])[CH3:6].[C:10]1([C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][O:12]1)=[O:11].O>ClC(Cl)C>[CH2:5]([N:7]([CH2:8][CH3:9])[C:10](=[O:11])[C:19]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:13][OH:12])[CH3:6]
Reactant: O=C1OCc2ccccc21
Reactant: CCNCC
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: O
Product: CCN(CC)C(=O)c1ccccc1CO
Reaction time: 0.42 h

Procedure:
To a suspension of aluminium trichloride (12.67 g, 94.98 mmol) in dichloroethane (40 mL) is added diethylamine (13.5 g, 182.7 mmol) in dichloroethane (20 mL) while the temperature is maintained below 25° C. with an ice-bath. After another 25 min at r.t., phthalide (10.00 g, 74.5 mmol) is added in three portions and formation of a precipitate is observed. After 45 min, water and ice are added and the mixture is stirred for 30 min and filtered through celite. The aqueous phase is extracted with dichloromethane. After drying the combined organic phase over MgSO4 and filtering through a cotton plug, the volatiles are removed in vacuo to give an orange residue, which is purified by silica gel flash chromatography (dichloromethane-methanol, 49:1 to 97:3 to 19:1) to give N,N-diethyl-2-hydroxymethyl-benzamide as an orange oil; 1H NMR (400 MHz) δ 1.09 (3 H, t, J=7.0 Hz), 1.28 (3 H, t, J=7.0 Hz), 3.24 (2 H, q, J=7.0 Hz), 3.55 (1 H, t, J=6.8 Hz), 3.58 (2 H, q, J=7.0 Hz), 4.52 (2 H, d, J=6.8 Hz), 7.24 (1 H, dd, J=7.4, 1.5 Hz), 7.32 (1 H, td, J=7.4, 1.5 Hz), 7.39 (1 H, td, J=7.4, 1.5 Hz), 7.44 (1 H, td, J=7.4, 1.5 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[NH:5][C:6]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]([O:13][C:14]([F:17])([F:16])[F:15])[C:7]=1I)[CH3:2].CCN(CC)CC.[Si:27]([C:31]#[CH:32])([CH3:30])([CH3:29])[CH3:28]>C1COCC1.[Cu]I>[CH2:1]([O:3][C:4](=[O:19])[NH:5][C:6]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]([O:13][C:14]([F:17])([F:16])[F:15])[C:7]=1[C:32]#[C:31][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)Nc1c(F)ccc(OC(F)(F)F)c1I
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1c(F)ccc(OC(F)(F)F)c1C#C[Si](C)(C)C
Temperature: 60 °C
Yield: 93.5 %

Procedure:
A mixture of 3 (18.1 g, 45.9 mmol), Et3N (12.8 mL, 91.9 mmol), Pd(PPh)2Cl2 (1.6 g, 5% mol), CuI (0.7 g, 8% mol), and TMS-acetylene (19.6 mL, 137.8 mmol) in degassed THF (180 mL) is heated at 60° C. overnight. The mixture is cooled to rt, and then partitioned between H2O and EtOAc. This mixture is filtered through Celite to remove the insoluble material. The two layers of the filtrate are separated, and the organic layer is washed H2O and brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude material is purified on silica gel with heptane/EtOAc as eluant to give 15.6 g (93%) of the product 4 as beige solid. 1H NMR (CDCl3) δ 7.15-7.00 (m, 2H), 6.41 (br s, 1H), 4.26 (q, J=7.1 Hz, 2H), 1.31 (t, J=7.1 Hz, 3H), 0.27 (s, 9H); 19F NMR (CDCl3) δ −57.59 (s, 3F), −118.15 (s, 1F); MS 364 (M+1, 100%).