Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH3:7])[C:4]([OH:6])=[O:5].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH3:7][C:3]1([C:4]([OH:6])=[O:5])[CH2:8][O:9][CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:1][CH2:2]1
Reactant: CC(CO)(CO)C(=O)O
Reactant: O=Cc1ccccc1
Product: CC1(C(=O)O)COC(c2ccccc2)OC1

Procedure:
Synthesis of benzylidene protected 2,2-bis(hydroxymethyl)-propanoic acid, that is the acetal of benzaldehyde and 2,2-bis(hydroxymethyl)propanoic acid, yielding 5-methyl-2-phenyl-1,3-dioxane-5-carboxylic acid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:11][C:10]=1[C:19]([CH3:23])([CH3:22])[CH2:20][OH:21])C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:18])([CH3:16])[CH3:17])=[CH:11][C:10]=1[C:19]([CH3:23])([CH3:22])[CH2:20][OH:21]
Reactant: CC(C)(C)c1ccc(OCc2ccccc2)c(C(C)(C)CO)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1ccc(O)c(C(C)(C)CO)c1

Procedure:
Pd(OH)2 (1 g) and compound 9 (9.26 g, 0.030 mol) in MeOH (200 mL) were stirred under hydrogen at 20-30 psi pressure for 16-18 hours. The mixture was then filtered through Celite®, and the filtrate was concentrated to give compound 10 as a white solid. 1H NMR (DMSO-d6; 400 MHz) δ 9.16 (s), δ 7.16 (d), δ 7.00 (m), δ 6.65 (m), δ 4.71 (t), δ 3.62 (d), δ 1.27 (s), δ 1.22 (s).
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([N:19]=[CH:20][CH:21]([CH3:23])[CH3:22])[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[O:28]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([NH:19][CH2:20][C:21]3[CH:22]=[CH:11][CH:6]=[C:7]([CH3:8])[CH:23]=3)[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1
Reactant: CC(C)C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cccc(CNn2c(=O)c(C3=NS(=O)(=O)c4ccccc4N3)c(O)c3sccc32)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 269A (0.090 g, 0.2 mmol) in tetrahydrofuran (4 mL) and methanol (0.015 mL, 0.4 mmol) at 0° C. was treated dropwise with a 2.0M solution of lithium borohydride in tetrahydrofuran (0.150 mL, 0.3 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of approximately 2-4, diluted with water (15 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with 2% methanol in chloroform to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.29 (s, 3 H) 4.15 (s, 2 H) 6.94 (s, 1 H) 7.22 (m, 4 H) 7.30 (d, J=5.15 Hz, 1 H) 7.56 (t, J=7.72 Hz, 1 H) 7.68 (d, J=8.46 Hz, 1 H) 7.79 (t, J=6.99 Hz, 1 H) 7.94 (d, J=7.72 Hz, 1 H) 8.24 (d, J=5.15 Hz, 1 H) 14.26 (s, 1 H) 14.84 (s, 1 H). MS (ESI−) m/z 465(M−H)−.
Reaction SMILES: O=O.[CH3:3][O:4]/[C:5](=[CH:9]\[C:10]1[C:15]2[S:16][CH:17]=[CH:18][C:14]=2[C:13]([O:19][CH2:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])=[CH:12][CH:11]=1)/[C:6]([OH:8])=[O:7].C1([C@@H](N)C)C=CC=CC=1.[H][H]>O1CCCC1.CO>[CH3:3][O:4][C@H:5]([CH2:9][C:10]1[C:15]2[S:16][CH:17]=[CH:18][C:14]=2[C:13]([O:19][CH2:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])=[CH:12][CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: [H][H]
Reactant: CO/C(=C\c1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)C(=O)O
Agent: C[C@H](N)c1ccccc1
Agent: O=O
Solvent: CO
Solvent: C1CCOC1
Product: CO[C@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)C(=O)O

Procedure:
In a glove box (O2 content≦2 ppm), a 185-ml stainless steel autoclave was charged with 2.00 g of (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylic acid (4.59 mmol), 2.84 mg of [Ir((Ra,S)-DBT-Bn-SIPHOX)(COD)]OTf (0.0023 mmol, S/C 2,000), 24 ml of methanol, 16 ml of tetrahydrofuran and 0.12 ml of (S)-1-phenylethylamine (0.92 mmol). The autoclave was sealed and the hydrogenation was run at 60° C. for 20 h and subsequently 80° C. for 2 h under 30 bar of hydrogen. After the autoclave was opened and the yellowish solution was rotary evaporated to dryness (50° C./5 mbar) to afford crude (R)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid (Acid I) as a white solid with a chemical purity of 98.7% (99.7% conversion) and an enantiomeric purity of 99.8%.
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]1[C:76](=[O:77])[NH:75][C@@:6]2([O:11][C@@H:10]([CH2:12][C@H:13]([OH:71])[C@H:14]([CH2:16][CH2:17]/[CH:18]=[CH:19]/[CH:20]=[C:21](/[C@H:23]3[O:51][C:49](=[O:50])[C@H:47]4[NH:48][N:43]([CH2:44][CH2:45][CH2:46]4)[C:41](=[O:42])[C@H:40]([CH2:52][C:53]4[CH:54]=[CH:55][CH:56]=[C:57]([OH:59])[CH:58]=4)[NH:39][C:37](=[O:38])[C@H:36]([CH:60]([CH3:62])[CH3:61])[NH:35][C:33](=[O:34])[C@H:32]([CH2:63][CH2:64][C:65]([CH3:67])=[O:66])[C@H:31]([OH:68])[C@@H:30]([CH3:69])[C@@H:29]([OH:70])[CH:28]=[CH:27][CH:26]=[CH:25][CH2:24]3)\[CH3:22])[CH3:15])[C@H:9]([CH3:72])[C@H:8]([OH:73])[C@@H:7]2[CH3:74])[C@@H:5]([CH3:78])[CH2:4]1.[CH3:79]O>>[CH3:1][CH2:2][C@@H:3]1[C:76](=[O:77])[NH:75][C@@:6]2([O:11][C@@H:10]([CH2:12][C@H:13]([OH:71])[C@H:14]([CH2:16][CH2:17]/[CH:18]=[CH:19]/[CH:20]=[C:21](/[C@H:23]3[O:51][C:49](=[O:50])[C@@H:47]4[NH:48][N:43]([CH2:44][CH2:45][CH2:46]4)[C:41](=[O:42])[C@H:40]([CH2:52][C:53]4[CH:54]=[CH:55][CH:56]=[C:57]([OH:59])[CH:58]=4)[NH:39][C:37](=[O:38])[C@H:36]([CH:60]([CH3:61])[CH3:62])[NH:35][C:33](=[O:34])[C@@H:32]4[CH2:63][CH2:64][C@:65]([O:66][CH3:79])([CH3:67])[O:68][C@@H:31]4[C@@H:30]([CH3:69])[C@@H:29]([OH:70])[CH:28]=[CH:27][CH:26]=[CH:25][CH2:24]3)\[CH3:22])[CH3:15])[C@H:9]([CH3:72])[C@H:8]([OH:73])[C@@H:7]2[CH3:74])[C@@H:5]([CH3:78])[CH2:4]1
Reactant: CC[C@H]1C[C@H](C)[C@@]2(NC1=O)O[C@@H](C[C@H](O)[C@@H](C)CC/C=C/C=C(\C)[C@@H]1CC=CC=C[C@H](O)[C@H](C)[C@@H](O)[C@@H](CCC(C)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](Cc3cccc(O)c3)C(=O)N3CCC[C@H](N3)C(=O)O1)[C@H](C)[C@H](O)[C@@H]2C
Reactant: CO
Agent: CC[C@H]1C[C@H](C)[C@@]2(NC1=O)O[C@@H](C[C@H](O)[C@@H](C)CC/C=C/C=C(\C)[C@@H]1C/C=C/C=C/[C@H](O)[C@H](C)[C@@H](O)[C@@H](CCC(C)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](Cc3cccc(O)c3)C(=O)N3CCC[C@H](N3)C(=O)O1)[C@H](C)[C@H](O)[C@@H]2C
Agent: CC[C@H]1C[C@H](C)[C@@]2(NC1=O)O[C@@H](C[C@H](O)[C@@H](C)CC/C=C/C=C(\C)[C@@H]1C/C=C\C=C/[C@H](O)[C@H](C)[C@H]3O[C@](C)(OC)CC[C@H]3C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](Cc3cccc(O)c3)C(=O)N3CCC[C@@H](N3)C(=O)O1)[C@H](C)[C@H](O)[C@@H]2C
Product: CC[C@H]1C[C@H](C)[C@@]2(NC1=O)O[C@@H](C[C@H](O)[C@@H](C)CC/C=C/C=C(\C)[C@@H]1CC=CC=C[C@H](O)[C@H](C)[C@H]3O[C@](C)(OC)CC[C@H]3C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](Cc3cccc(O)c3)C(=O)N3CCC[C@@H](N3)C(=O)O1)[C@H](C)[C@H](O)[C@@H]2C
Reaction time: 1 h

Procedure:
To a stirred, cooled (0° C.) solution of 20 mg (18.3 μmol) of Sanglifehrin A in 0.5 mL of methanol is added one crystal of paratoluenesulfonic acid monohydrate. The resulting yellow solution is stirred for one hour and the reaction is quenched with saturated aqueous sodium bicarbonate solution. The resulting mixture is extracted twice with ethyl acetate. The organic solution is washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (95:5 methyl-tert.-butyl ether:methanol) to yield Sanglifehrin C as a white amorphous powder. The latter consisted of a 4:1 mixture of Sanglifehrin C and its C53 epimer, Sanglifehrin C having the (S) configuration as depicted below (R=Me). ##STR53##
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]=2[NH:23][C:24]2[C:25]3[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[N:30][C:26]=3[N:27]=[CH:28][N:29]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:39][C:40]1[CH:41]=[C:42]([CH:46]=[CH:47][CH:48]=1)[C:43]([NH2:45])=[O:44]>>[CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH:39][C:40]3[CH:48]=[CH:47][CH:46]=[C:42]([C:43](=[O:44])[NH2:45])[CH:41]=3)=[O:19])=[CH:16][C:15]=2[NH:23][C:24]2[C:25]3[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[N:30][C:26]=3[N:27]=[CH:28][N:29]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Cl)ccc3Oc3ccc(OCc4ccccc4)cc3)ncnc2n1
Reactant: NC(=O)c1cccc(N)c1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4cccc(C(N)=O)c4)ccc3Oc3ccc(OCc4ccccc4)cc3)ncnc2n1

Procedure:
A solution of the product from Example 43D and 3-Amino-benzamide was reacted to provide 4-(4-Benzyloxy-phenoxy)-N-(3-carbamoyl-phenyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzamide using the procedure from Example 43E. The material was then deprotected using the procedure from Example 43F to provide the crude title compound which was purified by HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (30 mg, 56%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.35 (d, J=6.62 Hz, 6 H) 3.28 (m, 1 H) 6.78 (m, 2 H) 6.94 (m, 3 H) 7.40 (m, 2 H) 7.60 (d, J=7.72 Hz, 1 H) 7.91 (m, 3 H) 8.02 (dd, J=8.82, 2.21 Hz, 1 H) 8.17 (d, J=2.21 Hz, 1 H) 8.22 (m, 1 H) 8.91 (s, 1 H) 9.00 (d, J=8.46 Hz, 1 H) 9.48 (s, 1 H) 10.37 (s, 1 H) 11.50 (s, 1 H); MS (ESI+) m/z 535 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:12][NH2:13])[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:14][C:15]([F:31])([F:30])[C:16]1[O:20][N:19]=[C:18]([C:21]2[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=2)[C:24](O)=[O:25])[N:17]=1>>[C:1]1([C:7]2[N:8]=[C:9]([CH2:12][NH:13][C:24](=[O:25])[C:23]3[CH:27]=[CH:28][CH:29]=[C:21]([C:18]4[N:17]=[C:16]([C:15]([F:31])([F:30])[F:14])[O:20][N:19]=4)[CH:22]=3)[S:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: NCc1nc(-c2ccccc2)cs1
Product: O=C(NCc1nc(-c2ccccc2)cs1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 38 %

Procedure:
This compound was synthesized from (4-phenylthiazol-2-yl)methanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (60 mg, yield 38%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.59 (m, 1H), 8.31-8.29 (dd, J=7.8 Hz, 1.0 Hz, 1H), 8.12-8.10 (m, 1H), 7.91-7.89 (m, 2H), 7.67 (t, J=7.8 Hz, 1H), 7.47 (s, 1H), 7.44 (t, J=7.5 Hz, 2H), 7.38-7.34 (m, 1H), 7.23 (t, J=4.8 Hz, 1H), 5.04 (d, J=5.5 Hz, 2H). MS (ESI) m/z: Calculated for C20H13F3N4O2S: 430.07. found: 431.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.C(OCC)(=O)C.O1C=CCCC1.Cl.CN>C(N(CC)CC)C>[N:3]1[CH:4]=[C:5]2[C:9]([N:8]=[CH:7][NH:6]2)=[N:10][CH:2]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: C1=COCCC1
Agent: CN
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: c1ncc2[nH]cnc2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 173.1 %

Procedure:
In a 100 ml three-mouth bottle, 2,6-dichloropurine (10 g), ethyl acetate (50 ml), pyridinium salt of paratoluenesulfonic acid (0.2 g) are mixed. The above mixture is stirred and heated to a temperature of 35° C., 2,3-dihydropyrane (12 ml) is added thereto within 5 min. The reaction mixture is reacted at 50˜60° C. for 3 h. The completion of reaction is checked with TCL analysis. Methylamine hydrochloride (4.6 g) is added to the bottle, and then triethylamine (21 ml) is added thereto at the temperature within 30 min, and the above mixture is reacted at the temperature for 1 h. The completion of reaction is checked with TCL analysis. The reaction mixture is cooled to room temperature. After filtration, a filter cake is completely washed with ethyl acetate, and a filtrate is washed with water for 3 times and delaminated. Organic layer is concentrated till large amounts of solid is separated out. After filtration, a filter cake is washed with ethyl acetate for 3 times and then dried in vacuum at 50° C. for 5 h to obtain solid purin (11.0 g). The yield is about 77.7%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Br)=[CH:6][C:5]=1[O:12][CH2:13][CH2:14][CH2:15][CH3:16].[Li+].[OH-:19].Cl.[Si](C=[N+]=[N-])(C)(C)C.CCCCCC>CO.O.C1COCC1>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][OH:19])=[CH:6][C:5]=1[O:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCOc1cc(CBr)ccc1C(=O)OC
Reactant: [OH-]
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: Cl
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: CCCCCC
Product: CCCCOc1cc(CO)ccc1C(=O)OC
Temperature: 50 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
A mixture of 4-bromomethyl-2-butoxy-benzoic acid methyl ester (0.0500 g, 1.67 mmol), THF (10 mL), H2O (10 mL), and LiOH (0.0160 g, 6.68 mmol) is stirred at 50° C. overnight. The mixture is acidified with 1.0 M HCl and the product is extracted with EtOAc (40 mL). The organic phase is washed with brine (20 mL) and dried (Na2SO4). After filtration, the filtrate is concentrated under reduced pressure to a residue. The residue is dissolved in CH2Cl2 (10 mL) and MeOH (10 mL) and treated with 2.0 M TMSCHN2 in hexane (5.0 mL, 10 mmol) at room temperature for 30 minutes. After concentration the residue is purified by flash chromatography to give 2-Butoxy-4-hydroxymethyl-benzoic acid methyl ester as a syrup (270 mg, 68%). LC-ES/MS: 239.3 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].C(N(CC)CC)C.[C:20]([O:24][O:25][C:26](=[O:32])[CH2:27][CH2:28][C:29](Cl)=[O:30])([CH3:23])([CH3:22])[CH3:21].[OH-].[Na+]>CCCCC.C(OC)(C)(C)C>[CH3:1][N:2]1[C:7]([CH3:8])([CH3:9])[CH2:6][CH:5]([O:10][C:29](=[O:30])[CH2:28][CH2:27][C:26]([O:25][O:24][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:32])[CH2:4][C:3]1([CH3:12])[CH3:11]
Reactant: CC(C)(C)OOC(=O)CCC(=O)Cl
Reactant: CN1C(C)(C)CC(O)CC1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCC
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Product: CN1C(C)(C)CC(OC(=O)CCC(=O)OOC(C)(C)C)CC1(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 62.2 %

Procedure:
Into a 500 ml flask equipped with a magnetic stirbar, thermometer, addition funnel, and nitrogen atmosphere sparger were placed 7.6 g (0.044 mole) of 1,2,2,6,6-pentamethyl-4-piperidinol, 4.4 g (0.044 mole) of triethylamine, and 100 ml of pentane. The addition funnel was charged with 9.7 g (0.044 mole) of 4-t-butylperoxy-4-oxobutanoyl chloride, 50 ml of methyl t-butyl ether and 50 ml of pentane. The acid chloride was added dropwise to the reaction mixture at a rate maintaining the temperature of the reaction less than 27° C. (about 70 min. for complete addition). After this addition, the reaction mixture was allowed to stir at ambient temperature for 45 minutes. To the mixture 100 ml of 5% aqueous sodium hydroxide (chilled to 5° C.) was then added with rapid stirring. The mixture was transferred to a separatory funnel with 100 ml of methyl t-butyl ether and 100 ml of pentane. The funnel was shaken and allowed to separate; and the aqueous phase was drawn off. The organic phase was extracted with 100 ml of aqueous 5% sodium hydroxide (chilled to 5° C.), and twice with 100 ml portions of cold (5° C.) water. The organic solution was dried with anhydrous sodium sulfate and the solvent was stripped using aspirator and high vacuum systems. The residue was transferred to a flask with 30 ml of pentane and treated with 5.3 g of decolorizing carbon (occasional swirling for 90 minutes). The mixture was diluted with 200 ml of pentane, filtered free from carbon, and stripped of solvent using aspirator and high vacuum. The product was a yellow oil weighing 9.7 g. Analysis showed an assay of 96.1% and corrected yield of 62.2%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[NH:11][C:12](=[O:27])[C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=1.[Br:29][CH2:30][CH2:31][CH2:32]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:32][CH2:31][CH2:30][Br:29])=[CH:6][C:5]=1[NH:11][C:12](=[O:27])[C:13]1[CH:14]=[C:15]([C:23]([F:24])([F:25])[F:26])[CH:16]=[C:17]([C:19]([F:21])([F:22])[F:20])[CH:18]=1
Reactant: COC(=O)c1ccc(O)cc1NC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCCCBr)cc1NC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 77.8 %

Procedure:
To a solution of 2-(3,5-bis-trifluoromethyl-benzoylamino)-4-hydroxy-benzoic acid methyl ester (10.10 g, 2.70 mmol) and 1,3-dibromopropane (2.18 g, 10.8 mmol) in acetone (75 mL) was added potassium carbonate (1.87 g, 13.5 mmol). The reaction mixture was heated to reflux for 3 hours and allowed to cool back down to room temperature. The mixture was partitioned between ethyl acetate and brine, and the layers were separated. The aqueous layer was extracted with one additional portion of ethyl acetate. The organics were combined, washed with one portion of brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude oil was purified by flash chromatography through silica gel using ethyl acetate/hexanes (0/100 gradient to 8/92) to give 2-(3,5-bis-trifluoromethyl-benzoylamino)-4-(3-bromo-propoxy)-benzoic acid methyl ester (1.11 g, 78%) as a white powder. 1H NMR (400 MHz, CDCl3); δ 12.58 (s, 1H), 8.53 (d, 1H), 8.51 (s, 2H), 8.08 (s, 1H), 8.04 (d, 1H), 6.70 (dd, 1H), 4.24 (t, 2H), 3.96 (s, 3H), 3.62 (t, 2H), 2.37 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH:5]([NH:23]C=O)[CH:6]=[C:7]([CH2:12][P:13]([O:19]C(C)C)([O:15]C(C)C)=[O:14])[CH2:8][CH2:9][O:10][CH3:11])[CH3:2].C[Si](C)(C)Br.C(O)C>ClCCl>[CH2:1]([O:3][C:4](=[O:26])[CH:5]([NH2:23])[CH:6]=[C:7]([CH2:12][P:13]([OH:15])([OH:19])=[O:14])[CH2:8][CH2:9][O:10][CH3:11])[CH3:2]
Reactant: CCOC(=O)C(C=C(CCOC)CP(=O)(OC(C)C)OC(C)C)NC=O
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)C(N)C=C(CCOC)CP(=O)(O)O
Temperature: 25 °C
Reaction time: 22 h

Procedure:
1.77 g (4.5 mmol) of 4-diisopropylphosphonomethyl-2-formylamino-6-methoxy-hex-3-enoic acid ethyl ester are dissolved in 12 ml of dichloromethane, and 2.32 ml (18.0 mmol) of trimethylbromosilane are added dropwise at room temperature. The mixture is left to stand at room temperature for 22 hours, 12 ml of ethanol are added dropwise, the mixture is left to stand for a further 24 hours and is concentrated by evaporation in a rotary evaporator, the residue is dissolved in 10 ml of ethanol, and a mixture of 2 ml of propylene oxide and 2 ml of ethanol is added. A suspension forms, which is stirred for a further 2 hours at room temperature and for 2 hours with ice cooling, and is then filtered with suction. 2-amino-6-methoxy-4-phosphonomethyl-hex-3-enoic acid ethyl ester having a melting point of 242° (decomp.) is obtained.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][CH2:12][C:13]3=O)[CH:5]=[CH:4][N:3]=[CH:2]1.C1(C)C=CC(S([CH2:28][N+:29]#[C-])(=O)=O)=CC=1.[Na].C(O)C>C(COC)OC>[C:28]([CH:13]1[C:14]2[C:10](=[C:9]([O:8][CH2:7][CH2:6][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)[CH:17]=[CH:16][CH:15]=2)[CH2:11][CH2:12]1)#[N:29]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=C1CCc2c(OCCn3ccnc3)cccc21
Agent: [Na]
Solvent: CCO
Solvent: COCCOC
Product: N#CC1CCc2c(OCCn3ccnc3)cccc21
Yield: 30.7 %

Procedure:
To a solution of 2.68 g 4-[β-(1H-imidazol-1-yl)ethoxy]-1-indanone and 3.3 g of (p-toluenesulfonyl)methylisocyanide in 80 ml of dimethoxyethane, 0.36 g of sodium dissolved in 13.5 of absolute ethanol and 29 ml of dimethoxyethane are added as described in Ex. 3. 2.9 g of crude product are isolated and under purification by silica-gel chromatography allows to isolate 0.86 g (32%) of the nitrile in the form of oil which solidifies along the time (M.P. 115°-117° C.) and is chromatographically pure.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6](/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].[C:18](OC1C=CC(Cl)=C(Cl)C=1Cl)(=[O:23])[CH2:19][C:20]([O-])=[O:21]>C1(C)C=CC=CC=1>[OH:23][C:18]1[N:17]=[C:13]2[CH:12]=[C:11](/[CH:10]=[CH:9]/[C:6]3[S:7][CH:8]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:5]=3)[CH:16]=[CH:15][N:14]2[C:20](=[O:21])[CH:19]=1
Reactant: CC(C)c1csc(/C=C/c2ccnc(N)c2)n1
Reactant: O=C([O-])CC(=O)Oc1ccc(Cl)c(Cl)c1Cl
Solvent: Cc1ccccc1
Product: CC(C)c1csc(/C=C/c2ccn3c(=O)cc(O)nc3c2)n1
Yield: 92.8 %

Procedure:
The 4-[(E)-2-(4-isopropyl-1,3-thiazol-2-yl)-1-ethenyl]-2-pyridinamine (2.65 g, 10.8 mmol) obtained in (D) was dissolved in toluene (100 ml), added with trichlorophenyl malonate (5.50 g, 11.9 mmol), and refluxed by heating for 1.5 hours. After the reaction mixture was concentrated, the deposited solid was collected by filtration and washed with n-hexane and ether to obtain the title compound (3.14 g, 93%) as yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][C:15](O)=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN.[C:22](N1C=CN=C1)([N:24]1C=CN=C1)=O>>[CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][C:15]([NH:24][CH3:22])=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)COc1ccc(OCc2ccccc2)cc1
Agent: CN
Product: CNC(=O)COc1ccc(OCc2ccccc2)cc1

Procedure:
In analogy to the procedure described in Example 1c), the (4-benzyloxy-phenoxy)-acetic acid was reacted with methylamine using 1,1′-carbonyl-diimidazole as the condensation reagent. 2-(4-benzyloxy-phenoxy)-N-methyl-acetamide was obtained as white crystals; MS: m/e=272 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14](=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1)[CH3:12]>>[CH2:11]([O:13][C:14](=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=2)=[O:10])[CH:17]=1)[CH3:12]
Reactant: CCOC(=O)Cc1cccc(N)c1
Reactant: O=C(O)c1cccc(Br)n1
Product: CCOC(=O)Cc1cccc(NC(=O)c2cccc(Br)n2)c1

Procedure:
6-Bromo-2-pyridinecarboxylic acid (113 mg, 0.56 mmol) was coupled with ethyl ester (6) (100 mg, 0.56 mmol) following Method C to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:16][CH2:17][C:18](=[O:20])[NH2:19])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[CH2:26](I)[CH3:27]>O>[CH2:26]([O:14][C:13](=[O:15])[CH:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[CH2:16][CH2:17][C:18](=[O:20])[NH2:19])[CH3:27]
Reactant: CCI
Reactant: NC(=O)CCC(NC(=O)OCc1ccccc1)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C(CCC(N)=O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.9 %

Procedure:
A mixture of acid (1) (64 g, 0.228 mol), dimeththylformamide (210 ml) and sodium bicarbonate (111 g, 1.32 mol, 5.8 equiv.) was stirred at room temperature for 30 min. Ethyl iodide (34 ml, 66.3 g, 0.425 mol, 1.86 equiv.) was added and stirring was continued overnight under nitrogen. The reaction mixture was slowly diluted with water to 1 L and stirred for 40 min. The solid was collected by filtration, washed well with water and partitioned between ethyl acetate (8 L) and water (3 L). Phases were separated and the aqueous phase was extracted with ethyl acetate (2.5 L). The combined organic extracts were washed with water (1 L), dried over sodium sulfate, stripped and dried in a vacuum oven (50° C.) to produce (2) (47 g, 66.7%).