Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[N:12]1[CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:3]=2)[CH2:9][C:10]([C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])=[N:11]1
Reactant: C1COCCN1
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cccc(Br)c2)c(F)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cccc(N3CCOCC3)c2)c(F)c1
Temperature: 100 °C
Reaction time: 12 h
Yield: 21.7 %

Procedure:
5-(3-Bromo-phenyl)-1-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (30.0 mg, 0.07 mmol) prepared in Step 2 of Preparation 5, morpholine (17.2 mg, 0.20 mmol), Pd2(dba)3 (3.0 mg, cat.), BINAP (4.1 mg, cat.) and sodium t-butoxide (9.5 mg, 0.10 mmol) were added to toluene (1.0 mL). The reaction mixture was stirred at 100° C. for 12 hours and then filtered through celite pad. A saturated solution of ammonium chloride was added to the filtrate, which was then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2) to give 7.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[CH:10]=[N:11][NH:12][C:5]=12.Br[CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1>CN(C=O)C>[I:3][C:4]1[C:5]2[C:6](=[CH:10][N:11]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[N:12]=2)[N:7]=[CH:8][CH:9]=1
Reactant: Ic1ccnc2cn[nH]c12
Reactant: CC(C)(C)OC(=O)N1CCC(Br)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2cc3nccc(I)c3n2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 12.5 %

Procedure:
Sodium hydride (55.2 mg, 1.379 mmol) was added to a solution of 7-iodo-1H-pyrazolo[4,3-b]pyridine (260 mg, 1.061 mmol) in DMF (1.5 mL) at 0° C., and the reaction was stirred for 5 minutes. tert-Butyl 4-bromopiperidine-1-carboxylate (364 mg, 1.379 mmol) was added and the reaction was warmed to room temperature and then heated at 65° C. for 2 hours. The reaction was cooled, quenched with water, and concentrated in vacuo. The residue was partitioned between saturated NH4Cl solution and EtOAc. The organic layer was separated, dried over Na2SO4, and concentrated in vacuo to afford a residue. The residue was purified with silica column chromatography eluted with hexanes/ethyl acetate step gradient (0-100% EtOAc over 45 minutes), to afford tert-butyl 4-(7-iodo-2H-pyrazolo[4,3-b]pyridin-2-yl)piperidine-1-carboxylate (57 mg, 13%). The fractions containing tert-butyl 4-(7-iodo-1H-pyrazolo[4,3-b]pyridin-1-yl)piperidine-1-carboxylate were chromatographed again under the same conditions to give tert-butyl 4-(7-iodo-1H-pyrazolo[4,3-b]pyridin-1-yl)piperidine-1-carboxylate (60 mg, 13%). MS [M+H] found 429.2
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[CH2:9][CH3:10])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:31]I>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][I:31])=[CH:4][CH:3]=1
Reactant: CCC(O)c1ccc(Cl)cc1
Reactant: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Clc1ccc(CCCI)cc1

Procedure:
To a solution of 1.55 g of 3 (4-chlorophenyl)propanol and 2.51 g of triphenylphosphine in 10 ml of N,N-dimethylformamide, there was gradually added dropwise at room temperature a solution of 2.42 g of iodine in 8 ml of N,N-dimethylformamide while confirming the consumption of iodine. When the color of the reaction mixture ceased to disappear any more, water was added to the reaction mixture, the excess iodine was reduced by addition of 5% aqueous sodium thiosulfate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (20 g). Elution with hexane gave 1.82 g of 3-(4-chlorophenyl)propyl iodide.
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([O:20][C:21](=[O:23])[CH3:22])[C@H:8]([N:24]2[C:32]3[C:27](=[C:28]([CH3:33])[CH:29]=[CH:30][CH:31]=3)[CH:26]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([Br:41])=[CH:37][CH:36]=3)[CH2:25]2)[O:7]1)(=[O:3])[CH3:2]>ClCCl.[O-2].[Mn+4].[O-2]>[C:1]([O:4][CH2:5][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([O:20][C:21](=[O:23])[CH3:22])[C@H:8]([N:24]2[C:32]3[C:27](=[C:28]([CH3:33])[CH:29]=[CH:30][CH:31]=3)[C:26]([CH2:34][C:35]3[CH:36]=[CH:37][C:38]([Br:41])=[CH:39][CH:40]=3)=[CH:25]2)[O:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](N2CC(Cc3ccc(Br)cc3)c3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(Cc3ccc(Br)cc3)c3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 67.9 %

Procedure:
Add manganese (IV) oxide (172.5 mmol) to a solution of [(2R,3R,4S,5R,6R)-3,4,5-triacetoxy-6-[3-[(4-bromophenyl)methyl]-4-methyl-indolin-1-yl]tetrahydropyran-2-yl]methyl acetate (5.85 mmol) in dichloromethane (20 mL). Stir at room temperature for 48 hours. Filter the reaction through diatomaceous earth and concentrate under reduced pressure. Treat the crude product with dichloromethane/methanol (30 mL of 10:1) and stir for 15 minutes. Filter the resulting precipitate and rinse the filter cake with methanol (2×10 mL). Dry the filter cake under vacuum to yield the title compound as a colorless solid (2.5 g 3.97 mmol): MS (m/z): 630 (M+H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Cl:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11](Cl)=[O:12]>>[Cl:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:12]
Reactant: O=C(Cl)CCCCCl
Reactant: c1ccsc1
Product: O=C(CCCCCl)c1cccs1

Procedure:
Using thiophene (1.00 ml) and 5-chlorovaleryl chloride (1.63 ml) according to the same method as that of Reference Example 1, the title compound (2.20 g) was obtained as a pale yellow solid.
Reaction SMILES: CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC.[C:16]([O:20][C:21](=[O:35])[NH:22][CH:23]1[C:30](=[O:31])[N:29]2[CH:25]([S:26][CH2:27][CH:28]2[C:32](=O)[NH2:33])[CH2:24]1)([CH3:19])([CH3:18])[CH3:17]>C1COCC1>[C:16]([O:20][C:21](=[O:35])[NH:22][CH:23]1[C:30](=[O:31])[N:29]2[CH:25]([S:26][CH2:27][CH:28]2[C:32]#[N:33])[CH2:24]1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)NC1CC2SCC(C(N)=O)N2C1=O
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CC2SCC(C#N)N2C1=O
Reaction time: 8 h
Yield: 44.7 %

Procedure:
Burgess reagent (0.8 g, 3.3 mmol) was added in portions to a solution of 5 (0.5 g, 1.58 mmol) in dry THF (20 mL) at room temperature, and was stirred overnight. The mixture was washed with water (20 mL), dried over Na2SO4, concentrated and purified by column chromatography on silica gel to produce compound 6 (0.2 g, 50%) 1H NMR (400 MHz, CDCl3) δ1.44 (s, 9 H), 2.08-2.11 (m, 1 H), 3.17-3.21 (m, 1H), 3.68 (d, 2 H), 4.50-4.60 (m, 1 H), 5.07 (s, 1 H), 5.14 (t, 1 H), 5.37 (t, 1 H).
Reaction SMILES: Br[CH2:2][CH:3](OCC)OCC.Br.C(=O)(O)[O-].[Na+].[Br:16][C:17]1[C:18]([NH2:24])=[N:19][CH:20]=[C:21]([Br:23])[N:22]=1.C(=O)([O-])[O-].[K+].[K+]>>[Br:23][C:21]1[N:22]=[C:17]([Br:16])[C:18]2[N:19]([CH:2]=[CH:3][N:24]=2)[CH:20]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: CCOC(CBr)OCC
Agent: Br
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Product: Brc1cn2ccnc2c(Br)n1
Temperature: 40 °C
Yield: 94.8 %

Procedure:
A 1-L four-neck round bottom flask equipped with a temperature probe, mechanical stirrer and reflux condenser was charged with 2-bromo-1,1-diethoxyethane (68.1 g, 346 mmol) and 48% aqueous hydrogen bromide (11.3 mL, 99.2 mmol), and the reaction mixture was stirred at reflux for 2 h. The resulting mixture was allowed to cool to 40° C. and solid sodium bicarbonate (8.50 g, 101 mmol) was added in small portions until gas evolution was observed to cease. Caution: initial addition of sodium bicarbonate to the warm solution resulted in vigorous gas evolution (foaming). The resulting suspension was filtered into a 1-L four-neck round bottomed flask and the filter cake was washed with ethanol (200 mL). The flask was equipped with a temperature probe, mechanical stirrer and reflux condenser. 3,5-Dibromopyrazin-2-amine (50.0 g, 198 mmol) was added and the reaction mixture was heated at reflux, with vigorous stirring, for 16 h. After this time, the suspension was cooled to 0° C. and filtered. The filter cake was washed with cold ethanol (50 mL), dried under vacuum and added to a 1-L three-neck round bottomed flask equipped with a mechanical stirrer. Water (200 mL) was added and the vigorously stirred suspension was treated portion-wise with solid potassium carbonate (27.4 g, 198 mmol). Caution: gas evolution upon the addition of potassium carbonate observed. After stirring for 30 min, the resulting precipitate was isolated by filtration and the filter cake washed with water (100 mL) followed by ethanol (50 mL). The filter cake was dried at 50° C. to a constant weight, under vacuum to provide 6,8-dibromoimidazo[1,2-a]pyrazine (3) (52.0 g, 94%) as a light yellow solid: 1H NMR (300 MHz, DMSO-d6) δ 9.02 (s, 1H), 8.23 (s, 1H), 7.90 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12](O)=[O:13])=[CH:4][CH:3]=1.B.C1COCC1>O1CCCC1>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][OH:13])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)c2ccccc12
Agent: B
Solvent: C1CCOC1
Product: OCc1ccc(Br)c2ccccc12

Procedure:
Into a 250-mL 3-necked round-bottom flask, was placed tetrahydrofuran (200 mL), 4-bromonaphthalene-1-carboxylic acid (7 g, 27.88 mmol, 1.00 equiv). This was followed by the addition of BH3.THF (55.7 mL, 2.00 equiv) dropwise with stirring. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of hydrogen chloride. The pH was adjusted to 6. The resulting solution was diluted with 200 mL of ethyl acetate. The resulting mixture was washed with 3×100 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting residue was washed with 30 mL of n-hexane. This resulted in 6.3 g (95%) of (4-bromonaphthalen-1-yl)methanol as a white solid.
Reaction SMILES: C([N:3](CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:35][O:36][C:37]1[C:38]([CH3:62])=[C:39]([C:49](=[O:61])[C:50]2[CH:55]=[CH:54][C:53]([N+:56]([O-:58])=[O:57])=[C:52]([O:59][CH3:60])[CH:51]=2)[N:40]2[C:45]=1[CH:44]=[CH:43][C:42]([C:46](O)=[O:47])=[CH:41]2.N.C(=O)(O)[O-].[Na+]>CN(C)C=O.O1CCCC1.C(OC(C)C)(C)C.O>[CH3:35][O:36][C:37]1[C:38]([CH3:62])=[C:39]([C:49](=[O:61])[C:50]2[CH:55]=[CH:54][C:53]([N+:56]([O-:58])=[O:57])=[C:52]([O:59][CH3:60])[CH:51]=2)[N:40]2[C:45]=1[CH:44]=[CH:43][C:42]([C:46]([NH2:3])=[O:47])=[CH:41]2
Reactant: CCN(CC)CC
Reactant: COc1cc(C(=O)c2c(C)c(OC)c3ccc(C(=O)O)cn23)ccc1[N+](=O)[O-]
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)OC(C)C
Product: COc1cc(C(=O)c2c(C)c(OC)c3ccc(C(N)=O)cn23)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
104 μl (0.74 mmol) of triethylamine and then 330 mg (0.74 mmol) of benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) are added to 260 mg (0.66 mmol) of [1-methoxy-3-(3-methoxy-4-nitrobenzoyl)-2-methylindolizin-6-yl]carboxylic acid in 5 mL of N,N-dimethylformamide and the medium is stirred for one hour at room temperature. 0.9 mL (2.71 mmol) of a 3N solution of ammonia in tetrahydrofuran is added to the reaction medium and the medium is kept stirred at room temperature overnight. Water and a saturated aqueous sodium bicarbonate solution are added. The medium is extracted several times with ethyl acetate. The organic phase is separated by decantation, dried over sodium sulfate and concentrated under vacuum. The solid residue obtained is taken up in isopropyl ether, filtered, washed with isopropyl ether and then dried. 210 mg of a red solid are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:15]=[CH:14][C:13](F)=[N:12][C:8]=2[N:9]=[CH:10][N:11]=1.[NH3:20]>CCO>[NH2:20][C:13]1[CH:14]=[CH:15][C:7]2[C:6]([NH:5][C:4]3[CH:17]=[CH:18][CH:19]=[C:2]([Br:1])[CH:3]=3)=[N:11][CH:10]=[N:9][C:8]=2[N:12]=1
Reactant: Fc1ccc2c(Nc3cccc(Br)c3)ncnc2n1
Reactant: N
Solvent: CCO
Product: Nc1ccc2c(Nc3cccc(Br)c3)ncnc2n1
Temperature: 100 °C
Yield: 90 %

Procedure:
A solution of 4-(3-bromoanilino)-7-fluoropyrido[2,3-d]pyrimidine (0.20 g, 0.63 mmol) in EtOH (20 mL) is saturated with ammonia and warmed at 100° C. in a pressure vessel for 30 h. The solvent is removed under reduced pressure to give 7-amino-4-(3-bromoanilino)pyrido[2,3-d]pyrimidine (0.18 g, 90%). 1H NMR (DMSO) δ 9.97 (1H, brs), 8.59 (1H, s), 8.51 (1H, d, J=9.3 Hz), 8.11 (1H, sl brs), 7.77 (1H, brd, J=6.3 Hz), 7.44 (2H, brs), 7.37-7.30 (2H, m), 6.81 (1H, d, J=9.3 Hz).
Reaction SMILES: C([O:5][C:6](=[O:22])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:21])[C@H:13]([CH3:20])[NH:14][S:15]([CH2:18][CH3:19])(=[O:17])=[O:16])(C)(C)C.C(=O)(O)[O-].[K+:27]>Cl.O1CCOCC1>[K+:27].[CH2:18]([S:15]([NH:14][C@H:13]([C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:6]([O-:22])=[O:5])=[O:21])[CH3:20])(=[O:17])=[O:16])[CH3:19]
Reactant: CCS(=O)(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1COCCO1
Product: CCS(=O)(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)[O-]
Reaction time: 3 h
Yield: 79.3 %

Procedure:
N-ethanesulfonyl-L-alanyl-L-proline t-butylester was dissolved in 4.5N hydrochloric acid in dioxane (15 ml) solution and stirred for 3 hours. The solvent was distilled 1 off under reduced pressure and the oily residue thus Obtained (0.72 g) was dissolved in 0.5M aqueous potassium bicarbonate (5.2 ml). The solution was washed with diethyl ether and the water layer was freeze-dried to give N-ethanesulfonyl-L-alanyl-L-proline potassium salt(yield: 0.75 g, 79.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:29]=[CH:28][C:11]3[NH:12][C:13]([NH:15][C:16]([C:18]4[N:19]=[C:20]5[CH:25]=[CH:24][C:23](Cl)=[N:22][N:21]5[CH:27]=4)=[O:17])=[N:14][C:10]=3[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.O1CCCCC1[O:36][CH2:37][CH2:38][OH:39]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:29]=[CH:28][C:11]3[NH:12][C:13]([NH:15][C:16]([C:18]4[N:19]=[C:20]5[CH:25]=[CH:24][C:23]([O:36][CH2:37][CH2:38][OH:39])=[N:22][N:21]5[CH:27]=4)=[O:17])=[N:14][C:10]=3[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OCCOC1CCCCO1
Reactant: O=C(Nc1nc2cc(-c3cccc(Cl)c3)ccc2[nH]1)c1cn2nc(Cl)ccc2n1
Product: O=C(Nc1nc2cc(-c3cccc(Cl)c3)ccc2[nH]1)c1cn2nc(OCCO)ccc2n1

Procedure:
6-(2-Hydroxy-ethoxy)-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-chloro-phenyl)-1H-benzoimidazol-2-yl]-amide (41 mg) was prepared from 6-chloro-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-chloro-phenyl)-1H-benzoimidazol-2-yl]-amide (80 mg) and 2-(tetrahydro-pyran-2-yloxy)-ethanol as described in Example 122. LCMS (m/z): 449.7. 1H NMR (400 MHz, DMSO-d6): δ 12.38 and 11.4 (1H, s) 8.84 (1H, s) 8.15 (1H, d) 7.78 1H, s) 7.71 (1 h, s) 7.56-7.66 (2H, m) 7.45-7.51 (2H, m) 7.39 (1H, d) 7.07 (1H, d) 4.98 (1H, t) 4.38 (2H, t) 3.79 (2H, q).
Reaction SMILES: [Si:1]([O:8][CH:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)[CH:10]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:19][C:20]([S:23]([NH2:25])=[O:24])([CH3:22])[CH3:21]>ClCCl.S([O-])([O-])(=O)=O.[Cu+2]>[Si:1]([O:8][CH:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)/[CH:10]=[N:25]/[S:23]([C:20]([CH3:22])([CH3:21])[CH3:19])=[O:24])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC(C=O)c1cccc(Cl)c1
Reactant: CC(C)(C)S(N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)S(=O)/N=C/C(O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
To a solution of 3.0 g (10.6 mmol) of {[tert-butyl (dimethyl)silyl]oxy}(3-chlorophenyl)acetaldehyde (from Step C) and 1.3 g (10.6 mmol) of (R or S)-2-methyl-2-propanesulfinamide in 50 mL anhydrous dichloromethane was added copper(II) sulfate (3.4 g, 21.2 mmol) and the resulting mixture was stirred at room temperature under nitrogen atmosphere for 16 h. Wash reaction with water and extract with dichloromethane. Dry the organics with magnesium sulfate, filter and concentrate under vacuum. The residue was purified by Horizon MPLC, with a 40M+ silica gel column, eluting with a gradient eluent system of 0-25% ethyl acetate in hexane to afford the title compound (3.26 g, 80%). %). m/z (ES) 387, 390 (M, M+2)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[CH2:22]Br)[CH:7]=1)[CH3:2].[NH:25]1[CH2:29][CH2:28][NH:27][C:26]1=[O:30]>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[CH2:22][N:25]2[CH2:29][CH2:28][NH:27][C:26]2=[O:30])[CH:7]=1)[CH3:2]
Reactant: O=C1NCCN1
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CBr)c1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CN2CCNC2=O)c1

Procedure:
Prepared according to the procedure described in Example 116, Step 1, using the following starting materials: [3-(4-bromo-2-bromomethyl-phenoxy)-4-methoxy-phenyl]acetic acid ethyl ester and 2-imidazolidone.
Reaction SMILES: [C:1]([O:12][CH2:13][CH2:14][CH:15]([CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])[CH3:16])(=[O:11])[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4]([O-])=[O:5].C(Cl)(=O)C(Cl)=O.[BH4-].[Na+].OS([O-])(=O)=O.[K+]>CO>[OH:5][CH2:4][C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[C:1]([O:12][CH2:13][CH2:14][CH:15]([CH3:16])[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[O:11]
Reactant: CC(C)=CCCC(C)CCOC(=O)c1ccccc1C(=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: O=S(=O)([O-])O
Agent: [BH4-]
Solvent: CO
Product: CC(C)=CCCC(C)CCOC(=O)c1ccccc1CO
Reaction time: 4 h

Procedure:
5 g (16.4 mmol) monocitronellyl (+)-phthalate was heated at reflux in 25 ml oxalyl chloride (18 eq.) for 3 h. The excess oxalyl chloride was distilled under vacuum. 5.3 g crude acid chloride was then diluted in 40 ml THF cooled to −8° under argon, and 1.87 g (3 eq.) NaBH4 was added. The reaction mixture was maintained under stirring at 0° for 4 h, then at ambient temperature for 16 h. The reaction mixture was then cooled again to 0°, and then 10 ml methanol was added dropwise. After 15 min, the mixture was poured over cold 5% KHSO4 then extracted using cold ethyl acetate. Chromatography of the crude product over silica gel (9:1 toluene/ether) yielded 1.41 g (31%) of almost pure 3,7-dimethyl-6-octenyl 2-hydroxymethylbenzoate in the form of a colourless oil.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7]([OH:9])=O.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([C:26]2([CH2:31][NH2:32])[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:21]=[CH:22][C:23]=1[O:24][CH3:25].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([C:26]2([CH2:31][NH:32][C:7]([C:6]3[CH:5]=[C:4]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[O:3][C:2]=3[CH3:1])=[O:9])[CH2:27][CH2:28][CH2:29][CH2:30]2)[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: COc1ccc(C2(CN)CCCC2)cc1OC
Reactant: Cc1oc(-c2ccccc2)cc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(C2(CNC(=O)c3cc(-c4ccccc4)oc3C)CCCC2)cc1OC
Reaction time: 16 h
Yield: 20.3 %

Procedure:
2-Methyl-5-phenyl-furan-3-carboxylic acid (40.4 mg, 0.200 mmol) and C-[1-(3,4-Dimethoxy-phenyl)-cyclopentyl]-methylamine (47.1 g, 0.200 mmol) were dissolved in acetonitrile (1 mL) containing triethylamine (83.6 μL, 0.600 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (76.0 mg, 0.200 mmol) was added and the solution was allowed to stir for 16 hours. The mixture was then purified by reverse phase preparative liquid chromatography to yield the pure product (17.0 mg, 0.0405 mmol, 20.3%) ESI-MS m/z calc. 419.2, found 420.4 (M+1)+. Retention time of 3.62 minutes.
Reaction SMILES: C(O[CH:6]([N:29]=[C:30]=[O:31])[CH2:7][CH2:8][NH:9][C:10](=[O:28])[NH:11][C:12]1[CH:13]=[C:14]([CH:25]=[CH:26][CH:27]=1)[C:15]([NH:17][CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])=[O:16])(C)(C)C.[OH-:32].[Na+]>C(O)C>[C:14]([O:32][C:30]([NH:29][CH2:6][CH2:7][CH2:8][NH:9][C:10](=[O:28])[NH:11][C:12]1[CH:13]=[C:14]([CH:25]=[CH:26][CH:27]=1)[C:15]([NH:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[O:16])=[O:31])([CH3:25])([CH3:15])[CH3:13]
Reactant: CCOC(=O)CCNC(=O)c1cccc(NC(=O)NCCC(N=C=O)OC(C)(C)C)c1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCNC(=O)Nc1cccc(C(=O)NCCC(=O)O)c1
Reaction time: 25 h

Procedure:
0.61 g (1.33 mmol) of ethyl 3-(3-(3-(3-tert-butyloxy-carbonylaminopropyl)ureido)benzoylamino)propionate is dissolved in 50 ml of ethanol and treated with 0.73 ml of 2N NaOH. After 25 h at room temperature, the solvent is removed in vacuo and the residue is treated with 20 ml of water and 20 ml of ethyl acetate and acidified with citric acid. The phases are separated and the aqueous phase is extracted a further two times with 20 ml of ethyl acetate each time. After drying (MgSO4), the solvent is removed in vacuo and the residue (0.62 g) is employed without further purification.
Reaction SMILES: [C:1]([OH:18])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH:41]1[CH:46]=[CH:45][C:44]([NH:47][C:48]([CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][C:56]([NH:58]O)=[O:57])=[O:49])=[CH:43][CH:42]=1>CN(C=O)C>[C:11]1([NH:10][C:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:18][NH:58][C:56](=[O:57])[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][C:48]([NH:47][C:44]2[CH:45]=[CH:46][CH:41]=[CH:42][CH:43]=2)=[O:49])=[O:17])=[O:9])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(O)CCCCCCC(=O)Nc1ccccc1
Reactant: O=C(CCCCCCC(=O)Nc1ccccc1)NO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(CCCCCCC(=O)Nc1ccccc1)NOC(=O)CCCCCCC(=O)Nc1ccccc1
Reaction time: 0.08 h
Yield: 77.3 %

Procedure:
To a stirring solution of suberanilic acid (3.0 g, 12.0 mmol) in DMF (60 mL) was added 1-hydroxybenzotriazole (1.79 g, 13.2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (2.54 g, 13.2 mmol). After 5 mins, a solution of SAHA (3.18 g, 12.0 mmol) in DMF (30 mL) was added to the mixture with stirring. After 24 h, the solvent was removed and the residue was triturated with EtOAc (50 mL). The slurry was filtered to yield an off-white solid, which was triturated in CH2Cl2 (50 mL). The slurry was filtered yielding a white solid (4.6 g, 77%). Half of the material was purified further by repeating the washing procedures with an addition of H2O (20 mL) in the EtOAc wash. The white solid was filtered to yield the desired material (2.1 g). MP: 151-153° C. 1H NMR (DMSO-d6) δ 11.51 (s, 1H), 9.82 (s, 2H), 7.54 (d, J=7.9 Hz, 4H), 7.23 (dd, J=7.9, 7.6 Hz, 4H), 6.97 (t, J=7.6 Hz, 2H), 2.39 (t, J=7.2 Hz, 2H), 2.24 (t, J=6.8 Hz, 4H), 1.98 (t, J=6.8 Hz, 2H), 1.66-1.38 (m, 8H), 1.38-1.16 (m, 8H). 13C NMR (DMSO-d6) δ 171.33, 169.94, 139.49, 128.72, 123.02, 119.21, 36.49, 32.02, 31.06, 28.50, 28.37, 28.14, 25.12, 25.05, 24.79, 24.38. MS (EI): cal'd (MH+) 496, exp (MH+) 496.