Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:3]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)C(O)=O.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C([N:43]([CH2:46]C)CC)C.[OH2:48]>O1CCCC1>[C:18]1([CH:2]2[O:1][C:46](=[O:48])[NH:43][CH:3]2[CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:10][CH:9]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O
Reactant: O=C(O)C(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccccc1
Reactant: CCN(CC)CC
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: O=C1NC(Cc2ccc(C(F)(F)F)cc2)C(c2ccccc2)O1
Yield: 93 %

Procedure:
To a solution of (2RS,3RS)-3-hydroxy-3-phenyl-2-((4-(trifluoromethyl)phenyl)methyl)propionic acid (7 g, 21.6 mmol) in tetrahydrofuran (200 ml) were added diphenylphosphoryl azide (5.12 ml, 23.7 mmol) and triethylamine (4.5 ml, 32.4 mmol) and the mixture was heated under reflux for 4 hrs. The reaction solution was allowed to stand at room temperature, water (200 ml) was added, and the mixture was extracted with ethyl acetate (200 ml×2). The extract was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and evaporated-under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (4RS,5SR)-5-phenyl-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one (6.5 g, 93%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.N1C=CC=CC=1.[C:13]1([C:19](Cl)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C1C=CN=CC=1.O>[Br:1][C:2]1[CH:3]=[N:4][N:5]([C:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:6]=1
Reactant: Brc1cn[nH]c1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: Brc1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
In a 75 mL sealed tube, 4-bromopyrazole (1.0 g, 6.8 mmol), pyridine (21.0 mL, 258 mmol), triphenylmethyl chloride (2.1 g, 7.5 mmol), and 4-dimethylaminopyridine (0.17 g, 1.4 mmol) were added. The mixture was stirred at 80° C. for 24 hours. The mixture was diluted with water, and the solids which crashed out were filtered, rinsed with water and air-dried to yield 4-bromo-1-trityl-1H-pyrazole as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[CH2:4][C@H:5]1[CH2:10][C@H:9]([C:11](=[O:18])[CH2:12][C:13](OCC)=[O:14])[CH2:8][CH2:7][N:6]1[C:19]([O:21][CH3:22])=[O:20].[OH-].[Na+].[NH2:30]O.Cl>CO.O>[F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[CH2:4][C@H:5]1[CH2:10][C@H:9]([C:11]2[O:18][NH:30][C:13](=[O:14])[CH:12]=2)[CH2:8][CH2:7][N:6]1[C:19]([O:21][CH3:22])=[O:20]
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](Cc2ccc(F)cc2F)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccc(F)cc1F
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 101.4 %

Procedure:
Trans-methyl 2-(2,4-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.18 g, 3.08 mmol) (from example 134, step 1) was dissolved in MeOH (15 mL) and cooled to −40° C. Sodium hydroxide (0.123 g, 3.08 mmol) dissolved in water (1.7 mL) was added over 1 min and the resulting solution was stirred at −40° C. for 20 min. Then hydroxylamine (50% by weight in water, 0.2 mL, 3.26 mmol) was added over 1 min and stirring continued at −40° C. for 2 h. The reaction mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (30 mL, 180.00 mmol) and the mixture was continued to be stirred at 80° C. for 1 h. Then cooled to room temperature. Methanol was evaporated, then water was added. Extracted three times with DCM. Combined organic layers dried over MgSO4 and evaporated. Crude trans-methyl 2-(2,4-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.1 g, 101%) was isolated as a pale orange foam. 1H NMR (500 MHz, cdcl3) δ 1.43-2.15 (m, 4H), 2.66-3.23 (m, 4H), 3.39-3.79 (m, 3H), 4.04-4.41 (m, 1H), 4.45-4.78 (m, 1H), 5.67 (s, 1H), 6.73-6.90 (m, 2H), 7.03-7.37 (m, 1H). MS m/z 353 (M+H)+
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]([CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[N:39]1([C:46]([NH:48][C@@H:49]([CH2:53][CH:54]([CH3:56])[CH3:55])[C:50](O)=[O:51])=[O:47])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]([CH:19]2[CH2:24][CH2:23][N:22]([C:50](=[O:51])[C@@H:49]([NH:48][C:46]([N:39]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)=[O:47])[CH2:53][CH:54]([CH3:56])[CH3:55])[CH2:21][CH2:20]2)[CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:14][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)O
Reactant: CC(C)CCN(c1ccc(NC(=O)OCc2ccccc2)cc1)C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CCN(c1ccc(NC(=O)OCc2ccccc2)cc1)C1CCN(C(=O)[C@H](CC(C)C)NC(=O)N2CCCCCC2)CC1
Reaction time: 1 h
Yield: 77.2 %

Procedure:
(4-Benzyloxycarbonylamino-phenyl)-(3-methyl-butyl)-piperidin-4yl-amine (0.22 g, 5.64 mmol) was dissolved in DMF (30 mL), treated with Hunig's base (3.93 mL, 22.6 mmol), (S)-2-[(Azepane-1-carbonyl)-amino]-4-methyl-pentanoic acid (1.36 g, 5.64 mmol), and HBTU (2.04 g, 5.64 mmol), and stirred for 1 hour. The reaction was diluted with EtOAc (200 mL), washed with saturated bicarbonate solution and brine, dried over Na2SO4, and concentrated. The residue was chromatographed on silica gel eluting with 5% MeOH/CH2Cl2 to give 2.76 g (77%) of the desired product.
Reaction SMILES: [CH3:1][CH:2]([CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:3][CH2:4][Si:5]([Cl:8])([Cl:7])Cl.[CH2:15]([Mg]Br)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>O1CCCC1>[CH3:1][CH:2]([CH2:9][CH2:10][CH2:11][CH:12]([CH3:13])[CH3:14])[CH2:3][CH2:4][Si:5]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])([Cl:7])[Cl:8]
Reactant: CC(C)CCCC(C)CC[Si](Cl)(Cl)Cl
Reactant: CCCCCC[Mg]Br
Solvent: C1CCOC1
Product: CCCCCC[Si](Cl)(Cl)CCC(C)CCCC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
Tetrahydrofuran (50 ml) and 3,7-dimethyloctyl trichlorosilane (11.0 g, 40.0 mmol) were placed in a 200 mL four-necked flask in a nitrogen atmosphere, and cooled to −20° C. n-hexyl magnesium bromide (Sigma-Aldrich Co. LLC., 2.0 M, 21 ml) was added dropwise, and the mixture was agitated for 1 hour at 10° C. or less. The temperature was raised gradually to room temperature over the course of about 1 hour, and the mixture was left standing overnight. The precipitated salt was filtered out, the tetrahydrofuran was removed by concentration under reduced pressure, and distillation under reduced pressure was performed to obtain the target 3,7-dimethyloctyl-n-hexyl-dichlorosilane (Compound G18) (127-130° C./0.26 Torr, 9.5 g, yield 73%).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1>>[Cl:32][C:33]1[CH:38]=[C:37]([C:12]2[N:13]([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)[N:14]=[C:15]3[C:11]=2[CH2:10][CH2:9][NH:8][CH2:17][CH2:16]3)[CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CCCCC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Reactant: OB(O)c1cccc(Cl)c1
Product: Clc1cccc(-c2c3c(nn2C2CCCCC2)CCNCC3)c1
Yield: 10.2 %

Procedure:
The title compound (14.4 mg) was prepared as in Example 177, Steps C and D, using 199.3 mg of 2-cyclohexyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 177, Step B) and 216.2 mg of 3-chlorophenylboronic acid. MS (ESI): exact mass calculated for C19H24ClN3, 329.87. found, m/z 330.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.57-7.54 (m, 2H), 7.35 (s, 1H), 7.28-7.25 (m, 1H), 3.91-3.84 (m, 1H), 3.43-3.38 (m, 2H), 3.19-3.14 (m, 2H), 2.79-2.74 (m, 2H), 1.97-1.80 (m, 6H), 1.71-1.64 (m, 1H), 1.28-1.19 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:6]([CH:24]=[O:25])=[C:5]2[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[CH2:32]([Mg]Cl)[CH2:33][CH3:34].C(OCC)(=O)C.C(OC(C)C)(C)C>C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:18][CH:19]=1)[C:6]([CH:24]([OH:25])[CH2:32][CH2:33][CH3:34])=[C:5]2[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CS(=O)(=O)c1ccc(Cn2c(C=O)c(-c3ccccc3)c3cc(Cl)ccc3c2=O)cc1
Reactant: CCC[Mg]Cl
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Solvent: CCOCC
Product: CCCC(O)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1

Procedure:
In the same manner as in Example 313, the title compound was synthesized using 6-chloro-2-(4-methanesulfonylbenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carbaldehyde and a solution (2M) of propyl magnesium chloride in diethyl ether. Crystals (ethyl acetate-diisopropyl ether).
Reaction SMILES: Cl.[CH3:2][NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH2:10].[C:11](=[S:13])=S.[OH-].[Na+].Cl>C(O)C.O>[SH:13][C:11]1[N:3]([CH3:2])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:10]=1
Reactant: S=C=S
Reactant: CNc1ccccc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1c(S)nc2ccccc21
Yield: 49.5 %

Procedure:
11.7 g of N-methyl-o-phenylenediamine hydrochloride, 9.1 g of carbon disulfide and an aqueous solution containing 7.2 g of sodium hydroxide and 20 ml of water were added to 150 ml of ethanol and the mixture was heated and refluxed for 4 hours. After cooling, a 3 N hydrochloric acid aqueous solution was added to the reaction mixture to make the reaction solution slightly acidic and, thereby, crystals were precipitated. After filtration, the crystals were recrystallized from a mixture of water and ethanol (70:30 by volume) to obtain 6 g of 2-mercapto-1-methylbenzimidazole (Compound (III-11)) having a melting point of 194° to 195° C. (yield: 67%).
Reaction SMILES: Cl[C:2]1[CH:19]=[CH:18][C:5]2[C:6](=[O:17])[C:7]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1.[F:20][C:21]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:22]=1[NH2:23].P>C1(C)C=CC=CC=1.C(O)(C)(C)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:20][C:21]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:22]=1[NH:23][C:2]1[CH:19]=[CH:18][C:5]2[C:6](=[O:17])[C:7]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: Nc1ccc(F)cc1F
Reactant: COc1ccc2c(c1)CCc1cc(Cl)ccc1C2=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: P
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)CCc1cc(Nc3ccc(F)cc3F)ccc1C2=O
Yield: 66 %

Procedure:
In accordance with general method O, 0.52 g (1.9 mmol) of 2-chloro-8-methoxy-10,11-dihydrodibenzo[a,d]cyclohepten-5-one, 0.30 g (2.3 mmol) of 2,4-difluoroaniline, 0.04 g of Pd(OAc)2, 0.16 g of phosphine ligand and 0.86 g (8.9 mmol) of Na—O-tert-butylate are reacted in 10 ml of toluene and 2 ml of tert-BuOH. Purification is carried out by column chromatography (flash; SiO2; hexane 90%/ethyl acetate 10%). Yield: 66%; m.p.: 157° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][I:20]>C(O)C>[IH:20].[CH2:1]([NH:8][C:9](=[N:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[S:10][CH3:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: S=C(NCc1ccccc1)NCc1ccccc1
Reactant: CI
Solvent: CCO
Product: CSC(=NCc1ccccc1)NCc1ccccc1
Product: I

Procedure:
A solution of 25.6 g. of 1,3-dibenzylthiourea and 10 ml. of methyl iodide in 500 ml. of absolute ethanol is heated at reflux for 16 hours to give a solution of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([N:6]=[CH:7][C:8]2[CH:13]=[CH:12][C:11]([S:14](=[O:17])(=[O:16])[NH2:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C[Si]([C:24]#[N:25])(C)C>>[F:1][C:2]1[CH:19]=[CH:18][C:5]([NH:6][CH:7]([C:8]2[CH:13]=[CH:12][C:11]([S:14](=[O:17])(=[O:16])[NH2:15])=[CH:10][CH:9]=2)[C:24]#[N:25])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C#N
Reactant: NS(=O)(=O)c1ccc(C=Nc2ccc(F)cc2)cc1
Product: N#CC(Nc1ccc(F)cc1)c1ccc(S(N)(=O)=O)cc1

Procedure:
Following a procedure similar to that described in Example 1(ii), but using 4-fluoro-N-(4-sulfamoylbenzylidene)aniline [prepared as described in step (i) above] and trimethylsilyl cyanide as starting materials, the title compound was obtained as a slightly yellow powder (yield 83%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][Br:8].[S:9]1[CH2:13][C:12](=[O:14])[NH:11][C:10]1=[O:15].C(N(CC)CC)C>C(#N)C>[Br:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:11]1[C:12](=[O:14])[CH2:13][S:9][C:10]1=[O:15]
Reactant: BrCCCCCCBr
Reactant: O=C1CSC(=O)N1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1CSC(=O)N1CCCCCCBr
Temperature: 25 °C
Yield: 69.4 %

Procedure:
36.6 g of 1,6-dibromohexane, 5.9 g of 2,4-thiazolidinedione and 7.1 g of triethylamine were added to 125 ml of acetonitrile and the mixture was heated with stirring under reflux for 8 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure and the residue was poured into water. The mixture was extracted with methylene chloride and the methylene chloride layer was washed with saturated brine and dried over sodium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1→4:1) to obtain 9.8 g of the title compound as pale yellow oil (yield: 70%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([OH:13])[CH:12]=1)[C:9](=[O:14])[CH2:8][CH2:7][C:6]2([CH3:16])[CH3:15])#[CH:2].[CH3:17][O:18][C:19](=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=1.C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:17][O:18][C:19](=[O:28])[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:2]#[C:1][C:3]2[CH:12]=[C:11]([OH:13])[C:10]3[C:9](=[O:14])[CH2:8][CH2:7][C:6]([CH3:16])([CH3:15])[C:5]=3[CH:4]=2)=[CH:25][CH:26]=1
Reactant: COC(=O)Cc1ccc(I)cc1
Reactant: C#Cc1cc(O)c2c(c1)C(C)(C)CCC2=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(C#Cc2cc(O)c3c(c2)C(C)(C)CCC3=O)cc1

Procedure:
Following General Procedure B and using 6-ethynyl-8-hydroxy-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 67, 1.58 g, 7.4 mmol), 4-iodo phenyl acetic acid methyl ester (2.2 g, 7.94 mmol), triethyl amine (12 mL), copper(I)iodide (0.38 g, 1.99 mmol) and dichlorobis(triphenylphosphine)palladium(II) (1.2 g, 1.71 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 16% ethyl acetate in hexane as the eluent, the title compound was obtained as a yellow oil (2.1 g, 78%).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C@@H:17]2[O:22][C:21]3[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:20]=3[O:19][CH2:18]2)[CH2:12][CH2:11]1.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1.C(OCC)C>ClCCl>[Cl:27][C:24]1[CH:25]=[CH:26][C:20]2[O:19][CH2:18][C@H:17]([CH2:16][N:13]3[CH2:14][CH2:15][CH:10]([CH2:9][NH:8][S:36]([C:33]4[CH:32]=[CH:31][C:30]([O:29][CH3:28])=[CH:35][CH:34]=4)(=[O:38])=[O:37])[CH2:11][CH2:12]3)[O:22][C:21]=2[CH:23]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCC1CCN(C[C@H]2COc3ccc(Cl)cc3O2)CC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)NCC2CCN(C[C@H]3COc4ccc(Cl)cc4O3)CC2)cc1
Reaction time: 20 h
Yield: 28.9 %

Procedure:
Triethylamine (0.62 ml) was added to a solution of (S)-4-(aminomethyl)-1-(7-chloro-1,4-benzodioxan-2-ylmethyl)piperidine (0.44 g) and 4-methoxybenzene-sulphonyl chloride (0.61 g) in dichloromethane (22 ml) under nitrogen. The reaction was stirred for 20 hours, diluted with dichloromethane (100 ml) and washed with water (100 ml) and brine (100 ml). After drying over anhydrous magnesium sulphate, the mixture was concentrated under reduced pressure to afford an orange oil. Purification by flash chromatography on silica gel eluting with a 20:1 mixture of dichloromethane and methanol gave a colourless gum. Trituration with diethyl ether (20 ml) yielded (S)-(-)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]-methyl}-4-methoxybenzenesulphonamide as a white solid (0.20 g); m.p. 130-131° C., [α]D22.5 28.9° (c=0.51, CH2Cl2).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].Cl.[NH2:9][C:10]1([OH:13])[CH2:12][CH2:11]1.CCN(CC)CC>C1COCC1.C(=O)=O>[Br:1][CH2:2][CH2:3][CH2:4][C:5]([NH:9][C:10]1([OH:13])[CH2:12][CH2:11]1)=[O:6]
Reactant: O=C(Cl)CCCBr
Reactant: NC1(O)CC1
Agent: Cl
Agent: O=C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CCCBr)NC1(O)CC1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
In a 50 ml three necked flask fitted with a magnetic stirrer, under inert atmosphere, 4-bromo-butyryl-chloride (1.69 g, 9.13 mmol) is added onto a suspension 1-aminocyclopropanol hydrochloride (1.0 g, 9.13 mmol; synthesized following the method of Matthies, D.; Buechling, U. in Arch. Pharm. (Weinheim Ger.) 1983, 316, 598-608) and Et3N (2.21 g, 0.022 mol. in dry THF (20 ml at 0° C.). After 4 h, the reaction mixture is left overnight in dry ice and another portion of 4-bromo-butyryl-chloride (0.34 g) and Et3N (0.44 g) are added. After 2 h at room temperature, the reaction mixture is cooled down to 0° C., filtrated and concentrated in vacuo to give the crude 4-bromo-N-(1-hydroxy-cyclopropyl)-butyramide a16 which is used in the next step without any further purification.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Li+].CC([N-]C(C)C)C.[CH3:21][O:22][C:23]1[CH:39]=[CH:38][C:26]([CH2:27][N:28]2[CH:32]=[C:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:30]=[N:29]2)=[CH:25][CH:24]=1.CN(C)[CH:42]=[O:43]>C1COCC1.CCOC(C)=O>[CH:42]([C:32]1[N:28]([CH2:27][C:26]2[CH:25]=[CH:24][C:23]([O:22][CH3:21])=[CH:39][CH:38]=2)[N:29]=[CH:30][C:31]=1[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:43]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1cnn(Cc2ccc(OC)cc2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(Cc2ccc(OC)cc2)c1C=O
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 60.2 %

Procedure:
According to Scheme 17 Step 1: Butyl lithium 2.5 M (16.9 mmol, 8.45 mL) was added to a solution of diisopropylamine (16.9 mmol, 2.37 mL) in THF (10 mL) at −78° C. and the reaction mixture was stirred at −78° C. for 5 minutes and then at room temperature. To the resulting LDA solution was added at −78° C. a solution of ethyl 1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate (7.68 mmol, 2 g) in THF (30 mL) and the reaction mixture was stirred for 5 minutes at −78° C. N,N-Dimethylformamide (61.5 mmol, 4.73 mL) was added and then the reaction mixture was stirred at room temperature. The reaction mixture was diluted with AcOEt and was washed with a saturated aqueous solution of NH4Cl. The combined organic phases were dried over MgSO4, were filtered and were evaporated. The crude mixture was purified by flash chromatography over silica gel using cyclohexane/AcOEt (100:0 to 80:20) as eluent to yield ethyl 5-formyl-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate (4.62 mmol, 1.33 g, 60%).
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])([O-:5])=[O:4].Cl[CH2:14][CH:15]=[CH2:16].CS(C)=O>O>[CH2:16]([O:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[N+:3]([O-:5])=[O:4])[CH:15]=[CH2:14]
Reactant: C=CCCl
Reactant: O=[N+]([O-])c1ccccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: C=CCOc1ccccc1[N+](=O)[O-]
Reaction time: 18 h

Procedure:
A solution of 64 g of sodium hydroxide in 75 ml of water was added drop-by-drop (over 15 minutes) to a stirred mixture of 209.6 g of 2-nitrophenol, 115.5 g of 3-chloropropene and 500 ml of dimethyl sulfoxide (DMSO), at room temperature. The mixture was stirred at 85°-90° C. for 18 hours and then mixed with 3 liters of water. The resulting mixture was extracted with methylene chloride, the extract was washed with ice water, dried (MgSO4) and the solvent was evaporated, to give 1-(2-propen-1-yloxy)-2-nitrobenzene (1A), as an amber syrup.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][O:12][CH3:13])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C([Li])CCC.C([O:22][B:23]([O:28]C(C)C)[O:24]C(C)C)(C)C.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH2:11][O:12][CH3:13])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:22][B:23]([OH:28])[OH:24]
Reactant: COCc1cc(OC)cc(OC)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCc1cc(OC)c(OB(O)O)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3,5-dimethoxy(methoxymethyl)benzene (23.7 g) in tetrahydrofuran (500 mL) was added n-butyllithium (1.56M hexane solution; 100 mL) at −78° C., and the reaction mixture was stirred for 30 minutes while cooling with ice. After cooling the internal temperature of the obtained reaction mixture to −78° C., to a reaction mixture was added triisopropoxyborane (39 mL), and the internal temperature was raised to room temperature while stirring. After completion of the reaction, saturated aqueous ammonium chloride was added to the reaction mixture while cooling with ice, and then ethyl acetate was added to the reaction mixture, the organic extract was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and the title compound (7.5 g) was obtained as a yellow oil from the ethyl acetate fraction.
Reaction SMILES: C[Si](C)(C(C)(C)C(C)C)[O:3][C:4]1[C:21]2[CH2:20][S:19][CH2:18][C@@H:17]([C:22]3[O:26][N:25]=[C:24]([CH3:27])[N:23]=3)[NH:16][C:15](=[S:28])[CH2:14][CH2:13][CH2:12][C@H:11]([O:29][C:30](=[O:40])[C@@H:31]([NH:33]C(OCC=C)=O)[CH3:32])[O:10][C:9](=[O:41])[C:8]=2[C:7]([CH3:42])=[C:6]([O:43][CH3:44])[CH:5]=1.[F-].[NH4+].[ClH:54]>CO.C(OCC)(=O)C.C(OCC)C>[ClH:54].[OH:3][C:4]1[C:21]2[CH2:20][S:19][CH2:18][C@@H:17]([C:22]3[O:26][N:25]=[C:24]([CH3:27])[N:23]=3)[NH:16][C:15](=[S:28])[CH2:14][CH2:13][CH2:12][C@H:11]([O:29][C:30](=[O:40])[C@@H:31]([NH2:33])[CH3:32])[O:10][C:9](=[O:41])[C:8]=2[C:7]([CH3:42])=[C:6]([O:43][CH3:44])[CH:5]=1
Reactant: C=CCOC(=O)N[C@@H](C)C(=O)O[C@H]1CCCC(=S)N[C@H](c2nc(C)no2)CSCc2c(O[Si](C)(C)C(C)(C)C(C)C)cc(OC)c(C)c2C(=O)O1
Agent: Cl
Agent: [F-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(O)c2c(c1C)C(=O)O[C@@H](OC(=O)[C@H](C)N)CCCC(=S)N[C@H](c1nc(C)no1)CSC2

Procedure:
(S)-2-Allyloxycarbonylamino-propionic acid (4R,10S)-16-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-14-methoxy-13-methyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)-12-oxo-6-thioxo-1,3,4,5,6,7,8,9,10,12-decahydro-11,2,5-benzoxathiaazacyclotetradecin-10-yl ester was treated with ammonium fluoride in methanol in an analogous manner to the procedure described in Example 1. The resulting product was dissolved in ethyl acetate. Upon addition of 3N hydrochloric acid in diethyl ether, a precipitate formed which was collected to yield (S)-2-amino-propionic acid (4R,10S)-16-hydroxy-14-methoxy-13-methyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)-12-oxo-6-thioxo-1,3,4,5,6,7,8,9,10,12-decahydro-11,2,5-benzoxathiaazacyclotetradecin-10-yl ester hydrochloride as a white solid.