Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1>>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][CH:11]=[C:2]([NH:17][C:16]2[CH:18]=[CH:19][C:13]([Br:12])=[CH:14][CH:15]=2)[CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: COC(=O)c1cccc(Br)c1
Product: COC(=O)c1cccc(Nc2ccc(Br)cc2)c1

Procedure:
Reaction of methyl 3-bromobenzoate with 4-bromoaniline according to general procedure A provided methyl ester of Compound 9 as a green oil (46% yield). 1H NMR (CDCl3, 500 MHz): δ=7.71 (s, 1H), 7.61 (d, J=7.7 Hz, 1H), 7.38 (d, J=8.6 Hz, 2H), 7.34 (t, J=7.9 Hz, 1H), 7.23 (d, J=8.1 Hz, 1H), 6.96 (d, J=8.7 Hz, 2H), 5.81 (s, 1H), 3.91 (s, 3H). 13C NMR (CDCl3, 125 MHz): δ=167.2, 143.1, 141.9, 132.6, 131.7, 129.7, 122.6, 122.1, 119.9, 118.8, 113.8, 52.4.
Reaction SMILES: CO[C:3](=[C:10]([C:13]#[N:14])[C:11]#[N:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.[CH2:16]([O:18][C:19](=[O:23])[CH2:20][CH2:21][NH2:22])[CH3:17]>C(#N)C.C(N(CC)CC)C>[NH2:14][C:13]1[C:10]([C:11]#[N:12])=[C:3]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:22]([CH2:21][CH2:20][C:19]([O:18][CH2:16][CH3:17])=[O:23])[C:20]=1[C:19]([O:18][CH3:16])=[O:23]
Reactant: CCOC(=O)CCN
Reactant: COC(=C(C#N)C#N)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)CCn1c(C(=O)OC)c(N)c(C#N)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
After dissolving (methoxyphenylmethylene)methane-1,1-dicarbonitrile (15.10 g) and β-alanine ethyl ester hydrochloride (15.11 g) in acetonitrile (300 mL), triethylamine (23.00 mL) was added and the mixture was stirred for 10 minutes at room temperature. After confirming complete consumption of the (methoxyphenyl-methylene)methane-1,1-dicarbonitrile by thin-layer chromatography (hexane/ethyl acetate=3/1), the solvent was distilled off under reduced pressure. Ethyl acetate and water were added to the residue, and extraction was performed 3 times with ethyl acetate. The organic layer was washed with water and saturated brine and then dried over anhydrous magnesium sulfate. After filtering off the magnesium sulfate, the solvent was distilled off under reduced pressure. Acetonitrile (700 mL) and anhydrous cesium carbonate (53.65 g) were added to the residue. Methyl bromoacetate (16.00 mL) was added thereto and the mixture was heated to reflux for 40 minutes. After cooling the mixture to room temperature, it was allowed to stand, the supernatant was separated by decantation, and the solvent was distilled off under reduced pressure. The residue was combined with the solid portion remaining after decantation, ethyl acetate and water were added, and extraction was performed 3 times with ethyl acetate. The organic layer was washed with water and saturated brine and then dried over anhydrous magnesium sulfate. After filtering off the magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was passed through a chromatography column packed with a small amount of silica gel (elution with dichloromethane), for removal of the highly polar impurities, to obtain the title compound as a crude product (35.31 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH2:11])=[S:10].BrBr>C(Cl)(Cl)Cl>[F:1][C:2]1[C:3]2[N:8]=[C:9]([NH2:11])[S:10][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=S)Nc1ccccc1F
Agent: BrBr
Solvent: ClC(Cl)Cl
Product: Nc1nc2c(F)cccc2s1
Yield: 71.3 %

Procedure:
To a suspension of (2-fluorophenyl)thiourea (1.7 g, 10.0 mmol) in chloroform (25 ml) was added a solution of bromine (0.51 mL; 10.0 mmol) dropwise at room temperature. The resulting mixture was heated under reflux for 3 hrs. The solvent was evaporated, water was added and the mixture was neutralized with ammonium hydroxide. The resulting white precipitation was collected by filtration and dried to yield 1.2 g (72%) of the title compound which was used in the subsequent step without further purification.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][OH:6])[CH3:2].[H-].[Na+].[CH2:12]([O:14][CH:15]([O:18][CH2:19][CH3:20])[CH2:16]Br)[CH3:13].[I-].[K+]>O1CCCC1.O>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][O:6][CH2:16][CH:15]([O:18][CH2:19][CH3:20])[O:14][CH2:12][CH3:13])[CH3:2]
Reactant: CCOC(CBr)OCC
Reactant: CCOC(CO)OCC
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(COCC(OCC)OCC)OCC

Procedure:
Hydroxyacetaldehyde diethylacetal (3.75 g) was added to sodium hydride (0.8 g, 80% in mineral oil) in tetrahydrofuran (100 ml) under an atmosphere of nitrogen. The mixture was stirred and bromoacetaldehyde diethyl acetal (5.0 g) and potassium iodide (0.1 g) were added. The mixture was heated to reflux for 16 hours, water added and evaporated under reduced pressure. The residue was dissolved in diethyl ether, the organic phase washed with water, dried (MgSO4) and evaporated under reduced pressure to give bis(2,2-diethoxyethyl)ether, 3.43 g, as a yellow oil.
Reaction SMILES: [C:1]([CH:5]([C:8]#[N:9])[C:6]#[N:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:11][NH2:12]>C(O)CCC>[C:1]([C:5]1[C:8]([NH2:9])=[N:11][NH:12][C:6]=1[NH2:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C(C#N)C#N
Reactant: NN
Solvent: CCCCO
Solvent: O
Product: CC(C)(C)c1c(N)n[nH]c1N
Temperature: 25 °C
Reaction time: 19 h
Yield: 100.1 %

Procedure:
A mixture of tert-butylmalononitrile (5.01 g, 41.0 mmol) and hydrazine monohydrate (10.0 mL, 205 mmol) in 1-butanol (40 mL) was heated to reflux and stirred overnight (19 hours). The mixture was cooled to ambient temperature. Concentration afforded 6.33 g (100%) of the title compound. MS (DCI) m/z 155 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].[N+]([O-])(O)=O.[Br:16]Br>C(O)(=O)C.O.[N+]([O-])([O-])=O.[Ag+]>[Br:16][C:8]1[C:7]([CH3:11])=[C:3]([C:2]([F:1])=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: Cc1cccc(F)c1C(=O)O
Reactant: BrBr
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: O=[N+]([O-])O
Solvent: CC(=O)O
Product: Cc1c(Br)ccc(F)c1C(=O)O
Reaction time: 1.5 h
Yield: 90 %

Procedure:
To a stirred solution of 2-fluoro-6-methyl-benzoic acid (1 g, 6.4 mmol, 1.0 eq) in acetic acid (32 mL) was added nitric acid (3.27 mL), water (3 mL) and bromine (0.36 mL). A solution of silver nitrate (1.43 g, 8.4 mmol 1.3 eq) in water (10 mL) was then added dropwise over a period of 15 min. After the addition was completed, stirring was continued a further 1.5 h at room temperature. The reaction was diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo to afford a crude product, which was triturated with hexane to give the title compound as a yellow solid (1.35 g, 90%).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1C1C=CC=C[NH+]=1.[Cr](Cl)([O-])(=O)=O.[CH:23]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[OH:32])([CH3:25])[CH3:24]>ClCCl>[CH:23]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C:27]1=[O:32])([CH3:25])[CH3:24]
Reactant: CC(C)C1CCCCC1O
Agent: O=[Cr](=O)([O-])Cl
Agent: c1ccc(-c2cccc[nH+]2)[nH+]c1
Solvent: ClCCl
Product: CC(C)C1CCCCC1=O

Procedure:
To a suspension of 4.0 g. (13.7 mmole) of 2,2'-bipyridinium chlorochromate in 15 ml of dichloromethane is added, while stirring, 0.5 g. (3.5 mmole) of 2-isopropylcyclohexanol in 10 ml of dichloromethane. The resulting reaction mixture is stirred for 4 hours and then filtered through a Hirsch funnel packed with 2 cm of Celite®. The resulting clear filtrate is washed with 5% hydrochloric acid and 10% sodium carbonate, and dried over magnesium sulfate. The drying agent is then removed and the solvent evaporated to yield a colorless oil which is distilled via Kugelrohr to yield pure 2-isopropylcyclohexanone in a typical yield of 0.425 g. which is 86% of theoretical yield.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C:17]1([C:26]([OH:28])=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18]1>>[C:26]([C:17]1([NH:16][C:2]2[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=3)[N:3]=2)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18]1)([OH:28])=[O:27]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: NC1(C(=O)O)CCc2ccccc21
Product: O=C(O)c1cc2cc(Cl)ccc2nc1NC1(C(=O)O)CCc2ccccc21
Yield: 8 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with DL-1-aminoindan-1-carboxylic acid to provide the title compound in 8% yield as yellow needles (flash chromatography on SiO2, eluent CHCl3, MeOH, AcOH—15, 1, 0.2 and recrystallization from MeOH).
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:32]([OH:34])[CH3:33])/[CH:3]=[CH:4]/[CH2:5][C@@H:6]1[C@@H:11]([OH:12])[C@@H:10]([OH:13])[C@H:9]([CH2:14]/[C:15](/[CH3:31])=[CH:16]/[C:17]([O:19]CCCCCCCCC(O)=O)=[O:18])[O:8][CH2:7]1.[OH-:35].[Na+]>>[CH3:1][C@@H:2]([C@@H:32]([OH:34])[CH3:33])[C:3]1[O:35][C:4]=1[CH2:5][C@@H:6]1[C@@H:11]([OH:12])[C@@H:10]([OH:13])[C@H:9]([CH2:14]/[C:15](/[CH3:31])=[CH:16]/[C:17]([OH:19])=[O:18])[O:8][CH2:7]1
Reactant: [OH-]
Reactant: C/C(=C\C(=O)OCCCCCCCCC(=O)O)C[C@@H]1OC[C@H](C/C=C/[C@@H](C)[C@H](C)O)[C@@H](O)[C@H]1O
Agent: [Na+]
Product: C/C(=C\C(=O)O)C[C@@H]1OC[C@H](CC2=C([C@@H](C)[C@H](C)O)O2)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
Pseudomonic acid C (80 mgs) was dissolved in 0.1 M sodium hydroxide (20 ml) and stirred overnight at room temperature. After evaporation to low volume the solution was adjusted to pH 2 (5 M HCl), saturated with sodium chloride and extracted with ethyl acetate. The combined extracts were dried (MgSO4) then evaporated to dryness and chromatographed on silica (2 g) eluting with gradient of 0 to 8% methanol/chloroform. Fractions containing pure product (by hplc and tlc) were combined to give monic acid C(40 mgs, 74%), νmax (KBr) 3400 (broad) 1692 (broad), 1644, 1238, 975 cm-1 ; λmax (EtOH) 218 nm (ε9679); δH (CD3OD) 0.97 (3H, d, J 8 Hz, CH3 -17), 1.08 (3H, d, J 7 Hz, CH3 -14), 2.13 (3H, s, CH3 -15), 5.4 (2H, m, H-10, H-11), 5.67 (1H, s, H-2); δC (CD3OD) 170.2 (Cl), 159.0 (C3), 135.8, 129.7 (C10, C11), 118.6 (C2), 76.2 (C5), 72.5 (C7), 71.6 (C13), 70.0 (C6), 65.8 (C16), 45.3 (C12), 44.1 (C4), 43.7 (C8), 33.7 (C9), 20.4 (C14), 19.3 (C15), 16.7 (C17). (Found: 284.1624. C16H28O6M.+ --C2H4O requires 284.1623).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[F:12][C:13]([F:26])([F:25])[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21](Cl)(=[O:23])=[O:22]>CN(C1C=CN=CC=1)C>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[NH:1][S:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][C:13]([F:12])([F:25])[F:26])(=[O:23])=[O:22])[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1cccc2cccnc12
Reactant: O=S(=O)(Cl)c1ccccc1OC(F)(F)F
Agent: CN(C)c1ccncc1
Product: O=S(=O)(Nc1cccc2cccnc12)c1ccccc1OC(F)(F)F
Yield: 59 %

Procedure:
In the similar fashion using route 14 general procedure 27, 8-aminoquinoline (100 mg, 0.69 mmol), 2-trifluoromethoxybenzenesulfonyl chloride (200 mg, 0.69 mmol) and DMAP (cat.) gave the title compound (150 mg, 60%) after column purification with DCM elution.
Reaction SMILES: C([O:3][C:4](=[O:37])[CH2:5][CH:6]1[N:11]=[CH:10][CH:9]=[CH:8][N:7]1[CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][C:16]([O:24][CH3:25])=[C:17]([O:22][CH3:23])[CH:18]=2)[CH:13]1[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)C.[OH-].[Na+]>O1CCOCC1.CO>[CH3:36][O:35][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[O:33][CH3:34])[CH2:26][CH:13]1[C:14]2[C:19](=[CH:18][C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[CH2:20][CH2:21][CH:12]1[N:7]1[CH:8]=[CH:9][CH:10]=[N:11][CH:6]1[CH2:5][C:4]([OH:37])=[O:3]
Reactant: CCOC(=O)CC1N=CC=CN1C1CCc2cc(OC)c(OC)cc2C1Cc1ccc(OC)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCC2N2C=CC=NC2CC(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 20 h
Yield: 93.1 %

Procedure:
To a solution of 1-[(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl]-pyrimidin-acetic acid ethyl ester (1.4 g, 2.75 mmol) in a mixture dioxane/MeOH (4/3) (35 ml) was added dropwise 2M NaOH(aq) (24 ml). The resulting mixture was stirred at RT for 20 h under nitrogen. The mixture was then concentrated in vacuo, combined with water and AcOEt. The aqueous phase was acidified until pH 1 with 2N HCl, extracted three times with with CH2Cl2, the combined organic phases were dried over anhydrous MgSO4, filtered and concentrated to give the titled product (1.23 g, 93%) as yellow-green crystals.
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([CH3:25])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH:14]=2)[C:8]1=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([CH3:25])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH:14]=2)[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN1CC2C(C1=O)C2(C)c1cccc(-c2ccccn2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCN1CC2C(C1)C2(C)c1cccc(-c2ccccn2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.2 %

Procedure:
3-Hexyl-6-methyl-6-[3-(2-pyridinyl)phenyl]-3-azabicyclo[3.1.0]hexan-2-one (Preparation 68, 33 mg, 0.09 mmol) was dissolved in tetrahydrofuran (10 ml) at 0° C. Lithium aluminium hydride (1M in tetrahydrofuran, 0.2 ml, 0.2 mmol) was added under nitrogen and then the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched by adding aqueous sodium hydroxide solution (2N, 0.4 ml), followed by solid sodium hydrogen carbonate and ethyl acetate. The reaction mixture was stirred vigorously and then filtered through Celite®. The filtrate was concentrated in vacuo and the residue was chromatographed on silica gel eluting with ethyl acetate to give the product as a colourless oil (13 mg, 41%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[CH3:18][C:16]1[NH:15][N:14]=[C:13]([NH:12][C:4]2[N:3]=[C:2]([C:24]3[CH:25]=[CH:26][C:21]([C:20]([F:31])([F:30])[F:19])=[CH:22][CH:23]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:17]=1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: Cc1cc(Nc2cc3ccccc3c(-c3ccc(C(F)(F)F)cc3)n2)n[nH]1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 4-trifluoromethyl-phenylboronic acid to give (5-methyl-1H-pyrazol-3-yl)-[1-(4-trifluoromethyl-phenyl)-isoquinolin-3-yl]-amine. LC-MS m/e 369(MH+).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:23])[CH:15]=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([O:32][CH2:33][CH3:34])(=[O:31])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[O:23]=[C:14]([C:11]1[CH:12]=[CH:13][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1)[CH2:15][CH:16]([CH:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:24]([O:32][CH2:33][CH3:34])=[O:31])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(C=Cc1ccccc1)c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)C(C(=O)OCC)C(CC(=O)c1ccc(Oc2ccccc2)cc1)c1ccccc1

Procedure:
By a procedure similar to that of example 1.59.2, starting from 1-(4-phenoxyphenyl)-3-phenylprop-2-en-1-one and diethyl malonate, diethyl 2-[3-oxo-3-(4-phenoxyphenyl)-1-phenylpropyl]malonate was obtained as colourless solid.
Reaction SMILES: [N:1]1([C:21]([CH3:23])=[O:22])[CH2:20][CH2:19][CH2:18][C@H:2]1[C:3]([NH:5][C@H:6]([C:11]([NH:13][CH2:14][C:15]([OH:17])=O)=[O:12])[CH2:7][CH:8]([CH3:10])[CH3:9])=[O:4].[SH:24][NH:25][C@H:26]([C:31]([NH:33][C@H:34]([C:39]([NH:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37])=[O:32])[CH2:27][CH:28]([CH3:30])[CH3:29].C(Cl)CCl>CN(C)C=O>[N:1]1([C:21]([CH3:23])=[O:22])[CH2:20][CH2:19][CH2:18][C@H:2]1[C:3]([NH:5][C@H:6]([C:11]([NH:13][CH2:14][C:15]([S:24][NH:25][C@H:26]([C:31]([NH:33][C@H:34]([C:39]([NH:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37])=[O:32])[CH2:27][CH:28]([CH3:30])[CH3:29])=[O:17])=[O:12])[CH2:7][CH:8]([CH3:9])[CH3:10])=[O:4]
Reactant: CCOC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NS
Reactant: CC(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCOC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NSC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CCCN1C(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
To a solution of Ac-Pro-Leu-Gly-OH (0.7 g, 2.1 mmol), HS-Leu-Leu-Gly-OC2H5 (0.6 g, 1.7 mmol) and HBT (0.26 g, 1.7 mmol) in 15 ml dimethylformamide was added EDC (0.4 g, 2.1 mmol). The solution was stirred at room temperature overnight. The solvent was removed in vacuo and the residue partitioned between salt water and ethyl acetate. The ethyl acetate layer was washed consecutively with dilute sodium bicarbonate in salt (NaCl) water, dilute hydrochloric acid in salt water, salt water, 1.0 mM cupric sulfate in salt water (to remove any mercapto products) and finally salt water. The ethyl acetate was dried over magnesium sulfate. The magnesium sulfate was removed by filtration and the filtrate concentrated in vacuo, yielding 0.8 g (73%) glassy residue of crude thiopeptolide product. A 100 mg sample of this crude product was purified by low pressure C18 column chromatography. The purified thiopeptolide, had an acceptable amino acid analysis, a consistent mass spectrum and a single peak on HPLC analysis. Anal. Calcd. for C31H 53 N5O8S.3H2O: C, 52.4; H, 8.3; N. 9.9. Found: C, 52.5; H, 7.9; N. 9.9.
Reaction SMILES: [C:1]([O:5][CH2:6][C@@:7]1([CH2:57][O:58][S:59]([C:62]2[C:63]([CH3:68])=[CH:64][CH:65]=[CH:66][CH:67]=2)(=[O:61])=[O:60])[O:11][C@@:10]([SiH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([N:12]2[CH:19]=[CH:18][C:16](=[O:17])[NH:15][C:13]2=[O:14])[C@H:9]([O:33][N:34]2C(=O)C3=CC=CC=C3C2=O)[C@@H:8]1[O:45][CH2:46][C:47]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:50]=[CH:49][CH:48]=1)([CH3:4])([CH3:3])[CH3:2].O.NN>CCO>[NH2:34][O:33][C@@H:9]1[C@H:8]([O:45][CH2:46][C:47]2[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=3)[CH:50]=[CH:49][CH:48]=2)[C@@:7]([CH2:57][O:58][S:59]([C:62]2[C:63]([CH3:68])=[CH:64][CH:65]=[CH:66][CH:67]=2)(=[O:61])=[O:60])([CH2:6][O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[O:11][C@@:10]1([SiH:20]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[N:12]1[CH:19]=[CH:18][C:16](=[O:17])[NH:15][C:13]1=[O:14]
Reactant: Cc1ccccc1S(=O)(=O)OC[C@]1(COC(C)(C)C)O[C@](n2ccc(=O)[nH]c2=O)([SiH](c2ccccc2)c2ccccc2)[C@H](ON2C(=O)c3ccccc3C2=O)[C@@H]1OCc1cccc2ccccc12
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1ccccc1S(=O)(=O)OC[C@]1(COC(C)(C)C)O[C@](n2ccc(=O)[nH]c2=O)([SiH](c2ccccc2)c2ccccc2)[C@H](ON)[C@@H]1OCc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of Compound 50 (15.9 g, 16.7 mmol) in anhydrous EtOH (500 mL) is added hydrazine hydrate (1.46 mL, 30.1 mmol). After stirring at room temperature for 3 hours, the mixture is concentrated in vacuo to ˜100 mL, then poured into EtOAc (500 mL) and washed with saturated aqueous NaHCO3 (2×100 mL). The organic phase is dried over anhydrous Na2SO4, filtered and evaporated. The crude Compound 51 is used without further purification
Reaction SMILES: C(Br)C.[Mg].[CH3:5][C:6]([OH:10])([C:8]#[CH:9])[CH3:7].[CH3:11][CH:12]([CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH3:21])[CH2:13][CH2:14][OH:15]>O1CCCC1>[CH3:5][C:6]([OH:10])([C:8]#[C:9][CH:14]([OH:15])[CH2:13][CH:12]([CH3:11])[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH3:21])[CH3:7]
Reactant: C#CC(C)(C)O
Reactant: CCC/C=C\CC(C)CCO
Agent: [Mg]
Solvent: CCBr
Solvent: C1CCOC1
Product: CCC/C=C\CC(C)CC(O)C#CC(C)(C)O
Reaction time: 1.5 h
Yield: 77.1 %

Procedure:
A solution of 10.4 g (95.6 mmol) of ethyl bromide in 40 mL of dry tetrahydrofuran was added dropwise over a period of 30 min to a vigorously stirred suspension of 2.32 g (95.6 mmol) of magnesium turnings in 15 mL of dry tetrahydrofuran, with the reaction being initiated by occasional heating with a heat gun. After stirring the reaction mixture for 90 min under reflux, it was allowed to cool down to room temp., and a solution of 3.54 g (42.2 mmol) of 2-methylbut-3-yn-2-ol in 40 mL of dry tetrahydrofuran was added dropwise with stirring. The reaction mixture was then again refluxed for 3 h, the heating bath removed and a solution of 6.50 g (42.2 mmol) of (5Z)-3-methylnon-5-en-1-ol in 40 mL of dry tetrahydrofuran added at room temp. with stirring over a period of 30 min. The reaction mixture was refluxed with stirring overnight, allowed to cool to room temp., and quenched by pouring into 100 mL of an aqueous satd. NH4Cl solution. The organic layer was separated, and the aqueous one extracted three times with 500 mL of ether each. The combined organic extracts were dried with sodium sulphate, and concentrated to dryness in a rotary evaporator. The resulting residue (10.8 g) was purified by flash chromatography (200 g of silica gel, pentane/ether, 1:1, Rf=0.22) to furnish 7.76 g (77%) of (9Z)-2,7-dimethyltridec-9-en-3-yne-2,5-diol as a colourless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C@H:14]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:10]([CH2:11][C:12]([C:27]3[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][O:35][C:36]4[C:41]([Cl:42])=[CH:40][C:39]([CH3:43])=[CH:38][C:37]=4[Cl:44])=[CH:29][CH:28]=3)=[C:13]2[C:24](O)=[O:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[Cl:51][C:52]1[CH:62]=[CH:61][C:60]([CH2:63][CH2:64][CH2:65][O:66][CH3:67])=[CH:59][C:53]=1[CH2:54][NH:55][CH:56]1[CH2:58][CH2:57]1.CCN(CC)CC.CC[O-].[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl.CCO.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:15][C@H:14]2[N:16]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[C@H:10]([CH2:11][C:12]([C:27]3[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][O:35][C:36]4[C:41]([Cl:42])=[CH:40][C:39]([CH3:43])=[CH:38][C:37]=4[Cl:44])=[CH:29][CH:28]=3)=[C:13]2[C:24](=[O:25])[N:55]([CH2:54][C:53]2[CH:59]=[C:60]([CH2:63][CH2:64][CH2:65][O:66][CH3:67])[CH:61]=[CH:62][C:52]=2[Cl:51])[CH:56]2[CH2:57][CH2:58]2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COCCCc1ccc(Cl)c(CNC2CC2)c1
Reactant: Cc1cc(Cl)c(OCCc2ccc(C3=C(C(=O)O)[C@H]4CN(C(=O)OC(C)(C)C)C[C@@H](C3)N4C(=O)OC(C)(C)C)cc2)c(Cl)c1
Agent: CC[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCCc1ccc(Cl)c(CN(C(=O)C2=C(c3ccc(CCOc4c(Cl)cc(C)cc4Cl)cc3)C[C@@H]3CN(C(=O)OC(C)(C)C)C[C@H]2N3C(=O)OC(C)(C)C)C2CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
(rac.)-(1R*,5S*)-7-{4-[2-(2,6-Dichloro-4-methyl-phenoxy)-ethyl]-phenyl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid 3,9-di-tert-butyl ester (300 mg, 0.463 mmol) was dissolved in toluene (10 if L). DMF (1.8 μL) and oxalyl chloride (52.7 μl, 0.6 mmol) were added. The mixture was stirred at rt for 1 h. The solvents were thoroughly removed under reduced pressure, and the residue was dissolved in CH2Cl2 (7.5 μL). A sol. of [2-chloro-5-(3-methoxy-propyl)-benzyl]-cyclopropyl-amine (176 mg, 0.693 mmol) and Et3N (97 μL, 0.693 mmol) in CH2Cl2 (7.5 mL) was added over 10 min, then the mixture was stirred for 30 min. The mixture was evaporated and the residue was partitioned between Et2O and aq. 1M HCl. The org. fraction was washed with aq. sat. NaHCO3, and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. A sol. of this residue (402 mg, 0.455 mmol) and NaOEt (21% in EtOH, 0.257 mL, 0.683 mmol) in EtOH (2.84 mL) was heated at 80° C. overnight. The mixture was evaporated under reduced pressure, and the residue was dissolved in Et2O. This mixture was washed with aq. 1M HCl, aq. sat. NaHCO3, and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC yielded the title compound (300 mg).