Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:13])=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(#N)C>[CH2:20]([O:12][C:5]1[CH:4]=[C:3]([O:13][CH2:7][C:6]2[CH:11]=[CH:2][CH:3]=[CH:4][CH:5]=2)[C:2]([Br:1])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1cc(Br)c(O)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
7.86 kg (83%) of methyl 5-bromo-2,4-dihydroxybenzoate and 9.65 kg of potassium carbonate are suspended in 100 l of acetonitrile at 0° C. The mixture is subsequently heated to 80° C., and 7575 ml of benzyl bromide are added via a dropping funnel over a period of 40 min. After stirring at 80° C. for 16 h, the mixture is filtered, and the collected filtrate is evaporated in vacuo: 12.95 kg (95%) of methyl 2,4-bisbenzyloxy-5-bromobenzoate (slightly yellow crystals); MW 427.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[C:10]([NH:12][C:13]([NH2:15])=[NH:14])#N>>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:10]([NH:12][C:13]([NH2:15])=[NH:14])[NH:9][C:4]=2[CH:3]=1
Reactant: Nc1ccc(F)cc1N
Reactant: N#CNC(=N)N
Product: N=C(N)Nc1nc2ccc(F)cc2[nH]1
Yield: 72.9 %

Procedure:
4-Fluoro-o-phenylenediamine (10.40g) was reacted with cyanoguanidine (6.95g) in a manner analagous to that described in Example 3 to yield a brown crystaline precipitate (11.61g) which on crystalisation from water yielded 5-fluoro-2-quanidinobenzimidazole (9.17g) m.p. 217°-218°C as brown needles.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([CH3:21])[CH:13]=[CH:12][C:11]([NH:14][CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:10][CH:9]=1.[CH2:22]1[C:27]2([CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH2:26][CH2:25][O:24][CH:23]1O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>O1CCCC1.C(N(CC)CC)C>[C:8]1([CH3:21])[CH:9]=[CH:10][C:11]([NH:14][CH:15]2[CH2:20][CH2:19][N:18]([CH2:31][CH2:32][C:27]3([CH2:28][CH2:29][OH:30])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH2:17][CH2:16]2)=[CH:12][CH:13]=1
Reactant: OC1CC2(CCOCC2)CCO1
Reactant: Cc1ccc(NC2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: Cc1ccc(NC2CCN(CCC3(CCO)CCOCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a suspension of 4-(p-toluidino)piperidine trifluoroacetate (synthesized in Preparation Example 4-5) (656 mg) in tetrahydrofuran (5 mL) was added triethylamine (0.44 mL). The solution was stirred at room temperature for 25 minutes. Then, 3,9-dioxaspiro[5.5]undecan-2-ol (synthesized in Example 79) (135 mg) in tetrahydrofuran (3 mL) was added to the solution and it was stirred at room temperature for additional 5 minutes. The reaction solution was ice-cooled and sodium triacetoxyborohydride (333 mg) was added thereto. After allowing the reaction solution for its temperature rise to room temperature, it was stirred for additional 26 hours. To the reaction solution was added a 3N aqueous sodium hydroxide solution (10 mL) and it was extracted with ethyl acetate.
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15](I)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[N:33]1[CH:38]=[CH:37][CH:36]=[C:35](B(O)O)[CH:34]=1>>[CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15]([C:35]3[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=3)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1cccc(-c2nc(I)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1
Reactant: OB(O)c1cccnc1
Product: CCCCCCc1cccc(-c2nc(-c3cccnc3)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1

Procedure:
In analogy to the procedure described for example 7, [2-(3-hexyl-phenyl)-5-iodo-3-methyl-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 2) was reacted with pyridin-3-yl-boronic acid to give the title compound as light yellow oil. MS: 500.3 (MH+).
Reaction SMILES: [CH3:1][C:2]([OH:8])([CH3:7])[CH:3]([OH:6])[CH2:4][OH:5].C(N(CC)CC)C.[O-2].[Al+3].[O-2].[O-2].[Al+3].[CH3:21][C:22](C)([CH:24]1COC(C)(C)O1)O>CC(C)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(Cl)Cl>[CH3:21][C:22]1([CH3:24])[O:6][CH:3]([CH2:4][OH:5])[C:2]([CH3:7])([CH3:1])[O:8]1
Reactant: CC1(C)OCC(C(C)(C)O)O1
Reactant: CC(C)(O)C(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Al+3]
Agent: [O-2]
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC1(C)OC(CO)C(C)(C)O1
Reaction time: 120 h
Yield: 64.2 %

Procedure:
A solution of 1.2 g of (RS)-3-methyl-1,2,3-butanetriol in 20 ml of acetone is treated with 0.010 g of anhydrous p-toluenesulphonic acid and left at room temperature for 5 days. After the addition of 0.3 ml of triethylamine, the mixture is evaporated at 30°/11 Torr and the residue is distilled at 130°/11 Torr. The distillate (1.55 g) gives, after chromatography on 90 g of neutral aluminium oxide (activity III) with methylene chloride, as the non-polar fraction 0.81 g of (RS)-α,α,2,2-tetramethyl-1,3-dioxolane-4-methanol and as the polar fraction 0.52 g of the desired product.
Reaction SMILES: [C:1]([O:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[CH2:14][C@H:15]3[N:26](C(OCC4C=CC=CC=4)=O)[CH2:25][CH2:24][C@@:21]4([C:22]=2[CH:23]=1)[C@H:16]3[CH2:17][CH2:18][CH2:19][CH2:20]4)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]>CCO.[Pd]>[C:1]([O:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[CH2:14][C@H:15]3[NH:26][CH2:25][CH2:24][C@@:21]4([C:22]=2[CH:23]=1)[C@H:16]3[CH2:17][CH2:18][CH2:19][CH2:20]4)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)OCOc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(C(=O)OCc1ccccc1)CC3
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)C(=O)OCOc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)NCC3
Yield: 45 %

Procedure:
(+)-[N-(Benzyloxycarbonyl)morphinan-3-yloxy]methyl pivalate (13.2 g, 26.8 mmol) from Example 46 was subjected to hydrogenation (balloon) on 10% Pd/C (2.0 g) in EtOH (100 mL) at room temperature. After the reaction was completed, the reaction mixture was filtered through a Celite, and washed with EtOH (300 mL). The combined EtOH solution was evaporated under vacuum. The residue was further purified by reverse-phase prep HPLC to provide the title compound (4.31 g, 45%) as a light yellow gum.
Reaction SMILES: [CH2:1]([C:8]1[CH:24]=[CH:23][C:11]([C:12](=[O:22])[CH2:13][C:14]2[CH:15]=C([CH:19]=[CH:20][CH:21]=2)C#N)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[C:25]([OH:28])(=[O:27])[CH3:26]>S(=O)(=O)(O)O.O>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([C:12](=[O:22])[CH2:13][C:14]2[CH:15]=[C:26]([CH:19]=[CH:20][CH:21]=2)[C:25]([OH:28])=[O:27])=[CH:23][CH:24]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CC(=O)O
Reactant: CCCCCCCc1ccc(C(=O)Cc2cccc(C#N)c2)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCCCCCc1ccc(C(=O)Cc2cccc(C(=O)O)c2)cc1
Yield: 1.5 %

Procedure:
A mixture of 3-cyanophenylacetic acid (13 g, 0.08 mole) and thionyl chloride (100 ml) is heated under reflux for 90 minutes. The excess thionyl chloride is removed by evaporation under reduced pressure. The residue is dissolved in methylene chloride (20 ml) and the resulting solution added to aluminum chloride (16.2 g, 0.12 mole) in methylene chloride (200 ml) with vigorous stirring. A solution of 1-phenylheptane (14.3 g, 0.12 mole) in methylene chloride (50 ml) is then added over 20 minutes. The reaction mixture is heated under reflux (1 hour) and then poured into ice water (1 liter) with vigorous stirring. The mixture is extracted twice with ether (600 ml and 100 ml). The extracts are combined, dried over magnesium sulfate and evaporated under reduced pressure. The residue is chromatographed on silica gel (hexane/ether) to give 3-(4-n-heptylphenacyl)benzonitrile (7.6 g) as a White crystalline solid, m.p. 68° C. Then, 3-(4-n-heptylphenacyl)benzonitrile (1.5 g, 4.7 mole) is heated under reflux (1 hour) in a mixture of 75% aqueous sulfuric acid (12 g) and acetic acid (12 g). The reaction mixture is diluted with water (100 ml) and extracted with ether (2×75 ml). The ether extract is dried over magnesium sulfate, filtered and evaporated under reduced pressure. The resulting yellow solid is chromatographed on silica gel (hexane:ether:acetic acid; 60:40:1) and recrystallized from heptane to give 3-(4-n-heptylphenacyl)benzoic acid (1 g) as a pale yellow crystalline solid, 128°-133°C.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:12])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:13](Cl)[CH:14]=[CH2:15]>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:15]([O:12][CH2:3]/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:14]=[CH2:13]
Reactant: OCC=Cc1ccccc1
Reactant: C=CCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Product: C=CCOC/C=C/c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
Sodium hydride (60% in mineral oil, 26 g, 0.60 mol) was added portion-wise to a solution of cinnamyl alcohol (40 g, 0.29 mol) in dry THF (600 ml) at 5° C. under nitrogen. The reaction was warmed up to room temperature then refluxed. After 30 minutes, tetra butyl ammonium iodide (4 g, 0.011 mol) was added followed by allyl chloride (45.6 g, 0.60 mol) over a 1 h-period. The reaction was allowed reaching room temperature overnight, before being poured onto water. The organic phase was washed with water (3 times) and brine. Each aqueous phase was re-extracted with heptanes. Combined extracts were dried over solid anhydrous sodium sulfate. The solid was filtered off, rinsed with heptanes and the solvents were removed under vacuum. The product was purified by bulb-to-bulb distillation (80° C./0.062 mbar). 50 g of the desired compound were obtained (0.287 mol, 99%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:12](=[O:14])[CH3:13])[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[I-:15].[Na+].ClN1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+].Cl>CN(C)C=O.O.C(OCC)(=O)C>[C:1]([C:5]1[CH:6]=[C:7]([C:12](=[O:14])[CH3:13])[CH:8]=[C:9]([I:15])[C:10]=1[OH:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: [I-]
Reactant: CC(=O)c1ccc(O)c(C(C)(C)C)c1
Agent: Cl
Agent: O=C1CCC(=O)N1Cl
Agent: O=S([O-])([O-])=S
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)c1cc(I)c(O)c(C(C)(C)C)c1
Yield: 96.8 %

Procedure:
1-(3-tert-Butyl-4-hydroxyphenyl)ethanone (384 mg, 2 mmol) and sodium iodide (360 mg, 2.4 mmol) were dissolved in a mixed solution of N,N-dimethylformamide (3 mL) and water (1 mL), and this was cooled in an ice bath. While stirring, N-chlorosuccinimide (NCS) (320 mg, 2.4 mmol) was added portionwise over 10 minutes. After stirring for 50 minutes, 2% aqueous sodium thiosulfate (4 mL), 2 N hydrochloric acid (1 mL), and ethyl acetate (10 mL) were added, and the solution was separated. The organic layer was washed with a mixed solution of 2% aqueous sodium thiosulfate (5 mL) and saturated brine (1 mL), and then with saturated brine (5 mL). The organic layer was dried, and concentrated under reduced pressure (50° C.) to obtain 616 mg of the subject compound as a yellowish oily substance (yield: 96.8%, HPLC purity: 93.2%).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]([CH3:28])([CH3:27])[C:24]([OH:26])=O)[CH:8]=2)[N:3]=1.[C:29]([NH2:33])([CH3:32])([CH3:31])[CH3:30]>>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:15][C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:22]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]([CH3:27])([CH3:28])[C:24]([NH:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:26])[CH:8]=2)[N:3]=1
Reactant: CC(C)(C)N
Reactant: CC(C)(C(=O)O)c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Product: CC(C)(C)NC(=O)C(C)(C)c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1

Procedure:
(Preparation by reaction of 2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-2-methylpropanoic acid [“A62”] with tert-butylamine);
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH2:6][NH2:7].[CH:17]([O:20][C:21]([N:23]1[CH2:29][CH2:28][CH2:27][C:26](=O)[C:25]2[C:31]([CH3:35])=[CH:32][CH:33]=[CH:34][C:24]1=2)=[O:22])([CH3:19])[CH3:18].[BH4-].[Na+].[OH-].[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].CO>[CH:17]([O:20][C:21]([N:23]1[CH2:29][CH2:28][CH2:27][CH:26]([NH:7][CH2:6][C:5]2[CH:4]=[C:3]([C:2]([F:15])([F:16])[F:1])[CH:10]=[C:9]([C:11]([F:14])([F:12])[F:13])[CH:8]=2)[C:25]2[C:31]([CH3:35])=[CH:32][CH:33]=[CH:34][C:24]1=2)=[O:22])([CH3:19])[CH3:18]
Reactant: Cc1cccc2c1C(=O)CCCN2C(=O)OC(C)C
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CO
Product: Cc1cccc2c1C(NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2C(=O)OC(C)C
Reaction time: 14 h
Yield: 3.4 %

Procedure:
Add 3,5-bis(trifluoromethyl)benzylamine (423 mg, 1.62 mmol) followed by titanium isopropoxide (645 mg, 2.27 mmol) to 6-Methyl-5-oxo-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid isopropyl ester (423 mg, 1.62 mmol) at room temperature under an atmosphere of nitrogen and stir the solution for 14 h. Add methanol (6.7 mL) and sodium borohydride (92 mg, 2.43 mmol) and stir the mixture under nitrogen at room temperature for 45 min. Add 0.1M NaOH, stir for 30 min. Filter through celite and wash the residue with AcOEt. Separate organic layer, extract aqueous with AcOEt. Wash organic layer with brine and dry the organic layers over anhydrous sodium sulfate. Filter and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford (+/−)-5-(3,5-Bis-trifluoromethyl-benzylamino)-6-methyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid isopropyl ester (27 mg, 3%). Add acetic anhydride (0.037 mL, 0.39 mmol) dropwise to a solution of the amine (27 mg, 0.055 mmol) and pyridine (0.038 mL, 0.43 mmol) in dichloromethane (0.5 mL). Stir under nitrogen at room temperature for 14 h. Add 1 M hydrochloric acid and extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford the title compound (28 mg, 96%); MS (ES+): 531 (M+H).
Reaction SMILES: Cl[C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2([O:14][CH3:15])[O:13][CH:9]2[CH2:10][CH2:11][Cl:12])=[O:7])=[CH:4][CH:3]=1.COC1C=CC(C(C2(OC)OC2CCCl)=O)=CC=1>>[C:6]([C:8]1([O:14][CH3:15])[O:13][CH:9]1[CH2:10][CH2:11][Cl:12])(=[O:7])[C:5]1[CH:4]=[CH:3][CH:2]=[CH:17][CH:16]=1
Reactant: COC1(C(=O)c2ccc(Cl)cc2)OC1CCCl
Agent: COc1ccc(C(=O)C2(OC)OC2CCCl)cc1
Product: COC1(C(=O)c2ccccc2)OC1CCCl

Procedure:
1-p-chlorobenzoyl-1-methoxy-4-chloro-1,2-epoxy butane and 1-p-methoxybenzoyl-1-methoxy-4-chloro-1,2-epoxy butane.
Reaction SMILES: [CH2:1](O)[CH2:2][CH:3]([CH3:5])[CH3:4].C(N(CC)CC)C.CS(Cl)(=O)=O.O.[NH2:20][NH2:21].[P:22](=[O:26])([OH:25])([OH:24])[OH:23]>O1CCCC1.C(O)C.C(Cl)(Cl)Cl.O>[P:22]([OH:26])([OH:25])([OH:24])=[O:23].[CH3:4][CH:3]([CH3:5])[CH2:2][CH2:1][NH:20][NH2:21]
Reactant: CC(C)CCO
Reactant: NN
Agent: CS(=O)(=O)Cl
Agent: O=P(O)(O)O
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)CCNN
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of isoamyl alcohol (100 g, 1.13 mol) and triethylamine (173 mL, 1.25 mol) in tetrahydrofuran (1.13 L) was added dropwise methanesulfonyl chloride (136 g, 1.19 mol) with keeping the internal temperature below 17° C. over 1 hour, and the reaction mixture was stirred at the same condition for 1 hour. To the resultant was added dropwise water (1.0 L) with keeping the internal temperature below 13° C., and the mixture was extracted with toluene (1.7 L). The organic layer was dried over anhydrous MgSO4 and the solvent was evaporated under reduced pressure to give a crude product of Compound (Igg) (198 g), which was used in the next step without further purification. The resulting Compound (Igg) and hydrazine monohydrate (339 g, 6.77 mol) were dissolved in ethanol (1.13 L), and the reaction mixture was stirred at 50° C. (internal temperature) for 2 hours. The mixture was cooled to room temperature, and partitioned between chloroform (2.26 L) and water (339 mL). The chloroform layer was washed with water (339 mL, ×2). To the solution of chloroform was added phosphoric acid (85%, 130 g, 1.13 mol) at room temperature, and the solvent was evaporated under reduced pressure. To the obtained white-solid was added 2-propanol (300 mL), and the solvent was evaporated under reduced pressure (×3). To the concentrated residue was added 2-propanol (1.13 L). The mixture was stirred for 1.5 hours at 45° C. (internal temperature) and then stirred overnight with slowly cooling to room temperature. The resulting precipitate was collected by filtration, washed with cold 2-propanol (100 mL, ×2), and dried under reduced pressure to give the title Compound (IIgg) (181 g, 80%) as a white powder.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([N:13]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:14](=[O:21])[CH2:15][C:16]([O:18][CH2:19]C)=[O:17])[C:7]([Cl:12])=[C:8]([Cl:11])[C:9]=1[Cl:10])=O.C[O-].[Na+]>CO>[CH3:19][O:18][C:16]([C:15]1[C:14](=[O:21])[N:13]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:6]2[C:7]([Cl:12])=[C:8]([Cl:11])[C:9]([Cl:10])=[C:5]2[C:3]=1[OH:2])=[O:17]
Reactant: CCOC(=O)CC(=O)N(Cc1ccccc1)n1c(Cl)c(Cl)c(Cl)c1C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1c(O)c2c(Cl)c(Cl)c(Cl)n2n(Cc2ccccc2)c1=O
Temperature: 0 °C
Yield: 34.1 %

Procedure:
A mixture of 1-[benzyl-(2-ethoxycarbonyl-acetyl)-amino]-3,4,5-trichloro-1H-pyrrole-2-carboxylic acid methyl ester (278 mg, 0.62 mmol) and NaOMe in MeOH (5 mL, 2.5 mmol) in MeOH (3 mL) was refluxed for 4 h; then cooled, the reaction mixture was poured into ice cold 0.5 M HCl solution to quench, the precipitates were collected by filtration and then purified with silica gel column to give the desired product (85 mg) as slightly yellow solid. ESI (m/z): 401 (M+H)+.
Reaction SMILES: [CH:1]([CH:3]([N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=O.Cl.Cl.[NH2:24][CH:25]([C:29]1([SH:36])[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]1)[C:26]([OH:28])=[O:27].C([O-])(=O)C.[Na+]>C(O)C.O>[C:26]([CH:25]1[C:29]2([CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]2)[S:36][CH:1]([CH:3]([N:11]2[C:15](=[O:16])[C:14]3=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]3[C:12]2=[O:21])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[NH:24]1)([OH:28])=[O:27]
Reactant: CN1CCC(S)(C(N)C(=O)O)CC1
Reactant: CC(C)(C)OC(=O)C(C=O)N1C(=O)c2ccccc2C1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CN1CCC2(CC1)SC(C(C(=O)OC(C)(C)C)N1C(=O)c3ccccc3C1=O)NC2C(=O)O
Reaction time: 24 h
Yield: 81 %

Procedure:
To a solution of 166.9 g (0.57 mole) of tert-butyl 2-formyl-2-phthalimido-acetate in 1150 ml of ethanol, preheated to 60° C., there is added a solution of 160 g (0.57 mole) of alpha-amino-4-mercapto-1-methyl-4-piperidineacetic acid dihydrochloride and 235.6 g (1.73 mole) of sodium acetate (crystallized with three molecules of water) dissolved in 1150 ml of water. The reaction mixture is stirred for about ten minutes and then left to stand for 24 hours. The precipitate is filtered off, washed with water and dried. 223 g of the gamma-isomer of tert-butyl 4-carboxy-8-methyl-alpha-phthalimido-1-thia-3,8-diazaspiro-[4.5]decane-2-acetate is obtained; Yield: 81%; M.P. 276°-278° C. (decomposition).
Reaction SMILES: CON(C)[C:4](=O)[C@@H:5]([NH:22][C:23]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:6][C:7]1[CH:21]=[CH:20][C:10]([CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:9][CH:8]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].Cl.[CH3:51][S:52]([CH2:55]P(=O)(OCC)OCC)(=[O:54])=[O:53].[H-].[Na+]>CCOCC.C1COCC1.CCOC(C)=O>[CH3:51][S:52](/[CH:55]=[CH:4]/[C@@H:5]([NH:22][C:23]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:6][C:7]1[CH:21]=[CH:20][C:10]([CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[CH:9][CH:8]=1)(=[O:53])=[O:54]
Reactant: CCOP(=O)(CS(C)(=O)=O)OCC
Reactant: CON(C)C(=O)[C@H](Cc1ccc(CNC(=O)OC(C)(C)C)cc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NCc1ccc(C[C@@H](/C=C/S(C)(=O)=O)NC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Weinreb amide 16 (0.65 g, 1.12 mmol) was dissolved in Et2O (15 mL), put under an argon atmosphere and cooled to 0° C. LiAlH4 (2 eq., 2.25 mmol, 0.56 mL of a 4 M solution in Et2O) was added slowly and the mixture was stirred at 0° C. for 1 hour after which TLC analysis indicated complete conversion of the starting compound. 0.1 M aq. HCl (15 mL) was slowly added and the layers were separated. The organic layer was extracted with 0.1 M aq. HCl and brine, dried over MgSO4 and concentrated under reduced pressure. Diethyl ((methylsulfonyl)methyl)phosphonate (1.5 eq., 1.68 mmol, 0.39 g) was dissolved in THF (20 mL) and cooled to 0° C. under an argon atmosphere. NaH (1.5 eq., 1.68 mmol, 67.2 mg, 60% w/w in mineral oil) was slowly added and the mixture was stirred at 0° C. for 30 minutes. Next, the freshly obtained aldehyde (in THF (2 mL)) was slowly added and the mixture was stirred for 2 hours while slowly warming it to room temperature. After this time TLC analysis indicated complete conversion of the aldehyde. EtOAc (20 mL) was added and the mixture was extracted with mM aq. HCl (2×) and brine, dried over MgSO4 and concentrated under reduced pressure. The title compound was obtained after column chromatography (20%->50% EtOAc/PE) as a colourless foam (yield: 0.57 g, 0.95 mmol, 85%). 1H NMR (400 MHz, CDCl3): δ=7.46 (d, J=7.6 Hz, 6H), 7.28 (t, J=7.20, 6.80 Hz, 6H), 7.20 (t, J=7.20, 7.20 Hz, 3H), 7.13 (d, J=7.60 Hz, 2H), 6.87 (d, J=8.00 Hz, 2H), 6.57 (dd, J=14.80, 7.00 Hz, 1H), 5.96 (d, J=14.80 Hz, 1H), 4.80 (s, 1H), 4.24 (d, J=5.60 Hz, 2H), 3.49 (q, J=6.00 Hz, 1H), 2.61 (s, 3H), 2.54 (dd, J=13.20, 5.20 Hz, 1H), 2.33 (dd, J=13.20, 8.20 Hz, 1H), 1.44 (s, 9H) ppm. 13C NMR (100 MHz, CDCl3): δ=155.59, 150.21, 145.74, 137.42, 135.28, 129.53, 128.35, 128.02, 127.70, 127.14, 126.44, 78.91, 71.05, 55.33, 43.79, 42.43, 41.86, 28.09 ppm. [α]D23=−21.3 (c=1, CHCl3). HRMS: calcd. for C36H40N2O4S 619.26010 [M+Na]+. found 619.26001.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O-:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Na+].[CH3:12]N(N=O)C(N)=O>COCCOC>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:12])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CN(N=O)C(N)=O
Reactant: O=[N+]([O-])c1ccc([O-])cc1
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 91.4 %

Procedure:
0.80 grams (5 millimoles) of anhydrous sodium p-nitrophenolate and 0.52 grams (5 millimoles) of N-methyl,N-nitrosourea were added to 25 milliliters of 1,2-dimethoxyethane kept dry with molecular sieves and a drying tube. This mixture was maintained at 0° C. for one hour and then elevated to room temperature for six hours while constant stirring was maintained. Solvent was evaporated and the residue treated simultaneously with ether and water. This mixture was shaken and the aqueous layer was removed. The ether layer was washed with potassium hydroxide (0.1 N, 3× 50 milliliters) to remove any unreacted phenol. The ether layer was washed with water (3×50 milliliters) and dried with magnesium sulfate. Filtration afforded a clear solution which was concentrated under diminished pressure to yield 0.70 grams of p-nitroanisole (about 90 percent, melting point 52°-53°. This was shown to be identical with an authentic sample.