Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:8][C@@H:7]([C@@H:9]([N:44]=[N+]=[N-])[CH2:10][C@@H:11]([CH:41]([CH3:43])[CH3:42])[CH:12](OC(=O)C)[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][O:23]CC3C=CC=CC=3)=[C:15]([O:31][CH2:32][CH2:33][CH2:34][O:35][CH3:36])[CH:14]=2)[O:6][C:5]1=[O:47])([CH3:3])[CH3:2]>C(O)C>[CH:1]([C@@H:4]1[CH2:8][C@@H:7]([C@@H:9]([NH2:44])[CH2:10][C@@H:11]([CH:41]([CH3:43])[CH3:42])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][OH:23])=[C:15]([O:31][CH2:32][CH2:33][CH2:34][O:35][CH3:36])[CH:14]=2)[O:6][C:5]1=[O:47])([CH3:3])[CH3:2]
Reactant: COCCCOc1cc(C(OC(C)=O)[C@@H](C[C@H](N=[N+]=[N-])[C@@H]2C[C@@H](C(C)C)C(=O)O2)C(C)C)ccc1OCCCOCc1ccccc1
Solvent: CCO
Product: COCCCOc1cc(C[C@@H](C[C@H](N)[C@@H]2C[C@@H](C(C)C)C(=O)O2)C(C)C)ccc1OCCCO
Reaction time: 24 h

Procedure:
A solution of 151 mg of 3(S)-isopropyl-5(S)-{1(S)-azido-3(S)-isopropyl-4(R,S)-acetoxy-4-[4-(3-benzyloxypropyloxy)-3-(3-methoxypropyloxy)-phenyl]-butyl}-tetrahydrofuran-2-one in 10 ml of ethanol is hydrogenated under normal pressure and at room temperature in the presence of 70 mg of PdO for 170 hours. The reaction mixture is filtered and concentrated by evaporation, and the residue is dissolved in 10 ml of ethanol and is again hydrogenated for 24 hours in the presence of 140 mg of PdO under normal pressure and at room temperature. Filtration and concentration by evaporation yield the title compound in the form of a crude product: Rf (dichloromethane/methanol)=0.32; HPLC Rt =11.72 minutes; FAB-MS (M+H)+ =480.
Reaction SMILES: C[O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][C:6]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:5][C:4]=1[C:19]1[N:24]=[C:23]([CH:25]=[O:26])[CH:22]=[CH:21][CH:20]=1.B(Br)(Br)Br.O.C([O-])([O-])=O.[Na+].[Na+]>ClCCl>[OH:2][C:3]1[C:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:7][C:6]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:5][C:4]=1[C:19]1[N:24]=[C:23]([CH:25]=[O:26])[CH:22]=[CH:21][CH:20]=1
Reactant: COc1c(-c2ccccc2)cc(C(C)(C)C)cc1-c1cccc(C=O)n1
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1cc(-c2ccccc2)c(O)c(-c2cccc(C=O)n2)c1
Temperature: -80 °C
Reaction time: 1 h

Procedure:
In the glovebox, 6-(2′-methoxy-3′-phenyl-5′-tert-butylphenyl)-2-formyl-pyridine (11) (4.43 g, 12.3 mmol) was dissolved in 75 mL dichloromethane and cooled to −80° C. A 20 mL dichloromethane solution of BBr3 (4.62 g, 18.5 mmol) was slowly added dropwise and the solution was left to stir at −80° C. for 1 h. After warming to room temperature, the orange solution was taken out of the glovebox and under a purge of nitrogen, ˜1 mL of water was added, causing a large amount of smoke to form. A further 5 mL of water was slowly added, followed by 30 mL of dichloromethane and another 10 mL portion of water. This was stirred for 30 minutes, neutralized with 1M Na2CO3 and the water layer separated from the organic layer. The water layer was extracted with 2×75 mL dichloromethane, the organic layers combined and washed with water (2×100 mL), dried over MgSO4, filtered and dried to give compound 12 as a yellow solid. Yield: 4.25 g (100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[C:11](OCC)(=[O:19])[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].O(C(C)(C)C)[K].CC(OC(C)=O)=O.CC([O-])=O.[Na+]>Cl.O.CC(O)(C)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:4]=1[CH:5]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:12]=[C:11]2[OH:19]
Reactant: COc1ccccc1C=O
Reactant: CCOC(=O)CCC(=O)OCC
Agent: CC(=O)[O-]
Agent: CC(C)(C)O[K]
Agent: Cl
Solvent: CC(C)(C)O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1cc(O)c2cccc(OC)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.4 %

Procedure:
To a 250 mL round bottom flask were added 2-methoxybenzaldehyde (2.0 g, 14.7 mmol), diethyl butanedioate (6.4 g, 36.7 mmol) and t-BuOH (35 mL). KO-t-Bu (3.3 g, 29.4 mmol) was added in portions. The reaction mixture was stirred at room temperature for 2 hours and then diluted with 0.5 N HCl (120 mL) and extracted with EtOAc. The organic layer was back extracted with 5% KOH (60 mL). Aqueous layer was acidified with 1N HCl and extracted with EtOAc. Organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was treated with Ac2O (9.7 mL, 103 mmol) and NaOAc (2.05 g, 25 mmol) at 120° C. under nitrogen overnight. The reaction mixture was cooled with an ice bath and diluted with 150 mL of water. The aqueous solution was carefully removed by slow decantation. The remaining residue was dissolved in EtOAc (30 mL), dried over sodium sulfate, filtered and concentrated. The crude product was purified on a silica gel column eluting with a gradient of 100% hexanes to 25% EtOAc/hexanes to give the title intermediate (0.52 g) as a light yellow solid.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)=[C:18]([C:23]2[N:27]([CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])[N:26]=[N:25][N:24]=2)[CH:19]=[CH:20][CH:21]=[O:22])=[CH:13][CH:12]=1>O1CCCC1>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)=[C:18]([C:23]2[N:27]([CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])[N:26]=[N:25][N:24]=2)[CH:19]=[CH:20][CH:21]([OH:22])[CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])=[CH:13][CH:12]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: COCCOCn1nnnc1C(C=CC=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CC(O)C=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnnn1COCCOC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Ethyl acetoacetate dianion (2.6 mL of a freshly prepared 1M solution as described in Example 10) was added to a solution of 5,5-bis(4-fluorophenyl)-4-[1-(2-methoxyethoxy)methyl-1H-tetrazol-5-yl]-2,4-pentadienal (1.1 g, 2.6 mmoles) in 15 mL of tetrahydrofuran at -40° C. After stirring for 2 hours, analytical TLC eluted with 25% (v/v) ethyl acetate in hexane showed starting aldehyde and therefore, another 1.2 mL of dianion solution was added. The reaction mixture was allowed to warm to 0° C. and then quenched with 1N HCl. The mixture was extracted with methylene chloride, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 1% (v/v) methanol in methylene chloride to give 0.9 g of the title compound as an oil. MS (CI): m/e=557 for (M+H)+.
Reaction SMILES: C1([NH2+]C2CCCCC2)CCCCC1.[C:14]([O:18][C:19]([NH:21][C@@H:22]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=[CH2:32])[C:23]([O-:25])=O)=[O:20])([CH3:17])([CH3:16])[CH3:15].CN1CCOCC1.C(Cl)(=O)C(C)(C)C.[CH2:47]([O:49][C:50]([C@@:52]1([NH:57][C:58]([C@H:60]2[NH:64][CH2:63][C@H:62]([O:65][C:66]([N:68]3[CH2:76][C:75]4[C:70](=[CH:71][CH:72]=[CH:73][C:74]=4[F:77])[CH2:69]3)=[O:67])[CH2:61]2)=[O:59])[CH2:54][C@H:53]1[CH:55]=[CH2:56])=[O:51])[CH3:48].Cl>C1COCC1.O>[C:14]([O:18][C:19]([NH:21][C@@H:22]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=[CH2:32])[C:23]([N:64]1[C@H:60]([C:58](=[O:59])[NH:57][C@:52]2([C:50]([O:49][CH2:47][CH3:48])=[O:51])[CH2:54][C@H:53]2[CH:55]=[CH2:56])[CH2:61][C@@H:62]([O:65][C:66]([N:68]2[CH2:76][C:75]3[C:70](=[CH:71][CH:72]=[CH:73][C:74]=3[F:77])[CH2:69]2)=[O:67])[CH2:63]1)=[O:25])=[O:20])([CH3:15])([CH3:16])[CH3:17]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](OC(=O)N2Cc3cccc(F)c3C2)CN1)C(=O)OCC
Reactant: C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)[O-]
Agent: C1CCC([NH2+]C2CCCCC2)CC1
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CN1CCOCC1
Product: C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](OC(=O)N2Cc3cccc(F)c3C2)C[C@H]1C(=O)N[C@]1(C(=O)OCC)C[C@H]1C=C
Temperature: 22.5 °C
Reaction time: 0.75 h
Yield: 110.2 %

Procedure:
A solution of 1.15 g (2.55 mmoL) (S)-2-tert-butoxycarbonylamino-non-8-enoic acid dicyclohexylammonium salt (commercially available from Synthetech Oregon, USA) and 469 mg (4.64 mmol) N-methylmorpholine in 9.0 mL of THF was added dropwise to a solution of 302 mg (2.53 mmol) pivaloyl chloride in 1.5 mL of THF while maintaining the temperature at 20-25° C. The suspension was stirred for 45 min, then cooled to 0° C. A solution of 1.00 g (2.32 mmol) of 4-Fluoro-1,3-dihydro-isoindole-2-carboxylic acid (3R,5S)-5-((1R,2S)-1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-pyrrolidin-3-yl ester in 13 mL of THF was added to the mixed anhydride at 0° C. within 25 min. The mixture was first stirred for 2.5 h at 2° C., then for 19 h at 26° C. 9.5 mL water and 14.8 mL aqueous HCl (0.5 N) were added. The phases were separated and the aqueous layer was extracted with toluene (3×3 mL). The combined organic layers were washed with 2 mL of water, 5 mL of aqueous sodium carbonate (5% w/w) and dried over sodium sulfate. The solvent was removed at 50° C. under reduced pressure using a rotary evaporator. The resulting oil was finally dried under oil pump vacuum yielding 1.75 g (88.3%) of 4-fluoro-1,3-dihydro-isoindole-2-carboxylic acid (3R,5S)-1-((S)-2-tert-butoxycarbonylamino-non-8-enoyl)-5-((1R,2S)-1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-pyrrolidin-3-yl ester as a brown resin with an assay of 80.5% m/m.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([OH:10])=[O:9].[ClH:11].[CH3:12]O>>[ClH:11].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([O:10][CH3:12])=[O:9]
Reactant: O=C(O)Cc1ccccn1
Reactant: CO
Agent: Cl
Product: COC(=O)Cc1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A solution of 2-(2-pyridinyl)acetic acid (0.50 g, 3 mmol; prepared according to J. Prakt. Chem. 1961, 285, 118) in MeOH (20 mL) was saturated with HCl gas at 0° C., then was allowed to warm to RT. After stirring overnight, the reaction was concentrated under vacuum to afford the title compound (0.54 g, 100%) as a colorless solid: 1H NMR (CDCl3) δ8.90 (br s, 1H), 7.89 (m, 2H), 6.89 (t, J=6.5 Hz, 1H), 6.79 (d, J=8 Hz, 1H), 4.21 (m, 2H), 3.81 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([CH:21]=O)([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:23]([C:26]2[CH:27]=[N:28][C:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:30][CH:31]=2)(=[O:25])=[O:24])[CH2:16][CH2:15]4)=[CH:4][CH:3]=1.[NH:38]1[CH2:42][CH2:41][C@H:40]([OH:43])[CH2:39]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([CH2:21][N:38]5[CH2:42][CH2:41][C@H:40]([OH:43])[CH2:39]5)([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:23]([C:26]2[CH:27]=[N:28][C:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:30][CH:31]=2)(=[O:24])=[O:25])[CH2:16][CH2:15]4)=[CH:4][CH:3]=1
Reactant: O[C@H]1CCNC1
Reactant: O=C[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCOCC3)nc1)C2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: O=S(=O)(c1ccc(N2CCOCC2)nc1)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(CN2CC[C@H](O)C2)C1
Reaction time: 20 h
Yield: 29.7 %

Procedure:
A solution of (R)-1-(4-fluorophenyl)-6-[6-morpholin-4-yl-pyridine-3-sulfonyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalene-4a-carbaldehyde (0.074 g) in dry dichloroethane (2.8 mL) was treated with (S)-pyrrolidin-3-ol (0.062 g) and 4A powdered molecular sieves (0.14 g) for 4 hours. Sodium triacetoxyborohydride (0.045 g) was added and the reaction mixture stirred for 20 hours. The reaction mixture was diluted with dichloromethane, washed with saturated aqueous sodium hydrogen carbonate solution and brine. The organic extracts were dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by preparative reverse-phase HPLC eluting with a mixture of acetonitrile and water containing 0.1% formic acid (1:19 to 7:3 by volume) to give the title compound as a white solid (0.025 g). 1H NMR (400 MHz, CHCl3-d): δ 8.54 (d, 1H), 8.24 (s, 1H), 7.81 (dd, 1H), 7.43-7.32 (m, 3H), 7.16 (t, 2H), 6.63 (d, 1H), 6.28 (d, 1H), 4.40 (s, 1H), 4.30 (d, 1H), 3.90 (d, 1H), 3.81 (t, 4H), 3.67 (t, 4H), 3.36-3.23 (m, 2H), 3.13-3.01 (m, 3H), 2.78-2.63 (m, 2H), 2.54 (d, 1H), 2.44-2.25 (m, 3H), 2.24-2.13 (m, 2H), 1.90 (dt, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[NH:12][CH:11]=[C:10](SC)[O:9]1.O.[NH2:16][NH2:17]>COC(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[NH:12][CH:11]=[C:10]([NH:16][NH2:17])[O:9]1
Reactant: NN
Reactant: CSC1=CNN(c2ccccc2N)O1
Agent: COC(C)O
Solvent: O
Product: NNC1=CNN(c2ccccc2N)O1
Temperature: 120 °C
Reaction time: 30 h
Yield: 36.9 %

Procedure:
To a solution of 2-(2-aminophenyl)-5-(methylthio)oxadiazole (1.8 g) in methoxyethanol was added 4.4 g of hydrazine hydrate and the mixture was stirred for 30 h at 120° C. The solvent and excess hydrazine were removed and the residue was purified by column chromatography on silica gel to give 613 mg of 2-(2-aminophenyl)-5-hydrazinooxadiazole.
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].[Cl:8][C:9]1[S:13][C:12]([S:14](Cl)(=[O:16])=[O:15])=[CH:11][C:10]=1[N+:18]([O-:20])=[O:19].C(N(CC)CC)C.O>C1COCC1>[OH:4][CH2:3][C:2]([NH:1][S:14]([C:12]1[S:13][C:9]([Cl:8])=[C:10]([N+:18]([O-:20])=[O:19])[CH:11]=1)(=[O:16])=[O:15])([CH2:5][OH:6])[CH3:7]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)sc1Cl
Reactant: CC(N)(CO)CO
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(CO)(CO)NS(=O)(=O)c1cc([N+](=O)[O-])c(Cl)s1
Temperature: 25 °C
Reaction time: 17 h
Yield: 19.8 %

Procedure:
To a stirred solution of 2-amino-2-methyl-1,3-propanediol (0.44 g, 4.2 mmol) in THF (10 ml) was added at room temperature 5-chloro-4-nitrothiophene-2-sulfonyl chloride (1.0 g, 3.82 mmol) and triethylamine (0.58 ml, 4.2 mmol). The light yellow suspension was stirred at room temperature for 17 h, poured into water (100 ml) and extracted with dichloromethane (3×75 ml). The combined organic layers were washed with water (100 ml) and brine (70 ml), dried (MgSO4) and evaporated. The crude product was further purified by flash chromatography on silica gel (heptane/ethyl acetate) and subsequent crystallization from ethyl acetate/hexane to yield 5-chloro-4-nitro-thiophene-2-sulfonic acid (2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-amide (0.25 g, 20%) as a light brown solid. Mp 133° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].CC1C=C[C:9]([O:12]C)=CC=1.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>Cl>[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH:9]=[O:12])=[CH:17][CH:16]=1
Reactant: Fc1ccccc1
Reactant: COc1ccc(C)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=Cc1ccc(F)cc1
Temperature: 30 °C
Yield: 241.8 %

Procedure:
220.67 g of aluminum chloride (mol. Wt. 133.34; 1,654.9 mmol), 109.00 g (4-Methylanisole (mol. Wt. 122.17; 892.2 mmol), and about 500 g of fluorobenzene (mol. Wt. 96.10; 5,202.9 mmol) were charged to a 2 liter Parr®-brand 4522 stainless steel reaction vessel. To this mixture was added 5 drops of concentrated HCl. The vessel was sealed, heated to 30° C., and purged three times with carbon monoxide with the pressure of the vessel increased to 100 psi for each purging. After the third purge, the vessel was vented and a final introduction of CO was made at a pressure of about 550 psi, the pressure at which the reaction was maintained for the total reaction time of about 89 hours (the reaction temperature was maintained at 30° C. for the duration as well). Once the reaction was complete, the resultant mixture (exhibiting a orange-brown color) was poured into about 500 mL of ice water (which turned the solution a yellow color), to which was added 500 mL of cyclohexane. The top, organic layer was removed and washed three times with water using a separatory funnel and dried over magnesium sulfate. The residual organic phase was then distilled under vacuum to remove excess cyclohexane, fluorobenzene, and left about 60.90 g of 4-fluorobenzaldehyde product (mol. Wt. 124.11; 490.7 mmol; yield of approximately 64.3%). The 4-fluorobenzaldehyde product may then be easily separated from any residual 4-methylanisole by conversion into its corresponding bisulfite adduct, filtration, and decomposition of the bisulfite adduct under acidic or basic conditions.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li][CH2:11]CCC.[C:15]([O:19][C:20]([NH:22][C@H:23]([C:29]([O:31][CH3:32])=[O:30])[CH2:24][C:25]([O:27][CH3:28])=[O:26])=[O:21])([CH3:18])([CH3:17])[CH3:16].CI>C1COCC1>[C:15]([O:19][C:20]([NH:22][C@H:23]([C:29]([O:31][CH3:32])=[O:30])[CH:24]([CH3:11])[C:25]([O:27][CH3:28])=[O:26])=[O:21])([CH3:17])([CH3:18])[CH3:16]
Reactant: COC(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Reactant: [Li]CCCC
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of hexamethyldisilazane (88 mL, 0.421 mol), in THF (500 mL) at −30° C. was added BuLi (2.5M in hexanes, 169 mL, 0.423 mol) and the mixture stirred at this temperature for 15 minutes before cooling to −78° C. A solution of dimethyl N-(tert-butoxycarbonyl)-L-aspartate (Preparation 70, 50 g, 0.19 mol) in THF (200 mL) was added slowly over 15 minutes and the reaction stirred at −78° C. for 2 hours. MeI (14.3 mL, 0.23 mol) was added over 30 minutes and the reaction continued stirring at −78° C. for 18 hours. The reaction was quenched by pouring into an aqueous solution of KHSO4 (80 g in 600 mL, pH=3). THF was then removed in vacuo and the product extracted into EtOAc. The organic layer was collected, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 0-10% EtOAc in heptane to afford the title compound as a mixture of diastereomers in a ratio 7:3.
Reaction SMILES: [C:1]([CH:3](P(OCC)(OCC)=O)[N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)#[N:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[S:35]1[CH:39]=[CH:38][N:37]=[C:36]1[CH:40]=O>C1COCC1>[C:1]([C:3]([N:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH2:8][CH2:9]1)=[CH:40][C:36]1[S:35][CH:39]=[CH:38][N:37]=1)#[N:2]
Reactant: O=Cc1nccs1
Reactant: CCOP(=O)(OCC)C(C#N)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(C#N)=Cc2nccs2)CC1
Reaction time: 0.5 h

Procedure:
In a 100 ml 3 necked round bottle flask, tert-butyl 4-(cyano(diethoxyphosphoryl)methyl)piperazine-1-carboxylate (5.0 g) was taken in dry THF (25 ml) under nitrogen. Sodium bis trimethylsilyl amide (3.0 g) was added drop wise at 0° C. and stirred for 30 min, then thiazole-2-carboxaldehyde (1.60 g) in 15 ml dry THF was added drop wise to the above reaction mixture at 0° C. Reaction mixture was stirred at room temperature for overnight. TLC was checked no starting material and the reaction mixture was quenched with saturated ammonium chloride (50 ml) and ethyl acetate was added. The organic layer was washed with brine, dried and concentrated to get crude product tert-butyl 4-(1-cyano-2-(thiazol-2-yl)vinyl)piperazine-1-carboxylate as yellow liquid.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:16]=[CH:15][C:7]2[S:8][C:9]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:10][C:6]=2[CH:5]=1.C([O-])(=O)C.[Na+].CN(C=O)C>O>[CH:3]([C:4]1[CH:16]=[CH:15][C:7]2[S:8][C:9]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:10][C:6]=2[CH:5]=1)=[CH2:2]
Reactant: NS(=O)(=O)c1cc2cc(CCBr)ccc2s1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=Cc1ccc2sc(S(N)(=O)=O)cc2c1
Yield: 101 %

Procedure:
A solution of 4.0 g (0.012 mol) of 5-(2-bromoethyl)-2-sulfamoylbenzo[b]thiophene, 2.0 g (0.024 mol) of sodium acetate and 40 ml of DMF was heated at 100° C. under nitrogen. After 15 hours the mixture was poured into water and the aqueous phase was extracted 3X with ethyl acetate. The extracts were dried, filtered and concentrated to dryness. The residue was chromatographed on silica gel by elution with 20% (V/V) ethyl acetate-hexane to yield 2.9 g (30%) of 5-ethenyl-2-sulfamoylbenzo[b]thiophene, m.p. 168°-170° C. (1,2-dichloroethane). Further elution with 40% (V/V) ethyl acetate-hexane yielded 3.74 g (59%) of 5-(2-acetoxyethyl)2-sulfamoylbenzo[b]thiophene, m.p. 120°-122° C. (1,2-dichloroethane).
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])C.[C:8]([NH:11][C:12]1[N:16](CCO)[N:15]=[CH:14][CH:13]=1)(=[O:10])[NH2:9]>C(O)=O>[C:8]([NH:11][C:12]1[N:16]([CH2:6][CH2:5][O:4][CH:1]=[O:3])[N:15]=[CH:14][CH:13]=1)(=[O:10])[NH2:9]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)Nc1ccnn1CCO
Solvent: O=CO
Product: NC(=O)Nc1ccnn1CCOC=O
Reaction time: 0.5 h

Procedure:
Formic acid (2.09 ml) was added to acetic anhydride (4.17 ml) at room temperature and the mixture was stirred for 30 minutes at the same temperature. 5-Carbamoylamino-1-(2-hydroxyethyl)pyrazole (3.76 g) was added thereto under stirring and ice-cooling. The mixture was stirred for 2 hours at room temperature. The reaction mixture was evaporated in vacuo and diisopropyl ether was added thereto to give 5-carbamoylamino-1-(2-formyloxyethyl)pyrazole (4.15 g).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:23][CH:24]=[CH:25][C:26]#[C:27][C:28]([CH3:31])([CH3:30])[CH3:29]>CN(C)C=O>[CH3:29][C:28]([CH3:31])([CH3:30])[C:27]#[C:26]/[CH:25]=[CH:24]\[CH2:23][N:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:1]
Reactant: CC(C)(C)C#CC=CCBr
Reactant: CNCc1ccccc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C/C=C\C#CC(C)(C)C)Cc1ccccc1-c1ccccc1
Reaction time: 16 h

Procedure:
N-methyl-2-phenylbenzylamine (2.57 g) was dissolved in 17 ml of N,N-dimethylformamide (DMF), followed by the addition of 1.39 g of sodium carbonate. While stirring the resulting mixture under ice cooling, a solution of 2.5 g of 1-bromo-6,6-dimethyl-2-hepten-4-yne in DMF was added dropwise. The temperature of the mixture was allowed to rise to room temperature, at which a reaction was allowed to proceed for 16 hours. After the reaction mixture was concentrated under reduced pressure, water and diethyl ether were added to subject the resulting concentrate to liquid-liquid extraction. The organic layer was collected and then dried over magnesium sulfate. The solvent was then distilled off. The residue was purified by chromatography on a silica gel (eluent:hexane/ethyl acetate=10/1), whereby trans-N-(6,6-dimethyl-2-hepten-4-yn-1-yl)-N-methyl-2-phenylbenzylamine (Compound 5) and cis-N-(6,6-dimethyl-2-hepten-4-yn-1-yl)-N-methyl-2-phenylbenzylamine (Compound 6) were obtained in amounts of 2.15 g (yield: 54.5%) and 0.73 g (yield: 18.5%), respectively. The followings are their NMR spectrum data: