Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:14][CH3:15].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][Br:28]>C1COCC1>[Br:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH:14]([CH3:15])[C:13]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)CC
Reactant: BrCCCCCCCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(C)CCCCCCCBr
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (5.42 mL) in dry THF (30 mL) under argon at 0° C. was added 2.5M n-butyl lithium (15.5 mL) slowly, keeping the temperature below 10° C. The solution was stirred at 0° C. for 30 minutes before cooling to −78° C. Ethyl propionate (4.01 mL) was added dropwise and the solution stirred at −78° C. for 1 hour. 1,7-dibromoheptane (6.63 mL) was added and stirring continued at −78° C. for 1 hour then the cooling bath was removed and the reaction mixture was stirred at room temperature overnight. Saturated aqueous ammonium chloride (30 mL) was added to the reaction followed by ethyl acetate (30 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (2×30 mL). The organics were combined, washed with saturated aqueous sodium bicarbonate solution (50 mL), brine (50 mL), dried over sodium sulfate and evaporated. Purification was by silica gel chromatography eluting with 1-5% ethyl acetate in petroleum ether (40-60° C.) to give ethyl 9-bromo-2-methylnonanoate, which was used without further purification. This material (0.84 g) was dissolved in dry ether (27 mL) and cooled to 0° C. under argon. Diisobutylaluminium hydride (1M in toluene, 6.7 mL) was added dropwise and the reaction was stirred at 0° C. for 1 h 15 minutes. The reaction was quenched by addition of saturated aqueous potassium sodium tartrate and the resulting mixture was stirred for 15 minutes. Ethyl acetate (60 mL) and water (20 mL) were added and the phases separated. The aqueous layer was extracted with ethyl acetate (3×30 mL) then the combined organics were washed with brine, dried over sodium sulfate, filtered and evaporated. Purification was by silica gel chromatography eluting with 0 to 10% ethyl acetate in cyclohexane to afford the subtitled compound as a colourless oil. Yield 0.23 g.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br>CC(C)=O>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: BrCCCCCBr
Agent: [K]
Solvent: CC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCCCCBr

Procedure:
Potassium phthalimide (92.5 g) was added in six portions over 4 hours to a boiling solution of 1,5-dibromopentane (230 g) in acetone (670 ml). The mixture was boiled under reflux for 24 hours, then cooled and filtered. The filtrate was evaporated to dryness and the residue dissolved in petroleum ether, b.p. 60°-80° C./ethyl acetate (1:1) and the solution filtered. The filtrate was evaporated to dryness and the residue washed with several portions of petroleum ether, b.p. 60°-80° C. to remove excess dibromopentane. The remaining oil was dried under vacuum at 50° C. The petrol washings were evaporated to dryness and distilled under vacuum to give recovered dibromopentane and a second fraction b.p. 86°-120° C. at 17 mbar. This fraction solidified on cooling and scratching. A little of this solid was used to seed the remaining oil and the combined solids were recrystallised from absolute ethanol (300 ml) to give N-(5-bromopentyl)phthalimide, m.p. 62°-63° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=3)[C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=[N+]([O-])c1cccc(CNc2nc(Cl)nc3sc([N+](=O)[O-])cc23)c1
Reactant: c1cn[nH]c1
Product: O=[N+]([O-])c1cccc(CNc2nc(-n3cccn3)nc3sc([N+](=O)[O-])cc23)c1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-nitro-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-nitro-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)=[C:6]([CH3:16])[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].CO[CH2:25][CH2:26]OC>O.[Pd]>[CH3:16][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH:25]=[CH2:26])[C:7]=1[CH2:8][O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1
Reactant: COCCOC
Reactant: Cc1ccnc(Cl)c1COC1CCCCO1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C=Cc1nccc(C)c1COC1CCCCO1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
2-Chloro-4-methyl-3-(tetrahydro-pyran-2-yloxymethyl)-pyridine (500 mg. 2.07 mmol) was dissolved in a mixture of 1,2-dimethoxyethane (16.5 mL) and water (7 mL). K2CO3 (286 mg. 2.07 mmol) and 2,4,6-trivinyl-cyclotriboroxane pyridine complex (498 mg. 2.07 mmol) were added and the reaction mixture was degassed two times before the addition of Pd((PPh3)4 (120 mg. 0.10 mmol). The reaction mixture was stirred at 100° C. for 18 h. The solvents were removed in vacuo and the residue was purified by flash chromatography on silica gel (elution with hexane/EtOAc 6:1) to give the title compound. MS (m/z): 234.1 [M+H+]
Reaction SMILES: Cl.[CH2:2]([C@H:5]1[CH2:9][NH:8][CH2:7][C@@:6]1([N:22]=[N+:23]=[N-:24])[C:10]([O:12][CH2:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11])[CH:3]=[CH2:4].[C:25]([O:29][C:30]([N:32]1[CH:41]([C:42](O)=[O:43])[CH2:40][C:39]2[C:34](=[CH:35][C:36]([Cl:45])=[CH:37][CH:38]=2)[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].CCN(CC)CC.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>C(Cl)Cl>[CH2:2]([C@H:5]1[CH2:9][N:8]([C:42]([CH:41]2[CH2:40][C:39]3[C:34](=[CH:35][C:36]([Cl:45])=[CH:37][CH:38]=3)[CH2:33][N:32]2[C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])=[O:43])[CH2:7][C@@:6]1([N:22]=[N+:23]=[N-:24])[C:10]([O:12][CH2:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11])[CH:3]=[CH2:4]
Reactant: C=CC[C@H]1CNC[C@@]1(N=[N+]=[N-])C(=O)OCC(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)ccc2CC1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC[C@H]1CN(C(=O)C2Cc3ccc(Cl)cc3CN2C(=O)OC(C)(C)C)C[C@@]1(N=[N+]=[N-])C(=O)OCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
A stirred mixture of racemic 2-oxo-2-phenylethyl (3R,4S)-4-allyl-3-azidopyrrolidine-3-carboxylate hydrochloride (228 mg, 0.650 mmol) and 2-(tert-butoxycarbonyl)-7-chloro-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (258 mg, 0.826 mmol) in methylene chloride (6 mL) was treated with Et3N (0.272 mL, 1.95 mmol) followed by N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (HATU, 321 mg, 0.845 mmol), and the resulting nearly homogeneous mixture was stirred at room temperature. After 1 h, the reaction was diluted with methylene chloride (20 mL), washed successively with water (20 mL), 1 N aqueous HCl (20 mL), saturated aqueous NaHCO3 (20 mL) and saturated aqueous sodium chloride (10 mL), dried over Na2SO4, and concentrated. Purification by silica gel chromatography (40 g column, 15-25% ethyl acetate in hexanes) gave tert-butyl 3-({(3R,4S)-4-allyl-3-azido-3-[(2-oxo-2-phenylethoxy)carbonyl]pyrrolidin-1-yl}carbonyl)-7-chloro-3,4-dihydroisoquinoline-2(1 H)-carboxylate (214 mg, 54%) as a pale amber film which was used without further purification. LC-MS ESI+ MS found for C31H34ClN5O6 m/z 608.2 (M+H), 630.3 (M+Na); ESI− MS m/z 606.3 (M−H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]2[N:9]=[CH:10][CH:11]=[C:5]2[CH:4]=1)[CH3:2].C1C(=O)N([Br:19])C(=O)C1.O>ClCCl>[Br:19][C:11]1[CH:10]=[N:9][N:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][C:5]=12
Reactant: CCc1ccn2nccc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: O
Product: CCc1ccn2ncc(Br)c2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 116622.5 %

Procedure:
To a stirred solution of 5-ethylpyrazolo[1,5-a]pyridine (1.1 g, 0.008 mmol) in dichloromethane (10 mL) at 0° C. was added NBS (1.75 g, 0.009 mmol) and reaction mixture was stirred at room temperature for 5 min. Subsequently, water was added and the reaction mixture was extracted with dichloromethane (2×10 mL). The organic layer was washed with water (1×30 mL), sat. NaHCO3 solution (1×10 mL), brine (1×10 mL), dried over Na2SO4 and concentrated to afford 2.1 g (84%) of 3-bromo-5-ethylpyrazolo[1,5-a]pyridine (I-17) as a brownish highly viscous liquid. The crude was progressed to next step without any further purification. ESI-LC/MS (m/z): [M+H]+ 225.0, [(M+2)+H]+227.0, RT 2.50 min.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[S:10][C:9]([CH2:11][N:12]([CH3:20])[S:13]([CH2:16][CH2:17][CH2:18][Cl:19])(=[O:15])=[O:14])=[CH:8][C:6]=2[N:7]=1.[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[C:28]1B(O)O>>[NH:27]1[C:35]2[C:30](=[C:31]([C:2]3[N:3]=[C:4]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[C:5]4[S:10][C:9]([CH2:11][N:12]([CH3:20])[S:13]([CH2:16][CH2:17][CH2:18][Cl:19])(=[O:14])=[O:15])=[CH:8][C:6]=4[N:7]=3)[CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28]1
Reactant: OB(O)c1cc2ccccc2[nH]1
Reactant: CN(Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1)S(=O)(=O)CCCCl
Product: CN(Cc1cc2nc(-c3cccc4[nH]ccc34)nc(N3CCOCC3)c2s1)S(=O)(=O)CCCCl

Procedure:
3-Chloro-propane-1-sulfonic acid (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-amide was reacted with indole boronic acid in general procedure A. Purification on silica yielded 3-chloro-propane-1-sulfonic acid [2-(1H-indol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl]-methyl-amide.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[O:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[C:12]1([Mg]Br)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(OCC)C>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[OH:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: Br[Mg]c1ccccc1
Reactant: O=Cc1ccc2occc2c1
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1ccc2occc2c1
Reaction time: 1 h

Procedure:
To a solution of 1-benzofuran-5-carbaldehyde (2.70 g, 18.5 mmol) in 50 mL THF under N2 was added phenylmagnesium bromide 3.0M solution in diethyl ether (7.39 mL, 22.2 mmol). The reaction was allowed to stir for 1 h, then was quenched with NH4Cl sat'd aq., extracted with diethyl ether, washed with brine, dried over anhyd. sodium sulfate, filtered, and concentrated in vacuo to a solid to give benzofuran-5-yl(phenyl)methanol which was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.94 (d, J=2.0 Hz, 1H), δ 7.64 (s, 1H), 7.49 (d, J=8.5 Hz, 1H), 7.36-7.42 (m, 2H), 7.26-7.33 (m, 3H), 7.19 (t, J=7.3 Hz, 1H), 6.92 (d, J=1.5 Hz, 1H), 5.88 (d, J=4.0 Hz, 1H), 5.77-5.83 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH:10][C:11](=[O:22])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21].[CH3:23][NH2:24].O>CN(C)C=O>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH:13]1[CH2:12][C:11](=[O:22])[CH2:10][CH:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[N:24]1[CH3:23]
Reactant: CN
Reactant: COc1ccccc1C=CC(=O)C=Cc1ccccc1OC
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1C1CC(=O)CC(c2ccccc2OC)N1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 54.6 %

Procedure:
1,5-Bis(2-methoxyphenyl)-1,4-pentadien-3-one (20c, 0.26 g, 0.9 mmol) was dissolved in dimethyl formamide (5 ml). Methylamine (51, 0.40 ml, 4.6 mmol, 40% in water) was added and the mixture stirred for 24 hr at room temperature. The mixture was poured into water (50 ml) and stirred for 24 hr at room temperature. The resulting mixture was extracted into ethyl acetate, washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to afford a solid. The solid was recrystallized twice from ethanol to give 0.16 g (55%) of a white solid: mp 146-148° C.; 1H NMR δ 1.89 (s, 3H), 2.50 (d, 2H, J=13.7 Hz), 2.65 (t, 2H, J=11.9 Hz), 3.82 (s, 6H), 4.11 (d, 2H, J=11.5 Hz), 6.87 (d, 2H, J=8.3 Hz), 7.03 (t, 2H, J=7.2 Hz), 7.23 (t, 2H, J=5.8 Hz), 7.72 (d, 2H, J=7.6 Hz); 13C NMR: δ 40.3, 49.2, 55.4, 61.2, 110.7, 121.0, 127.6, 127.8, 131.5, 156.3, 208.1; Exact mass calcd for C20H23NO3: 325.1678, observed (M+H) 326.1754.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11](O)=[O:12])=[CH:7][C:6]=1[Cl:16])(=[O:3])[CH3:2].S(Cl)(Cl)=O.[N-:21]=[N+:22]=[N-:23].[Na+]>C1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11]([N:21]=[N+:22]=[N-:23])=[O:12])=[CH:7][C:6]=1[Cl:16])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C=CC(=O)O)cc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CC(=O)Oc1ccc(C=CC(=O)N=[N+]=[N-])cc1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
24.0 g (0.1 mol) of 4-acetoxy-3-chloro-cinnamic acid are suspended in 90 ml of benzene and 14.6 ml (0.2 mol) of thionyl chloride are added. The reaction mixture is heated to the boil for half an hour under a reflux condenser and thereafter the solvent and excess thionyl chloride are removed by distillation under reduced pressure. The residual crude 4-acetoxy-3-chloro-cinnamic acid chloride is dissolved in 100 ml of absolute 1,2-dimethoxyethane, 19.5 g (0.3 mol) of sodium azide are added and thereafter the mixture is stirred for 48 hours at room temperature. The inorganic salts are then filtered off and the filtrate is concentrated under reduced pressure at 30° C. Hereupon, colourless crystals separate out. The crystallisation is completed by adding ether. 4-Acetoxy-3-chloro-cinnamic acid azide of melting point 102°-103° C. (decomposition) is thus obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[C:13]([C:18](F)(F)F)[CH:14]=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[CH:5][CH:4]=1.[H-].[Na+].[CH2:24](Br)[CH:25]=[CH2:26]>>[CH2:26]([N:10]1[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[C:17]2[C:12]([C:13]([CH3:18])=[CH:14][CH:15]=[CH:16]2)=[N:11]1)[CH:25]=[CH2:24]
Reactant: COc1ccc(-c2n[nH]c3c(C(F)(F)F)cccc23)cc1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Product: C=CCn1nc2c(C)cccc2c1-c1ccc(OC)cc1
Yield: 5 %

Procedure:
Prepared according to Method D step B from 3-(4-methoxyphenyl)-7-trifluoromethyl-1H-indazole (0.146 g, 0.5 mmol), sodium hydride (60% in oil, 0.024 g, 0.6 mmol) and allylbromide (0.086 mL, 1.0 mmol) to give the title compound (0.007 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([CH2:18]P(=O)(OCC)OCC)[CH:15]=[C:14]2[C:9]=1[CH2:10][NH:11][C:12](=[O:35])[N:13]2[C:27]1[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=1[Cl:34].[H-].[Na+].[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][C:48](=O)[CH2:47][CH2:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39]>C1COCC1.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([CH:18]=[C:48]2[CH2:49][CH2:50][N:45]([C:43]([O:42][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:44])[CH2:46][CH2:47]2)[CH:15]=[C:14]2[C:9]=1[CH2:10][NH:11][C:12](=[O:35])[N:13]2[C:27]1[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=1[Cl:34]
Reactant: CCOP(=O)(Cc1cc(-c2ccccc2Cl)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)NC2)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(=Cc2cc(-c3ccccc3Cl)c3c(c2)N(c2c(Cl)cccc2Cl)C(=O)NC3)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of diethyl [5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl]methylphosphonate (422 mg, 0.762 mmol) in a mixture of THF (9 mL) and DMF (2 mL) at 0° C. was added sodium hydride (60%, 61 mg, 1.52 mmol). The resulting mixture was stirred at rt for 20 min and then cooled to 0° C. again. To this was added a solution of t-butyl-4-oxo-1-piperidinecarboxylate (310 mg, 1.524 mmol) in THF (2 mL). Then the reaction was stirred at rt for 22 h. The mixture was quenched with brine, and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. Removal of the solvent and subsequent purification by flash chromatography using 20% acetone/hexane as eluent provided tert-butyl 4-{[5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl]methylene}piperidine-1-carboxylate as a white solid. 1H NMR (CDCl3, 500 MHz): δ 1.48 (s, 9H), 2.24 (brs, 2H), 2.31 (t, 2H, J=5.7 Hz), 3.31 (t, 2H, J=5.5 Hz), 3.45 (t, 2H, J=5.5 Hz), 4.35 (abq, 2H, J=14.4 Hz), 5.10 (s, 1H), 5.96 (s, 1H), 6.21 (s, 1H), 6.74 (s, 1H), 7.30-7.58 (m, 7H). MS (API-ES+): 600 (M+H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].C(=O)([O-])O.[K+].[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1>O.CC(C)=O>[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH:5][CH2:4][CH:3]([O:6][CH3:7])[O:2][CH3:1])=[O:19])=[CH:16][CH:15]=1
Reactant: COC(CN)OC
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(CNC(=O)c1ccc(Br)cc1)OC
Reaction time: 0.5 h

Procedure:
A solution of 24 mmol aminoacetaldehyde dimethylacetal was dissolved in 30 ml of water and treated with 25 mmol of potassium hydrogencarbonate. A solution of 23 mmol of 4-bromobenzoyl chloride in 50 ml of acetone was slowly added under stirring over a period of 30 min. The acetone was evaporated and the aqueous phase was extracted 3 times with ethyl acetate to yield the crude title compound as a slightly brown solid.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]([C:10]1[O:16][C@H:15]2[N:12]([C:13](=[O:33])[C@@H:14]2[C@@H:17]([O:19]C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[CH3:18])[C:11]=1[C:34]([O:36]CC1C=CC([N+]([O-])=O)=CC=1)=[O:35])([CH3:9])[CH3:8])=[N+]=[N-].[H][H]>[Pd].C(OCC)(=O)C.O>[NH2:1][CH2:4][CH2:5][CH2:6][C:7]([C:10]1[O:16][C@H:15]2[N:12]([C:13](=[O:33])[C@@H:14]2[C@@H:17]([OH:19])[CH3:18])[C:11]=1[C:34]([OH:36])=[O:35])([CH3:8])[CH3:9]
Reactant: C[C@H](OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(C(C)(C)CCCN=[N+]=[N-])O[C@H]12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(C(C)(C)CCCN)O[C@H]12
Reaction time: 0.33 h
Yield: 74.7 %

Procedure:
In a 100 ml two necked flask fitted with a magnetic stirrer, a rubber septum and connected to a hydrogenation apparatus palladium on carbon catalyst (10%, 300 mg) in ethyl acetate (13 ml) and water (13 ml) was prehydrogenated for 20 min at 0° C. A solution of p-nitrobenzyl (5R,6R)-3-[4-azido-1,1-dimethylbutyl]-6-[(S)-1-p-nitrobenzyloxycarbonyloxyethyl]-7-oxo-4-oxa-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (280 mg, 0.44 mmol) in ethyl acetate (10 ml) was then added with a syringe at 0° C. with stirring. After 50 min of stirring at 0° C. hydrogen uptake came to an end (90 ml of hydrogen was consumed). The catalyst was removed by filtration, washed with a small portion of ethyl acetate and water and the chilled two phase mixture allowed to separate. The aqueous phase was washed twice with portions (3 ml) of cold ethyl acetate and water and the ethyl acetate phases were reextracted twice with portions (3 ml) of water. Residual ethyl acetate was removed from the combined water phases in vacuum and then in high vacuum at 0° C. and the volume was reduced to 13 ml in high vacuum. The solution was lyophilized at −25° C. for three days to give (5R,6R)-3-[4-amino-1,1-dimethylbutyl]-6-[(S)-1-hydroxyethyl]-7-oxo-4-oxa-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (YOB) as a colourless voluminous powder (98 mg, 75%)
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23](=[O:40])[N:24]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=2)[CH2:25][CH2:26][CH2:27][N:28]2[N:32]=[N:31][CH:30]=[N:29]2)[CH:20]=[C:19]([Cl:41])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[Cl:41][C:19]1[CH:20]=[C:21]([CH:22]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[CH:18]=1)[C:23]([N:24]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=1)[CH2:25][CH2:26][CH2:27][N:28]1[N:32]=[N:31][CH:30]=[N:29]1)=[O:40]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCCn2ncnn2)c2cccc(F)c2)c1)c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1cc(Cl)cc(OCCNc2ccncc2)c1)N(CCCn1ncnn1)c1cccc(F)c1
Yield: 72.1 %

Procedure:
A solution of {2-[3-chloro-5-(3-fluorophenyl-(3-tetrazol-2-yl-propyl)-carbamoyl)-phenoxy]-ethyl}-pyridin-4-yl-carbamic acid tert-butyl ester (0.07 g) in trifluoroacetic acid (0.75 ml) and dichloromethane (0.75 ml) was stirred at room temperature for 1 h then concentrated under vacuum. The residue was purified by flash chromatography, eluting with dichloromethane/methanol/ammonia (90:10:1) to give the title compound as a white foam (0.042 g).
Reaction SMILES: [C:1]([C:5]1[C:13]2S[CH2:11][C:10]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[C:7]([N+:16]([O-])=O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CCCCCC.CC[O:27]C(C)=O>CCO>[NH2:16][C:7]1[CH:6]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[C:13]2[O:27][CH2:11][C:10]([CH3:14])([CH3:15])[C:9]=2[CH:8]=1
Reactant: CCOC(C)=O
Reactant: CC(C)(C)c1cc([N+](=O)[O-])cc2c1SCC2(C)C
Solvent: CCCCCC
Solvent: CCO
Product: CC(C)(C)c1cc(N)cc2c1OCC2(C)C
Reaction time: 3 h

Procedure:
A suspension of 7-tert-butyl-2,3-dihydro-3,3-dimethyl-5-nitro-benzothiophene (2.6 g, 8.8 mmol) in absolute EtOH (60 mL) is hydrogenated at 40 psi of H2 pressure on a Parr hydrogenation apparatus for 3 h at 22° C. The reaction is judged complete by TLC (hexane:EtOAc, 19:1; visualized with Dragendorff reagent). The reaction mixture is filtered through Celite and evaporated to yield the title compound as a purple solid, which is used without further purification.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.C(=O)(O)[O-].[Na+].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O.CC(C)=O>[CH3:1][C@H:2]1[NH:3][CH2:4][CH2:5][N:6]([C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:20])[CH2:7]1
Reactant: C[C@@H]1CNCCN1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: C[C@@H]1CN(C(=O)c2ccccc2)CCN1

Procedure:
(R)-2-methylpiperazine (13.85 g, 138 mmol), and sodium bicarbonate (52.3 g, 622 mmol) were dissolved/suspended in water (182 mL) and acetone (112 mL). The flask was cooled in an ice bath and a solution of benzoyl chloride (17.7 mL, 152 mmol) in acetone (56 mL) was added drop-wise over 1 hour. After 16 hours the acetone was removed on the rotovap. Water (400 mL) was added and the resulting mixture acidified using 6 M HCl to pH <2. The aqueous layer was washed with 200 mL CH2Cl2 three times. Aqueous sodium hydroxide (5M) was added to pH >12, and this solution was extracted three times with 200 mL of CH2Cl2. The combined organics were dried (MgSO4) and evaporated to give a thick yellow oil. MS (M+H)+=205.1
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([SH:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[C:1](=[O:12])([S:19][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCS
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)SCCCCCC

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and n-hexylmercaptan as starting materials to give the aimed compound.