Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:53][C:54]1[S:55][CH:56]=[CH:57][N:58]=1>CN(C=O)C>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:53][C:54]2[S:55][CH:56]=[CH:57][N:58]=2)=[O:7])=[CH:4][C:3]=1[B:11]1[O:12][C:13]([CH3:19])([CH3:18])[C:14]([CH3:17])([CH3:16])[O:15]1
Reactant: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Nc1nccs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)Nc2nccs2)cc1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid (2.0 g, 7.63 mmol), DIPEA (4 ml, 22.89 mmol) and HATU (3.05 g, 8.02 mmol) were dissolved in DMF (20 ml) and stirred at room temperature for 15 mins. 2-Aminothiazole (801 mg, 8.01 mmol) was added and the reaction stirred at room temperature for 18 hours. The solvent was evaporated under vacuum and the reaction partitioned between ethyl acetate (250 ml) and water (50 ml). The organic phase was washed with hydrochloric acid (2N, 50 ml) and aqueous sodium bicarbonate (1M, 50 ml), then dried (magnesium sulphate) and the solvent evaporated under vacuum. The residue was absorbed onto silica and purified by flash column chromatography eluting with cyclohexane/ethyl acetate (4:1). The solvent was evaporated from the product fractions under vacuum to 4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(thiazol-2-yl)-benzamide (1.72 g). LCMS: retention time 3.66 min, MH+345. NMR: δH [2H6]-DMSO 12.65, (1H, b), 8.32, (1H, d), 8.08, (1H, dd), 7.56, (1H, d), 7.35, (1 h, d), 7.28, (1H, d), 2.54, (3H, s), 1.34, (12H, s).
Reaction SMILES: ClC(N(C)C)=C(C)C.[Si:9]([O:16][C@@H:17]([CH2:21][O:22][CH:23]1[CH2:26][CH2:25][CH2:24]1)[C:18]([OH:20])=O)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].N1C=CC=CC=1.[CH3:33][C:34]1[CH:35]=[CH:36][C:37]([NH2:40])=[N:38][CH:39]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[Si:9]([O:16][C@@H:17]([CH2:21][O:22][CH:23]1[CH2:26][CH2:25][CH2:24]1)[C:18]([NH:40][C:37]1[CH:36]=[CH:35][C:34]([CH3:33])=[CH:39][N:38]=1)=[O:20])([C:12]([CH3:13])([CH3:14])[CH3:15])([CH3:10])[CH3:11]
Reactant: Cc1ccc(N)nc1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](COC1CCC1)C(=O)O
Agent: CC(C)=C(Cl)N(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)[C@H](COC2CCC2)O[Si](C)(C)C(C)(C)C)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.8 %

Procedure:
1-Chloro-N,N,2-trimethylprop-1-en-1-amine (0.133 mL, 1.00 mmol) was added to a stirred solution of (S)-2-(tert-butyldimethylsilyloxy)-3-cyclobutoxypropanoic acid (Intermediate R4) (250 mg, 0.91 mmol) in DCM (5 mL) at room temperature under nitrogen. The resulting solution was stirred at room temperature for 30 minutes. Pyridine (0.147 mL, 1.82 mmol) was added followed by a solution of 5-methylpyridin-2-amine (108 mg, 1.00 mmol) in DCM (5 mL) and the resulting solution was stirred at ambient temperature for 1 hour. 1M citric acid (10 mL) and DCM (50 mL) were added and the phases were separated. The organic phase washed with water (10 mL) and brine (10 mL), dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with 0 to 30% ethyl acetate in isohexane to afford the product (195 mg, 58.7%). 1H NMR (400 MHz, DMSO) δ 0.01 (d, 6H), 0.80 (s, 9H), 1.24-1.37 (m, 1H), 1.43-1.53 (m, 1H), 1.59-1.72 (m, 2H), 1.94-2.06 (m, 2H), 2.13 (s, 3H), 3.33-3.44 (m, 2H), 3.77-3.87 (m, 1H), 4.29-4.34 (m, 1H), 7.49-7.54 (m, 1H), 7.86 (d, 1H), 8.02-8.06 (m, 1H), 9.25 (s, 1H); m/z (ESI+) (M+H)+=365.47; HPLC tR=3.60 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:14][CH:12]([CH2:13]2)[C:11](=O)[N:10]([CH3:16])[C:9]3=O)=[CH:4][CH:3]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]23[CH2:14][CH:12]([CH2:13]2)[CH2:11][N:10]([CH3:16])[CH2:9]3)=[CH:6][CH:7]=1
Reactant: CN1C(=O)C2CC(c3ccc(Cl)cc3)(C2)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CN1CC2CC(c3ccc(Cl)cc3)(C2)C1
Product: Cl

Procedure:
Analogously to Example 1a), 3.9 g of 1-(4-chlorophenyl)-3-methyl-3-azabicyclo[3.1.1]heptane-2,4-dione in 70 ml of toluene are reacted with 25 ml of a toluene solution of sodium dihydro-bis-(2-methoxyethoxy)aluminate (70%; FLUKA) and the mixture is worked up with 25 ml of concentrated sodium hydroxide solution. m.p. of the title compound: 180-182° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH3:11])=[CH:4][C:3]=1[F:12].[C:13](Cl)(=[O:17])[C:14](Cl)=[O:15].ClCCl.[CH3:22][CH2:23][OH:24]>CCOCC.CCOC(C)=O>[CH2:23]([O:24][C:13](=[O:17])[C:14]([C:6]1[C:5]2[C:9](=[CH:10][C:2]([Br:1])=[C:3]([F:12])[CH:4]=2)[N:8]([CH3:11])[CH:7]=1)=[O:15])[CH3:22]
Reactant: Cn1ccc2cc(F)c(Br)cc21
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCO
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)C(=O)c1cn(C)c2cc(Br)c(F)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
To a solution of 6-bromo-5-fluoro-1-methyl-1H-indol (0.23 g, 1.00 mmol) in Et2O (15.0 mL) cooled to 0° C. a 2.0 M solution of oxalyl chloride in dichloromethane (0.56 mL, 5.00 mmol) was added dropwise. The reaction was stirred for 0.5 h at 0° C. and allowed to warm to room temperature and stirred overnight. The mixture was cooled to −20° C. and dry EtOH (2 mL) was added. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography (ethyl acetate-hexane, 1:3) to give the product (0.21 g, 59%). 1H NMR (CDCl3, 300 MHz,): 1.43 (t, J=7.2 Hz, 3H), 3.82 (s, 3H), 4.40 (t, J=7.2 Hz, 2H), 7.47 (d, J=5.4 Hz, 1H), 8.08 (d, J=9.0 Hz, 1H), 8.30 (s, 1H).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](Cl)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].O.O.O.O.O.O.[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2]
Reactant: C1CNCCN1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Solvent: O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)cc21
Temperature: 170 °C

Procedure:
A mixture of 1-ethyl-6-fluoro-7-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.9 g), piperazine hexahydrate (15 g) and water (15 ml) was heated at 170° C. in a sealed tube for 16 hours. After evaporation of the solvent, the residue was acidified with diluted hydrochloric acid, heated at 100° C., and the hot solution was filtered. The filtrate was evaporated to dryness. The residue was dissolved in 10% sodium hydroxide and neutralized with acetic acid. The precipitate was collected, washed with water, dried, and recrystallized from ethanol to give 1-ethyl-6-fluoro-1,4-dihydro-7-(1-piperazinyl)-4-oxoquinoline-3-carboxylic acid as colorless powder.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]3[N:18]=[C:17]([NH:19][C:20]([C:22]4[N:26]([CH3:27])[N:25]=[CH:24][C:23]=4[C:28]([O:30]CC)=[O:29])=[O:21])[CH:16]=[CH:15][N:14]3[CH:33]=2)[CH:8]=[CH:9][CH:10]=1.C(O)C.C1COCC1.Cl>O>[F:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]3[N:18]=[C:17]([NH:19][C:20]([C:22]4[N:26]([CH3:27])[N:25]=[CH:24][C:23]=4[C:28]([OH:30])=[O:29])=[O:21])[CH:16]=[CH:15][N:14]3[CH:33]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccn2cc(-c3cccc(OCCF)c3)nc2n1
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2cc(-c3cccc(OCCF)c3)nc2n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Ethyl 5-(2-(3-(2-fluoro ethoxy)phenyl)imidazo[1,2-a]pyrimidin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylate (100 mg, 221 μmol) was combined with Ethanol (0.570 ml) and THF (0.570) to give a yellow solution. The reaction was stirred at RT for 6 h. H2O was added to the suspension and then HCl 1N was added until the mixture was acidic (pH=3). The suspension was stirred for 30 min and then the reaction mixture was filtered. The residual solvent was removed under vacuum. The title compound was obtained as a light yellow solid (73 mg, 78%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[N:5]=[C:4]([NH:18][CH:19]([CH2:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22])[N:3]=1.[CH3:26][N:27]1[CH2:32][CH2:31][CH:30]([NH:33][CH3:34])[CH2:29][CH2:28]1.[OH-].[Na+].Cl>O1CCOCC1.CC(C)=O>[OH-:15].[NH4+:3].[Cl:17][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[N:7]=[C:2]([N:33]([CH3:34])[CH:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)[N:3]=[C:4]([NH:18][CH:19]([CH2:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22])[N:5]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: CNC1CCN(C)CC1
Reactant: CCCC(CCC)Nc1nc(Cl)nc(Nc2ccc(OC)c(Cl)c2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: C1COCCO1
Product: CCCC(CCC)Nc1nc(Nc2ccc(OC)c(Cl)c2)nc(N(C)C2CCN(C)CC2)n1
Product: [NH4+]
Temperature: 80 °C
Reaction time: 2 h
Yield: 40.8 %

Procedure:
To a sample of 104 (0.363 g, 1.0 mmol) dissolved in 1,4-dioxane (6 mL) was added a solution of N-methyl-4(methylamino)piperidine (0.15 mL, 1.0 mmol) in acetone (1 mL) followed by addition of a NaOH solution (0.0414 g, 1.0 mmol dissolved in 1 mL of H2O). The reaction mixture was allowed to stir at about 80° C. for about about 2 hours. The reaction mixture was poured over crushed ice and neutralized with 10% HCl (aq). The resulting solid was collected by vacuum filtration, washed with water and dried under vacuum overnight. Column chromatography (silica gel, 96:3:1 dichloromethane:methanol:conc. ammonium hydroxide) yielded light purple solid 105 (97 mg, 20%), mp 249° C. HPLC: YMC Pack Pro C18, 40:30:30 [KH2PO4 (0.01 M, pH 3.2): CH3OH: CH3CN], 264 nm, Rt 14.4 min, 98% purity; MS (ESI): m/z 476 (M+H, 100), 412 (2.9), 366 (2.8), 239 (1.9).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:9]=[N:10][O:11][C:12]=2[CH:13]2[CH2:15][CH2:14]2)=[O:7])=[C:4]([CH2:18]SC)[CH:3]=1.Cl[C:22]1C=CC=C(C(OO)=O)C=1.[S:32](=[O:35])(O)[O-:33].[Na+]>ClCCl>[CH:13]1([C:12]2[O:11][N:10]=[CH:9][C:8]=2[C:6](=[O:7])[C:5]2[CH:16]=[CH:17][C:2]([Br:1])=[CH:3][C:4]=2[CH2:18][S:32]([CH3:22])(=[O:35])=[O:33])[CH2:14][CH2:15]1
Reactant: CSCc1cc(Br)ccc1C(=O)c1cnoc1C1CC1
Reactant: O=S([O-])O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)Cc1cc(Br)ccc1C(=O)c1cnoc1C1CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-[4-bromo-2-(methylsulphenylmethyl)benzoyl]-5-cyclopropylisoxazole (0.7 g) and 3-chloroperbenzoic acid (1.5 g) in dichloromethane was stirred for 30 minutes at 0° C. and then at 1 hour at 25° C. The mixture was then treated with an aqueous solution of sodium bisulphite and filtered. After decanting, the organic layer was washed with a solution of sodium acetate, brine, dried (sodium sulphate), filtered and evaporated to yield a clean oil which was crystallised from ether to give 5-cyclopropyl-4-[4-bromo-2-(methylsulphonylmethyl)benzoyl]isoxazole (compound 2, 0.61 g) as a white solid, m.p. 154.2° C.
Reaction SMILES: CC(OC[C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10](N)[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.C(Cl)(Cl)Cl>C(N(CC)CC)C>[O:12]=[C:11]1[N:8]2[CH:9]([S:14][CH2:15][CH:6]=[C:7]2[C:16]([OH:18])=[O:17])[CH2:10]1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(O)C1=CCSC2CC(=O)N12

Procedure:
By treating 4 g. of the product of Example 1 (c) with 4.5 g. of 7-aminocephalosporanic acid which has been dissolved in 100 ml. of anhydrous chloroform with 6 ml. of triethylamine according to the procedure of Example 1 (d), 2.8 g. of 3-[(acetyloxy)methyl]-7β-[[(4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)phenyl-acetyl[amino[-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid is obtained which decomposes between 95° and 100°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:20]3[CH2:21][CH:22]([C:24]([O:26]CC)=O)[CH2:23][CH:12]2[CH2:13][C:14]2([CH2:19]3)[O:18][CH2:17][CH2:16][O:15]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:29][CH2:30][Mg+].[Br-]>CCOCC.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH:12]3[CH2:23][CH:22]([C:24]4([OH:26])[CH2:30][CH2:29]4)[CH2:21][CH:20]2[CH2:19][C:14]2([CH2:13]3)[O:15][CH2:16][CH2:17][O:18]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CC[Mg+]
Reactant: CCOC(=O)C1CC2CC3(CC(C1)N2S(=O)(=O)c1ccc(Cl)cc1)OCCO3
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=S(=O)(c1ccc(Cl)cc1)N1C2CC(C3(O)CC3)CC1CC1(C2)OCCO1
Temperature: -78 °C
Reaction time: 18 h

Procedure:
Ethyl 9-[(4-chlorophenyl)sulfonyl]spiro[9-azabicyclo[3.3.1]nonane-3,2′-[1,3]dioxolane]-7-carboxylate (50) (395 mg, 0.918 mmol) was dissolved in Et2O (2 mL) and the resulting solution was cooled to −78° C. Ti(O-i-Pr)4 was added followed by EtMgBr dropwise over 10 minutes. The reaction mixture was warmed to room temperature and stirred for 18 h. The resulting solution was diluted with EtOAc and washed with saturated aqueous NH4Cl. The organic phase was dried (Na2SO4), filtered, and concentrated to give 1-{9-[(4-chlorophenyl)sulfonyl]spiro[9-azabicyclo[3.3.1]nonane-3,2′-[1,3]dioxolan]-7-yl}cyclopropanol (55). MS (ESI) 414.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[NH:14][N:13]=[C:12]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:11]=2[C:10](=O)[CH2:9]1.[C:25]([NH:28][NH2:29])([NH2:27])=[NH:26].Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[NH:14][N:13]=[C:12]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:11]=2[C:10](=[N:29][NH:28][C:25]([NH2:27])=[NH:26])[CH2:9]1
Reactant: N=C(N)NN
Reactant: O=C1CC(c2ccccc2Cl)Cc2[nH]nc(Nc3ccccc3)c21
Agent: Cl
Solvent: CCO
Solvent: O
Product: N=C(N)NN=C1CC(c2ccccc2Cl)Cc2[nH]nc(Nc3ccccc3)c21
Yield: 90.3 %

Procedure:
A mixture of 6-(2-chlorophenyl)-3-phenylamino-4,5,6,7-tetrahydroindazol-4-one (0.4 g), aminoguanidine hydrochloride (0.16 g), concentrated hydrochloric acid (0.31 ml), water (0.31 ml) and ethanol (20 ml) was refluxed for 6 hours. Under reduced pressure, the solvent was evaporated, and to the residue was added sodium hydrogen carbonate solution to make the solution alkaline. The mixture was extracted with ethylacetate, and the organic layer was washed with water and concentrated under reduced pressure. The residue was dissolved in ethanol, and to the solution was added 1N hydrochloric acid (5 ml) and concentrated. Precipitated crystals were recrystallized from ethanol to give 6-(2-chlorophenyl)-4-guanidinoimino-3-phenylamino-4,5,6,7-tetrahydroindazole hydrochloride (Compound 146) (0.23 g) as colorless crystals.
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:25][CH2:26][C:27]([CH3:29])=[CH2:28])[CH:6]([CH3:24])[CH2:7][CH2:8][CH2:9][C:10]1([CH3:23])[CH:16]2[O:17][C:13]([CH2:18][C:19]([O:21][CH3:22])=[O:20])([CH2:14][CH2:15]2)[CH2:12][O:11]1)(=[O:3])[CH3:2].C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC>[C:1]([O:4][CH:5]([CH2:25][CH:26]=[C:27]([CH3:28])[CH3:29])[CH:6]([CH3:24])[CH2:7][CH2:8][CH2:9][C:10]1([CH3:23])[CH:16]2[O:17][C:13]([CH2:18][C:19]([O:21][CH3:22])=[O:20])([CH2:14][CH2:15]2)[CH2:12][O:11]1)(=[O:3])[CH3:2]
Reactant: C=C(C)CCC(OC(C)=O)C(C)CCCC1(C)OCC2(CC(=O)OC)CCC1O2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOCC
Solvent: c1ccccc1
Product: COC(=O)CC12CCC(O1)C(C)(CCCC(C)C(CC=C(C)C)OC(C)=O)OC2
Temperature: 80 °C
Yield: 77.4 %

Procedure:
A mixture of methyl (1RS,4SR,5RS)-4-(5-acetoxy-4,8-dimethyl-8-nonenyl)-4-methyl-3,8-dioxabicyclo [3.2.1] octane-1-acetate (93 mg, 0.24 mM), benzene (6 ml) and p-toluenesulfonic acid monohydrate (1 crystal) is heated to 80° C. for sixteen hours under nitrogen. The resulting mixture is cooled to room temperature and treated with ether (100 ml). The organic phase is washed with 5% sodium bicarbonate solution (5 ml) and dried (sodium sulfate). The solvent is removed in vacuo to give methyl (1RS,4SR,5RS)-4-(5-acetoxy-4,8-dimethyl-7-nonenyl)-4-methyl-3,8-dioxabicyclo [3.2.1] octane-1-acetate (72 mg, 90%) as a colorless oil. This material is homogeneous by thin layer chromatography and is used directely in the next step.
Reaction SMILES: [C:1]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:4])[CH2:2][CH3:3].[CH:11](OCC)(OCC)OCC.[Br:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1>>[Br:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][CH:11]=[C:5]([C:1](=[O:4])[CH2:2][CH3:3])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:24][CH:23]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)CC(=O)CC
Product: CCOC(=O)C(=CNc1ccc(Br)cc1)C(=O)CC
Temperature: 150 °C
Yield: 33.5 %

Procedure:
A stirred mixture of ethyl propionylacetate (33 g, 0.23 mol), triethyl orthoformate (46 mL, 0.28 mol), and 4-bromoaniline (42 g, 0.24 mol) were heated at 150° C. for 2 h with a Dean Stark trap. The reaction was cooled to room temperature. Trituration with 1:1 hexanes/diethyl ether afforded the desired product (25.1 g, 33%) as a tan solid: 1H NMR (300 MHz, DMSO-d6) δ 12.44 (d, J=13.1 Hz, 1H), 8.42 (d, J=13.1 Hz 1H), 7.64-7.51 (m, 2H), 7.50-7.34 (m, 2H), 4.17 (q, J=7.1 Hz, 2H), 2.86 (q, J=7.3 Hz, 2H), 1.27 (t, J=7.1 Hz, 3H), 1.02 (t, J=7.3 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH:12][CH2:13][CH3:14])[CH3:11])=[CH:5][CH:4]=1.[O:15]=[C:16]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][N:17]1[CH2:23][CH:24]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:13]([N:12]([CH:10]([CH3:11])[CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH2:24][CH2:23][N:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:16]1=[O:15])[CH3:14]
Reactant: CCNC(C)Cc1ccc(OC)cc1
Reactant: O=CCN1CCCCCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCN(CCN1CCCCCC1=O)C(C)Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 91.9 %

Procedure:
A mixture of [2-(4-methoxyphenyl)-1-methylethyl]ethylamine (0.53 g, 2.75 mmole), (2-oxo-azepan-1-yl)acetaldehyde (0.5 g, 3.2 mmole), and sodium triacetoxyborohydride (0.88 g, 4.1 mmole) in 1,2-dichloroethane (15 mL) was stirred at room temperature for 60 hours. The mixture was concentrated, and the residue was partitioned between diethyl ether (50 mL) and saturated aqueous sodium bicarbonate (25 mL). The organic solution was extracted with 5% hydrochloric acid (20 mL), and the aqueous acidic phase was washed with diethyl ether and the pH was adjusted to 12 with 25% sodium hydroxide. The mixture was extracted with dichoromethane, and the organic phase was dried (sodium sulfate) and concentrated to give 1-(2-{ethyl-[2-(4-methoxyphenyl)-1-methylethyl]amino}ethyl)-azepan-2-one 11 (0.84 g) as a viscous oil, which was converted to the dibenzoyl-L-tartrate salt, Anal.: Calcd. for C38H46N2O10: C, 66.07; H, 6.71; N, 4.06%. Found C, 64.69; H, 6.45; N, 3.90%.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[CH2:8]=[O:9].N12CCC(CC1)CN2.Cl>O.CS(C)=O>[OH:9][CH2:8][C:2](=[CH2:3])[C:1]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: C=CC(=O)OCC
Reactant: C=O
Agent: C1CN2CCC1CN2
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: C=C(CO)C(=O)OCC
Temperature: 100 °C

Procedure:
Into a 2-liter separable flask fitted with a stirrer, a reflux condenser and a thermometer, dimethylsulfoxide (500 parts), water (170 parts), ethyl acrylate (200 parts), paraformaldehyde (purity: 80%, 72.5 parts) and diazabicyclo (2.2.2) octane (15.6 parts) were charged. They were heated to 100° C., and subjected to a reaction for 4 hours. Although the contents were not homogeneous at the time of the charging, they turned into a homogeneous clear mixture around 60° C. Dilute hydrochloric acid (500 parts) was then added, followed by extraction twice with diethylether (200 parts, each). The extract was dried over anhydrous magnesium sulfate. After the thus-dried extract was concentrated in an evaporator, the concentrate was subjected to distillation under reduced pressure. Ethyl 2-(hydroxymethyl)acrylate was obtained (yield: 193 parts). The reaction product was identified to be the target compound by IR and NMR, and its purity was determined to be 98.7% by GC.
Reaction SMILES: O=C1CCC(=O)N1O[C:9](=[O:35])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].[NH2:36][C@H:37]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:38][CH2:39][C:40](=[O:42])[OH:41]>C1COCC1.CN(C=O)C.O>[C:46]([O:45][C:43](=[O:44])[C@@H:37]([NH:36][C:9](=[O:35])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[CH2:38][CH2:39][C:40]([OH:42])=[O:41])([CH3:49])([CH3:47])[CH3:48]
Reactant: CC(C)(C)OC(=O)[C@@H](N)CCC(=O)O
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Eicosanedioic acid tert-butyl ester 2,5-dioxo-pyrrolidin-1-yl ester (6.01 g, 12.124 mmol) was dissolved in THF (150 mL) and mixed with a slurry of H-Glu-OtBu (2.71 g, 13.33 mmol) in DMF/water (1/1, 40 mL). This resulted in a gel-like solution which was heated to give a clear solution that was stirred at RT for 3 h. Then the solution was evaporated, 100 mL of water was added and the mixture was heated to 60° C. which resulted in a solution which crystallised on cooling. The precipitate was recrystallised from acetonitrile and the crystals were dried in vacuum. Yield 6.82 g (96%).
Reaction SMILES: [CH:1]1([CH:7]([CH3:10])[CH:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:11]([O-])([O-])[O:12]C.[Cl-].[NH4+].[CH3:18]O>>[CH3:18][O:9][CH:8]([O:12][CH3:11])[CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:10]
Reactant: CO
Reactant: CC(C=O)C1CCCCC1
Reactant: COC([O-])[O-]
Agent: [Cl-]
Agent: [NH4+]
Product: COC(OC)C(C)C1CCCCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Into a 200 ml round bottom flask 50 ml of methanol, 30.0 g of 2-cyclohexylpropanal, 36.1 g of methyl orthoformate, and 0.5 g of ammoniumchloride were charged and the mixture was stirred at room temperature for 12 hours. After washing the resulting reaction mixture with water, the residue was distilled to prepare 37.5 g of Compound No. 4 (purity: 99.3%, boiling point: 83° C./5 mmHg). The compound was a colorless, transparent liquid having a floral and fruity odor.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=O.[CH:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.S(Cl)(Cl)=O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:7]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: c1ccccc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=C(c1ccccc1)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 87 %

Procedure:
A solution of 14.61 g. (0.079 m.) of 3-fluoro-4-nitrobenzoic acid, 200 ml. of benzene, 10 ml. of thionyl chloride, and 1 ml. of N,N-dimethylformamide was stirred overnight at room temperature under a calcium chloride drying tube. The resulting clear solution was then heated to reflux for one hour, after which time the solution was concentrated to approximately 75% of the original volume by distillation. The mixture was cooled by placing the flask in an ice bath. With additional cooling, 20 g. of aluminum chloride was added in portions through Gooch tubing over a period of about 45 minutes. The resulting dark mixture was stirred and allowed to warm to room temperature overnight. The reaction flask was again cooled in an ice bath as 300 ml. of 1N hydrochloric acid was added dropwise. The mixture was extracted several times with ethyl acetate and the combined extracts were washed with water, a saturated solution of sodium bicarbonate, water, a saturated solution of sodium chloride, and then dried over magnesium sulfate. Filtration and evaporation of the solvent in vacuo provided 16.8 g. (87% yield) of the desired compound as an oil which solidified on scratching. Recrystallization from 95% ethanol afforded yellow needles, m.p. about 77°-79° C.