Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N:9]2[N:13]=[C:12]3[CH:14]=[CH:15][CH:16]=[C:17]([CH3:18])[C:11]3=[N:10]2)[CH:3]=1.[CH2:19]([O:21][C:22](=[O:35])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33]Br)=[CH:26][CH:25]=1)[CH3:20].C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[CH2:19]([O:21][C:22](=[O:35])[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([O:30][CH2:31][CH2:32][CH2:33][O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[N:9]2[N:13]=[C:12]3[CH:14]=[CH:15][CH:16]=[C:17]([CH3:18])[C:11]3=[N:10]2)=[CH:28][CH:29]=1)[CH3:20]
Reactant: CCOC(=O)Cc1ccc(OCCCBr)cc1
Reactant: Cc1cccc2nn(-c3cc(Cl)ccc3O)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)Cc1ccc(OCCCOc2ccc(Cl)cc2-n2nc3cccc(C)c3n2)cc1
Temperature: 25 °C

Procedure:
A mixture of 4-chloro-2-(4-methyl-benzotriazol-2-yl)-phenol (93 mg, 0.36 mmol), [4-(3-bromo-propoxyl)-phenyl]-acetic acid ethyl ester (130 mg, 1.2 eq.) and Cs2CO3 (140 mg, 1.2 eq.) in CH3CN (10 ml) was heated to reflux for I hr. After cooling to r.t., the solid was filtered off and the filtrate was concentrated in vacuo. The crude product was purified on silica gel to give the desired compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:15]([F:16])=[CH:14][C:12]([NH2:13])=[C:11]([F:17])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:18][N:19]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[N:20]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:17][C:11]1[CH:10]=[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:22]3[CH:21]=[N:20][N:19]([CH3:18])[CH:23]=3)[CH:7]=2)[C:15]([F:16])=[CH:14][C:12]=1[NH2:13]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Nc1cc(F)c(Oc2ccnc(Cl)c2)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc(Oc3cc(F)c(N)cc3F)ccn2)cn1
Temperature: 90 °C
Yield: 63 %

Procedure:
To a solution of 4-(2-chloropyridin-4-yloxy)-2,5-difluoroaniline (450 mg, 1.76 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (400 mg, 1.9 mmol) in N,N-dimethylformamide (30 mL) was added tetrakis(triphenylphosphine)palladium (105 mg, 0.09 mmol) and an aqueous solution of potassium phosphate (2 M, 1.8 mL). The mixture was flushed with nitrogen for 10 min, and then stirred with heating at 90° C. under nitrogen overnight. After cooling to RT, the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine, dried (Na2SO4), concentrated under reduced pressure and purified by column chromatography on silica gel to give 2,5-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)aniline (335 mg, 63% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.35 (d, J=5.7 Hz, 1H), 8.27 (s, 1H), 7.98 (s, 1H), 7.24-7.18 (m, 2H), 6.75 (dd, J=12.3, 8.1 Hz, 1H), 6.62 (dd, J=5.4, 2.1 Hz, 1H), 5.53 (br s, 2 E), 3.87 (s, 3H); MS (ESI): m/z 303.1 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](Br)[C:3]=1[C:4]#[N:5].[CH3:11][C:12]([CH3:16])([CH3:15])[C:13]#[CH:14].C([O-])([O-])=O.[K+].[K+]>COCCOC.O.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:14]#[C:13][C:12]([CH3:16])([CH3:15])[CH3:11])[C:3]=1[C:4]#[N:5]
Reactant: C#CC(C)(C)C
Reactant: N#Cc1c(N)cccc1Br
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)C#Cc1cccc(N)c1C#N
Temperature: 25 °C
Yield: 92.8 %

Procedure:
To a solution of 2-amino-6-bromobenzonitrile (1.97 g, 10.0 mmol), 3,3-dimethylbut-1-yne (2.46 g, 30 mmol), K2CO3 (2.76 g, 20.0 mmol), and CuI (191 mg, 0.1 mmol) in DME/H2O (4:1, 50 mL) was added Pd(PPh3)4 (1.16 g, 0.1 mmol) at room temperature under nitrogen. The reaction mixture was refluxed under nitrogen overnight. After it was cooled down to room temperature, the reaction was quenched with brine, extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by chromatography on silica gel eluting with 20% EtOAc in hexanes to give the title compound as a light brown oil (1.84 g, 93%). 1H NMR (400 MHz, DMSO-d6) δ 1.27 (s, 9H), 6.10 (s, 2H), 6.59 (d, J=7.2 Hz, 1H), 6.71 (d, J=8.0 Hz, 1H), 7.18-7.22 (m, 1H). MS 199 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH:25]([F:27])[F:26])[CH:19]=2)[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[C:20]([CH:25]([F:27])[F:26])[CH:19]=2)[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCCCCBr
Reactant: CC(C)(C)OC(=O)NC1(CCc2ccc(O)c(C(F)F)c2)COC(C)(C)OC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCOc1ccc(CCC2(NC(=O)OC(C)(C)C)COC(C)(C)OC2)cc1C(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compound 30-4 (600 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (412 mg) and 1-bromooctane (0.311 ml) were added, and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:1-3:1) to give the object product (230 mg) as a colorless oil.
Reaction SMILES: C(O)(=O)/C=C/C(O)=O.[NH2:9][C:10]([CH3:21])([CH3:20])[C:11]([NH:13][CH2:14][CH2:15][O:16][N+:17]([O-:19])=[O:18])=[O:12].CO.O.[O-:25][C:26]#[N:27].[K+]>C(O)(=O)C>[NH2:27][C:26]([NH:9][C:10]([CH3:21])([CH3:20])[C:11]([NH:13][CH2:14][CH2:15][O:16][N+:17]([O-:19])=[O:18])=[O:12])=[O:25]
Reactant: N#C[O-]
Reactant: CC(C)(N)C(=O)NCCO[N+](=O)[O-]
Agent: O=C(O)/C=C/C(=O)O
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(NC(N)=O)C(=O)NCCO[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.77 g. 2-Amino-2-methyl-N-(2-nitroxyethyl)-propionic acid amide fumarate is dissolved in 7.5 ml. methanol and 2.5 ml. water and 0.81 g. potassium cyanate added thereto. The reaction mixture is stirred for 10 minutes at ambient temperature and then 0.30 g. acetic acid added thereto. After stirring overnight, the inorganic salts are precipitated out by the addition of 25 ml. ethyl acetate and filtered off with suction. The filtrate is dried over anhydrous sodium sulphate, filtered with suction and evaporated, 0.60 g. of crude product being obtained. This is triturated with diethyl ether and filtered off with suction. There is obtained 0.40 g. of the title compound, i.e. 68% of theory; m.p. 98°-100° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[CH:3]=1.[N+:13]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)([O-:15])=[O:14].C([O-])([O-])=O.[Na+].[Na+].ClCCl>C1(C)C=CC=CC=1.CCOC(C)=O.O.O1CCOCC1>[CH3:12][C:4]1[CH:3]=[C:2]([C:19]2[CH:20]=[CH:21][C:16]([N+:13]([O-:15])=[O:14])=[CH:17][CH:18]=2)[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Reactant: COC(=O)c1ccc(Br)cc1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1C
Temperature: 25 °C
Yield: 111.4 %

Procedure:
To a solution of methyl 4-bromo-2-methylbenzoate (1.00 g, 4.37 mmol) and 4-nitrophenylboronic acid (2.91 g, 17.5 mmol) in toluene (12 mL) was added Na2CO3 (3.70 g, 34.9 mmol), 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride complex with dichloromethane (0.71 g, 0.87 mmol), 1,4-dioxane (6 mL), and water (6 mL). The mixture was heated at reflux for 3 h and then allowed to cool to rt. The mixture was diluted with EtOAc and water, and the organic layer was isolated, dried over MgSO4, and concentrated in vacuo. The material was purified by column chromatography (25% EtOAc in hexanes), yielding 1.32 g (89%) of the title compound. GC/MS m/z 271 (M+); retention time 13.00 min. 1H NMR (400 MHz, CD2Cl2) 2.65 (s, 3H), 3.95 (s, 3H), 7.52 (d, 2H), 7.78 (d, 2H), 8.11 (d, 1H), 8.30-8.39 (m, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:21]1[N:22]=[C:23]([C:30]([C:32]2[CH:33]=[C:34]3[C:39](=[CH:40][CH:41]=2)[N:38]([CH3:42])[C:37](=[O:43])[N:36]([CH2:44][C:45]2[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=2)[C:35]3=[O:52])=[O:31])[N:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=12>O.CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:51][C:48]1[CH:49]=[CH:50][C:45]([CH2:44][N:36]2[C:35](=[O:52])[C:34]3[C:39](=[CH:40][CH:41]=[C:32]([C:30]([C:23]4[N:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]5=[C:21]([C:3]5[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=5)[N:22]=4)=[O:31])[CH:33]=3)[N:38]([CH3:42])[C:37]2=[O:43])=[CH:46][CH:47]=1
Reactant: OB(O)c1cccnc1
Reactant: Cn1c(=O)n(Cc2ccc(F)cc2)c(=O)c2cc(C(=O)c3nc(Br)c4ccccn34)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)n(Cc2ccc(F)cc2)c(=O)c2cc(C(=O)c3nc(-c4cccnc4)c4ccccn34)ccc21
Temperature: 150 °C
Yield: 87.9 %

Procedure:
0.04 g (0.32 mmol) of 3-pyridylboronic acid, 0.2 g (0.81 mmol) of potassium phosphate dihydrate dissolved in 0.29 ml of water, and 6.2 mg (0.01 mmol) of tetrakis(triphenylphosphine)palladium are added to 0.15 g (0.27 mmol) of 6-[(1-bromoimidazo[1,5-a]pyridin-3-yl)carbonyl]-3-(4-fluorobenzyl)-1-methylquinazoline-2,4(1H,3H)-dione in 3 ml of DMF under an inert argon atmosphere. The reaction medium is microwave-heated at 150° C. for 20 minutes. After filtration over talc, the reaction medium is concentrated under reduced pressure. The residue obtained is purified by silica gel column chromatography, elution being carried out with a dichloromethane/methanol (95/5) mixture. 0.12 g of a yellow solid is obtained.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9](O)(O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].Cl.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:26])[NH:24][NH2:25])=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23](=[O:26])[NH:24][N:25]=[C:9]2[C:10](=[O:11])[C:4]3[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=3)[C:7]2=[O:8])=[CH:20][CH:21]=1
Reactant: NNC(=O)Nc1ccc(Cl)cc1
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Agent: Cl
Product: O=C(NN=c1c(=O)c2ccccc2c1=O)Nc1ccc(Cl)cc1

Procedure:
ninhydrin, 4-(4-chlorophenyl)-semicarbazide hydrochloride
Reaction SMILES: [CH3:1][N:2]([CH2:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[CH2:3][C:4]1[O:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[N:5]=1.[Cl:22][C:23]([Cl:30])([Cl:29])[CH2:24][O:25][C:26](Cl)=[O:27]>>[Cl:22][C:23]([Cl:30])([Cl:29])[CH2:24][O:25][C:26]([N:19]1[CH2:20][CH2:21][CH:16]([CH2:15][N:2]([CH3:1])[CH2:3][C:4]2[O:8][N:7]=[C:6]([C:9]3[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=3)[N:5]=2)[CH2:17][CH2:18]1)=[O:27]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CN(Cc1nc(-c2ccncc2)no1)CC1CCNCC1
Product: CN(Cc1nc(-c2ccncc2)no1)CC1CCN(C(=O)OCC(Cl)(Cl)Cl)CC1

Procedure:
The tert-butoxycarbonyl group of 4-{[methyl(3-pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethyl)amino]methyl}piperidine-1-carboxylic acid tert-butyl ester (Example 124) was removed using the procedure described in Example 51 to afford methylpiperidin-4-ylmethyl-(3 pyridin yl-[1,2,4]oxadiazol-5-ylmethyl)amine: RT=0.75 min; m/z (ES+)=288.0 [M+H]+. Derivatisation of methylpiperidin-4-ylmethyl-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethyl)amine with 2,2,2-trichloroethylchloroformate, using the procedure described for Example 52, afforded the title compound: RT=3.51 min; m/z (ES+)=461.9 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10](=O)[CH3:11])[CH:5]=[CH:6][C:7]=1[F:8].[NH2:13][C:14]1[C:19]([CH:20]=O)=[CH:18][N:17]=[C:16]([Cl:22])[CH:15]=1.[OH-].[K+]>CCO.[Cl-].[Na+].O>[Cl:22][C:16]1[CH:15]=[C:14]2[C:19]([CH:20]=[C:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([CH:3]=3)[NH2:1])[C:10]([CH3:11])=[N:13]2)=[CH:18][N:17]=1
Reactant: Nc1cc(Cl)ncc1C=O
Reactant: CC(=O)Cc1ccc(F)c(N)c1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1nc2cc(Cl)ncc2cc1-c1ccc(F)c(N)c1
Temperature: 25 °C
Yield: 60.3 %

Procedure:
Heat a solution of 1-(3-amino-4-fluorophenyl)propan-2-one (0.34 g, 2.034 mmol), 4-amino-6-chloronicotinaldehyde (0.318 g, 2.034 mmol) and KOH (0.057 g, 1.017 mmol) in EtOH (12 mL) at 60° C. for 1 h. Cool the mixture to RT, add brine and extract with EtOAc (3×). Dry the combined organics over MgSO4, concentrate to dryness and purify via silica gel chromatography (EtOAc/Hex) to afford the title compound (353 mg, 60%). MS (ESI) m/z: 288.1 (M+H+).
Reaction SMILES: C([Si]1(C(C)C)[O:11][C@H:10]2[CH2:12][C@H:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][C@@H:9]2[CH2:8][O:7][Si](C(C)C)(C(C)C)O1)(C)C.O.[F-].C([N+](CC)(CC)CC)C>O1CCCC1>[OH:11][C@@H:10]1[C@@H:9]([CH2:8][OH:7])[CH2:14][C@@H:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])[CH2:12]1
Reactant: CC(C)[Si]1(C(C)C)OC[C@H]2C[C@@H](NC(=O)OC(C)(C)C)C[C@@H]2O[Si](C(C)C)(C(C)C)O1
Agent: CC[N+](CC)(CC)CC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H](CO)[C@@H](O)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (-)-(6aR, 8R, 9aS)-tert-butyl N-(hexahydro-2,2,4,4-tetraisopropylcyclopenta [f]-1,3,5,2,4-trioxadisilocin-8-yl)carbamate(74.32 g, 0.1569 mol, corresponding to the first portion of product in the above Example) in tetrahydrofuran (300 mL) was added tetraethyl ammonium fluoride hydrate (24.62 g, about 0.15 mol, Aldrich). The lumps of solid were broken up, the mixture was degassed (nitrogen), then refluxed for 45 minutes. After cooling to room temperature, the reaction mixture was applied to a column of silica gel (200 g) and eluted with tetrahydrofuran (3 L). The eluate was concentrated under vacuum to an amber oil, which was taken up in hexanes (150 mL). Crystallization began spontaneously, and was allowed to continue at -5° for two days. The crystals of crude title compound were collected by filtration, washed sparingly with 10% ethyl acetate-hexanes, and dried by suction to constant weight (25.08 g, 0.1084 mol). The procedure was repeated on the second portion of product from the above Example (73.82 g, 0.1558 mol), giving additional crude title compound (27.28 g, 0.1180 mol). The two portions of crude title compound were combined and recrystallized from boiling ethyl acetate (250 mL), giving white crystals of the title compound (46.67 g., 0.2018 mol, 53.7% of theoretical from the triol product of Example 5) having the following characteristics: m.p. 126-127.9° C.; 1H-NMR (DMSO-d6), δ: 6.75 (dr d, J=7.8 Hz, 1H, NH), 4.49 (t, J=4.5 Hz, CH2OH) overlapping 4.47 (d,J=4.3 Hz, CHOH) with total integration of 2H, 3.80-3.93 (m, 2H, CHN and CHOH), 3.34 (m, w1/2=20 Hz, CH2OH), 2.25 (dt, 1H, CHCH2), 1.79-1.63 (m, 2H, CH2CHOH), 1.63-1.50 (m, 1H, 1/2CH2), 1.38 (s, 9H, C(CH3)3), 1.11-0.96 (m, 1H, 1/2CH2); Cl-MS (CH4): 232(M+1).
Reaction SMILES: C([CH:3]([C:7](=[O:11])[CH:8]([CH3:10])[CH3:9])[C:4]([OH:6])=[O:5])C.Cl.[Cl-].[Na+]>[OH-].[Na+]>[CH3:9][CH:8]([CH3:10])[C:7](=[O:11])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CCC(C(=O)O)C(=O)C(C)C
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Product: CC(C)C(=O)CC(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.5 %

Procedure:
Ethyl isobutyrylacetic acid (21 g, 132 mmol) was taken up in a 1.5M sodium hydroxide solution (15 g in 250 mL water) and stirred at room temperature over 16 h. The solution was cooled to 0° C. in an ice bath and was then acidified with 35 mL conc. Hydrochloric acid to pH 1-2. The resulting solution was saturated with sodium chloride and was then extracted with ethyl acetate (3×300 mL). The combined extracts were dried over sodium sulfate and then filtered and concentrated in vacuo to give the title compound as a clear oil (16.4 g, 95%).
Reaction SMILES: CC(CC1C=CC=CC=1)(C=CC)C=O.[CH:15]([C:19]([CH2:27]C)([CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[CH:20]=[O:21])=[CH:16][CH2:17]C.C(C(CC)(C=CCC)C=O)C1C=CC=CC=1.C(C(=CCCCCCC)C=O)C=C(C)C>>[CH3:27][C:19]([CH:15]=[CH:16][CH3:17])([CH2:22][CH:23]=[C:24]([CH3:25])[CH3:26])[CH:20]=[O:21]
Reactant: CCC=CC(C=O)(CC)CC=C(C)C
Agent: CC=CC(C)(C=O)Cc1ccccc1
Agent: CCC=CC(C=O)(CC)Cc1ccccc1
Agent: CCCCCCC=C(C=O)CC=C(C)C
Product: CC=CC(C)(C=O)CC=C(C)C

Procedure:
2-methyl-2-benzyl-pent-3-enal; 2-prenyl citral; 2-butenyl-2-ethyl-5-methyl hex-4-enal; 2-benzyl-2-ethyl-hex-3-enal; and 2-prenyl non-2-enal imparts a decided green, citrus, fruity, floral note, enhancing the orange note of this orange terpeneless perfume formulation.
Reaction SMILES: [CH:1]1([C:7]([N:9]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][C:34]([F:37])([F:36])[F:35])[CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=3[O:25][CH3:26])[CH2:14][CH2:13]2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.NC1C=CC=CC=1N(C(C1CCCCC1)=O)CCN1CCN([C:54]2C=CC=C[C:55]=2[O:60]C)CC1>>[CH:1]1([C:7]([N:9]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][C:34]([F:36])([F:37])[F:35])[CH2:10][CH2:11][N:12]2[CH2:13][CH2:14][N:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:55](=[O:60])[CH3:54])=[CH:20][C:19]=3[O:25][CH3:26])[CH2:16][CH2:17]2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(N)ccc1N1CCN(CCN(C(=O)C2CCCCC2)c2ccccc2OC(F)(F)F)CC1
Reactant: COc1ccccc1N1CCN(CCN(C(=O)C2CCCCC2)c2ccccc2N)CC1
Product: COc1cc(NC(C)=O)ccc1N1CCN(CCN(C(=O)C2CCCCC2)c2ccccc2OC(F)(F)F)CC1
Reaction time: 20 h

Procedure:
The title compound was synthesized according to the procedure reported in example 28 but substituting the compound of example 56 for the compound of example 27 and stirring for 20 h. The residue was purified by flash chromatography (CHCl3-2 N methanolic NH3 100:3) affording the title compound as a vitreous pink solid. Yield: 77%.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=O.C(Cl)(=O)C(C)(C)C.C([O:21][C:22](=[O:30])[C@H:23]([CH2:25][CH2:26][C:27](=[O:29])[NH2:28])[NH2:24])(C)(C)C>>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:24][C@H:23]([C:22]([OH:30])=[O:21])[CH2:25][CH2:26][C:27](=[O:29])[NH2:28])=[O:9]
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: CC(C)(C)OC(=O)[C@@H](N)CCC(N)=O
Agent: CC(C)(C)C(=O)Cl
Product: NC(=O)CC[C@H](NC(=O)[C@@H]1CCC(=O)N1)C(=O)O

Procedure:
A mixed anhydride from L-pyroglutamic acid 9 and pivaloyl chloride was coupled with L-glutamine t-butyl ester 10 followed by acidic workup to yield L-pyroglutamyl-L-glutamine 7 (Equation 2). This dipeptide was purified by reversed phase HPLC using a gradient system of acetonitrile/H2O.
Reaction SMILES: [Cl:1][C:2]1[C:13]2[C:12](=[O:14])[N:11]([CH:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[C:10](=[O:22])[C:9]=2[CH:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:23]1[C:24](=[O:43])[NH:25][CH:26]=[CH:27][C:28]=1NCC(O)COC1C=CC(C)=CC=1C)[NH:6]2.[CH3:44][CH:45]([NH2:52])[CH2:46][C:47]1[S:48][CH:49]=[CH:50][CH:51]=1.CCN(CC)CC>CCO>[Cl:1][C:2]1[C:13]2[C:12](=[O:14])[N:11]([CH:15]3[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]3)[C:10](=[O:22])[C:9]=2[CH:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:23]1[C:24](=[O:43])[NH:25][CH:26]=[CH:27][C:28]=1[NH:52][CH:45]([CH3:44])[CH2:46][C:47]1[S:48][CH:49]=[CH:50][CH:51]=1)[NH:6]2
Reactant: Cc1ccc(OCC(O)CNc2cc[nH]c(=O)c2-c2nc3c(Cl)c4c(cc3[nH]2)C(=O)N(C2CCN(C)CC2)C4=O)c(C)c1
Reactant: CC(N)Cc1cccs1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(Cc1cccs1)Nc1cc[nH]c(=O)c1-c1nc2c(Cl)c3c(cc2[nH]1)C(=O)N(C1CCN(C)CC1)C3=O

Procedure:
4-Chloro-2-{4-[3-(2,4-dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione (18 mg, 0.04 mmol), 1-methyl-2-thiophen-2-yl-ethylamine (8.5 mg, 0.06 mmol) and Et3N (0.2 mL, 1.43 mmol) in EtOH (1.0 mL) was heated at 80° C. for 17 h and then concentrated to result a residue which was subjected to HPLC purification to furnish the title compound in TFA salt form (6.73 mg, 25%). 1H NMR (DMSO-d6) δ 1.36 (d, J=6 Hz, 3H, CH3), 1.95 (m, 2H), 2.52 (m, 2H), 2.74 (s, 3H, CH3), 3.02-3.22 (4H), 3.45 (m, 2H), 4.08 (m, 1H), 4.28 (m, 1H), 6.19 (d, J=8 Hz, 1H), 6.89 (m, 1H), 7.00 (m, 1H), 7.29 (m, 1H), 7.39 (m, 1H), 8.09 (s, 1H), 11.01 (d, J=8 Hz, 1H), 11.35 (d, J=6 Hz, 1H); ESI-MS m/z 551.3 (MH+).
Reaction SMILES: C(OC(CCCCCCN1C(CCCCCCCC)C(=O)NC1=O)=O)C.[CH2:27]([N:31]1[C:35](=[O:36])[CH:34]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[N:33]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][C:51]([O:53]CC)=[O:52])[C:32]1=[O:56])[CH2:28][CH2:29][CH3:30]>>[CH2:27]([N:31]1[C:35](=[O:36])[CH:34]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[N:33]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][C:51]([OH:53])=[O:52])[C:32]1=[O:56])[CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCC1C(=O)N(CCCC)C(=O)N1CCCCCCC(=O)OCC
Agent: CCCCCCCCC1C(=O)NC(=O)N1CCCCCCC(=O)OCC
Product: CCCCCCCCC1C(=O)N(CCCC)C(=O)N1CCCCCCC(=O)O

Procedure:
By the method of Example 92, 1-(6-ethoxycarbonylhexyl)-5-octylhydantoin was converted into 3-butyl-1-(6-ethoxycarbonylhexyl)-5-octylhydantoin, which was hydrolysed to give 3-butyl-1-(6-carboxyhexyl)-5-octylhydantoin as a colourless oil.
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:19])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[N:6][CH:5]=1.[OH-].[Na+].O.Cl>CO>[CH3:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]([NH:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:20])=[O:2])=[CH:5][N:6]=1)=[O:19]
Reactant: COC(=O)c1ccc(NC(=O)c2ccccc2C)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)O)cn1
Yield: 105.5 %

Procedure:
To a solution of 6-(2-methylbenzoylamino)nicotinic acid methyl ester (2.1 g) in methanol (30 ml) is added 5% aqueous sodium hydroxide solution (24 ml), and the mixture is refluxed for two hours. To the reaction solution is added water, and the mixture is made weak acidic with 1N aqueous hydrochloric acid solution, and then, extracted with diethyl ether. The extract is dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent to give 6-(2-methylbenzoylamino)nicotinic acid (2.1 g) as white powder.