Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7](C2C=CC=CC=2)[NH:8][C:9]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14](=[O:21])[N:13]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:12]=2[CH3:28])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:36]([O:38][CH3:39])=[O:37]>ClCCCl>[CH3:39][O:38][C:36]([N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[NH:8][C:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[N:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:12]=1[CH3:28])=[O:10])=[O:37]
Reactant: COC(=O)Cl
Reactant: Cc1c(C(=O)NN(c2ccccc2)c2ccccc2)c2ccccc2c(=O)n1-c1ccccc1
Solvent: ClCCCl
Product: COC(=O)N(NC(=O)c1c(C)n(-c2ccccc2)c(=O)c2ccccc12)c1ccccc1
Temperature: 100 °C
Yield: 34.2 %

Procedure:
A mixture of 3-methyl-1-oxo-2-phenyl-1,2-dihydro-isoquinoline-4-carboxylic acid N′-phenyl-hydrazide (5a, 490 mg, 1.3 mmol) and methyl chloroformate (0.6 ml, 8 mmol) in 1,2-dichloroethane (10 ml) was heated under microwave irradiation for 10 min at 100° C. Volatiles were removed in vacuo and the product was purified by flash chromatography (SiO2, gradient heptane-1:1 ethyl acetate/heptane) to give 190 mg of solid. LC-MS (m/z) 428.8 (MH+); tR=1.22.
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH2:12][CH3:13])[CH:5]([CH3:11])[CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9].[OH:14][C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][CH2:21][O:22]2)=[CH:17][CH:16]=1>>[CH2:12]([C:4]([CH:5]([CH3:11])[CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])=[CH:3][CH2:2][O:14][C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][CH2:21][O:22]2)=[CH:17][CH:16]=1)[CH3:13]
Reactant: CCC(=CCBr)C(C)CC=C(C)C
Reactant: Oc1ccc2c(c1)OCCC2
Product: CCC(=CCOc1ccc2c(c1)OCCC2)C(C)CC=C(C)C

Procedure:
Following the procedure of Example 1, 1-bromo-3-ethyl-4,7-dimethyl-2,6-octadiene and 7-hydroxy-chromane are reacted to form 7-(3-ethyl-4,7-dimethyl-2,6-octadienyloxy)-chromane, nD20 = 1.5286.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:15]I)[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[NH2:21].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[Zn]>[NH2:21][C:20]1[CH:19]=[CH:18][C:24]([O:25][CH3:26])=[C:23]([CH2:15][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:22]=1
Reactant: COc1ccc(N)cc1I
Reactant: COC(=O)C[C@H](CI)NC(=O)OC(C)(C)C
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: [Zn]
Product: COC(=O)C[C@H](Cc1cc(N)ccc1OC)NC(=O)OC(C)(C)C
Yield: 66 %

Procedure:
Following the General Procedure of Description 15 (Part A), the zinc insertion product of (5c) was used in situ to cross couple with commercial 3-iodo-4-methoxy-aniline (249 mg, 1.0 mmol) in the presence of tris(benzylideneacetone)dipalladium (Pd2(dba)3) (23 mg, 0.025 mmol, 2.5 mol-%) and tris(o-tolyl)phosphine (P(o-tol)3) (30 mg, 0.10 mmol, 10 mol-%) in anhydrous degassed DMF (3 mL). Filtration, aqueous work-up, and purification by silica gel column chromatography with ethyl acetate (EtOAc)/hexane and dichloromethane(DCM)/EtOAc mixtures (EtOAc/hexane=1:1, v/v→DCM/EtOAc=1:1, v/v) furnished ˜280 mg (66% yield; ˜80% purity by AUC) of the title compound (7a) as a yellow viscous oil. Rf˜0.23 (EtOAc/hexane=1:1, v/v). 1H NMR (300 MHz, CDCl3): δ 6.90 (br s, 1H), 6.78 (br. d, J=8.1 Hz, 1H), 6.70 (d, J=8.7 Hz, 1H), 5.28 (br. d, J=8.1 Hz, 1H), 4.40-4.10 (m, 1H), 3.37 (s, 3H), 2.90-2.80 (br. m, 1H), 2.75 (dd, J=12.6, 6.3 Hz, 1H), 2.50 (d, J=5.1 Hz, 2H), 1.35 (s, 9H) ppm. LC/MS: Rt=0.908 min; ESI (pos.) m/z=339.15 (M+H+)+, 677.40 (2M+H+)+, 699.35 (2M+Na+)+.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[N:8]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:7]=1.[NH2:21][C:22]1[N:27]=[CH:26][C:25]([N:28]2[C:32](=[O:33])[CH2:31][C:30]3([CH2:39][CH:38]4[N:40]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH:35]([CH2:36][CH2:37]4)[CH2:34]3)[CH2:29]2)=[CH:24][CH:23]=1>>[CH:16]1([N:8]2[C:6]3[N:7]=[C:2]([NH:21][C:22]4[N:27]=[CH:26][C:25]([N:28]5[C:32](=[O:33])[CH2:31][C:30]6([CH2:34][CH:35]7[N:40]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH:38]([CH2:37][CH2:36]7)[CH2:39]6)[CH2:29]5)=[CH:24][CH:23]=4)[N:3]=[CH:4][C:5]=3[CH:10]=[C:9]2[C:11](=[O:12])[N:13]([CH3:15])[CH3:14])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC1(CC(=O)N(c3ccc(N)nc3)C1)C2
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CC5(CC4=O)CC4CCC(C5)N4C(=O)OC(C)(C)C)cn3)nc2n1C1CCCC1
Yield: 72.3 %

Procedure:
Following general N—C coupling procedure 1, 2-chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (162 mg, 0.55 mmole) was combined with tert-Butyl 1′-(6-aminopyridin-3-yl)-5′-oxo-8-azaspiro[bicyclo[3.2.1]octane-3,3′-pyrrolidine]-8-carboxylate (150 mg, 0.55 mmole) which gave tert-butyl 1′-(6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)-5′-oxo-8-azaspiro[bicyclo[3.2.1]octane-3,3′-pyrrolidine]-8-carboxylate (250 mg) in 86% yield. 1H NMR (400 MHz, CD2Cl2) δ 8.76 (s, 1H), 8.56-8.49 (m, 1H), 8.41 (s, 1H), 8.08-7.99 (m, 2H), 6.49 (s, 1H), 4.88-4.77 (m, 1H), 4.31 (s, 2H), 3.62-3.49 (m, 2H), 3.14 (s, 6H), 2.82 (s, 2H), 2.65-2.51 (m, 2H), 2.16-1.53 (m, 14H), 1.49 (s, 9H)
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[CH:10]=[C:11]([N+:15]([O-])=O)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[C].[Pd]>[C:1]1([CH2:7][CH2:8][C:9]2[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=2)[NH2:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1cccc(/C=C/c2ccccc2)c1
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(CCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
A mixture of 3-bromonitrobenzene (1 g), styrene (1.7 mL), palladium(II) acetate (95 mg), tris(2-methylphenyl)phosphine (0.3 g) and N,N-diisopropylamine (5 mL) was heated for reflux for 24 hours. The reaction mixture was diluted with diethyl ether, and the resulting mixture was washed with 1 mol/L hydrochloric acid, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate =10/1) to give 3-((E)-2-phenylvinyl)nitrobenzene (0.76 g). To the solution of the obtained 3-((E)-2-phenylvinyl)nitrobenzene (0.26 g) in methanol (10 mL) was added 10% palladium-carbon powder (50 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (0.22 g).
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[CH:5](=O)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C([BH3-])#N.[Na+].Cl>O.CO>[CH2:1]([NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH:2]=[CH2:3]
Reactant: C=CCN
Reactant: CCCCCCC=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C=CCNCCCCCCC

Procedure:
To 100 mL of methanol is added 2-propenylamine (5.7 g, 0.1 mol), 11.4 g (0.1 mol) of heptaldehyde, and 12 g (0.2 mol) of sodium cyanoborohydride. The pH is adjusted to six with concentrated HCl. Monitor the reaction by thin-layer chromatography. Upon completion, add concentrated HCl until gas evolution ceases. Add 300 mL of H2O and extract once with 200 mL of ether. Add 1N NaOH to the aqueous solution until it is basic and extract twice with 200 mL of ether. Dry the organic phase over Na2SO4. Filter off the drying agent and evaporate the solvent in vacuo to obtain the title compound.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:9]=[C:8]2[C:4]=1[N:5]=[C:6](OC)[N:7]2[CH2:17][CH:18]1[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]1>O1CCOCC1.CO>[ClH:1].[CH2:13]([O:12][C:10]1[N:9]=[C:8]2[C:4]([N:5]=[CH:6][N:7]2[CH2:17][CH:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]2)=[C:3]([NH2:2])[N:11]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CC3CCN(C(=O)OC(C)(C)C)CC3)c2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCCCOc1nc(N)c2ncn(CC3CCNCC3)c2n1
Reaction time: 4.5 h

Procedure:
4N hydrogen chloride in dioxane (5.3 mL) was added to a solution of 1,1-dimethylethyl 4-{[6-amino-2-(butyloxy)-8-(methyloxy)-9H-purin-9-yl]methyl}-1-piperidinecarboxylate (630 mg) in methanol (16 mL). After 4.5 hours at room temperature, the reaction mixture was concentrated and dried under high vacuum.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][NH:18][S:19]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)(=[O:21])=[O:20])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:28](Cl)(=[O:30])[CH3:29]>ClCCl>[CH:22]1([S:19]([NH:18][CH2:17][CH2:16][CH2:15][CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:4]3[CH:3]=[C:2]([NH:1][C:28](=[O:30])[CH3:29])[CH:7]=[CH:6][CH:5]=3)[CH2:9][CH2:10]2)(=[O:21])=[O:20])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: Nc1cccc(N2CCN(CCCCNS(=O)(=O)C3CCCCC3)CC2)c1
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)Nc1cccc(N2CCN(CCCCNS(=O)(=O)C3CCCCC3)CC2)c1

Procedure:
Reaction of cyclohexanesulfonic acid {4-[4-(3-amino-phenyl)-piperazin-1-yl]-butyl}-amide and acetyl chloride in dichloromethane as described in Example 3 gave the desired product, N-{3-[4-(4-Cyclohexanesulfonylamino-butyl)-piperazin-1-yl]-phenyl}-acetamide, as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].Cl[C:20]1[CH:21]=[CH:22][C:23]([N+:30]([O-:32])=[O:31])=[C:24]([CH:29]=1)[C:25]([O:27][CH3:28])=[O:26]>CS(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:5]=[CH:4][C:3]=1[O:12][C:20]1[CH:21]=[CH:22][C:23]([N+:30]([O-:32])=[O:31])=[C:24]([CH:29]=1)[C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Oc1ccc(C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 50 °C

Procedure:
To a flask fitted with a drying tube is charged DMSO (10 ml), 2-chloro-4-trifluoromethylphenol (3.93 g, 0.02 mole) and anhydrous potassium carbonate (2.76 g, 0.02 mole). Then methyl 5-chloro-2-nitrobenzoate (4.3 g, 0.02 mole) is added and the reaction mixture warmed to 50° C. for 3 hours. (Gas-liquid chromatography analysis suggested a low conversion to desired product.) The temperature is raised to 60° C. for 16 hours and then to 70° C. for 16 hours. Additional potassium carbonate (1.38 g, 0.01 mole) is added and heating at 70° C. is continued for an additional 5 days, the reaction mixture is cooled to room temperature, poured into a benzene/hexane cosolvent and extracted twice with water. The organic layer is dried with anhydrous sodium sulfate, filtered and the solvent removed under vacuum (110° C., 0.1 mm) to afford 2.0 g, (27% yield) of methyl 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoate which is determined by spectral data to be identical with the product of Example 1B.
Reaction SMILES: [O:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[CH:2]1.C(Cl)(=O)C(Cl)=O.[N-:15]=[N+:16]=[N-:17].[Na+]>CN(C=O)C.C(Cl)Cl.O.CCOC(C)=O>[O:1]1[CH:5]=[C:4]([C:6]([N:15]=[N+:16]=[N-:17])=[O:8])[N:3]=[CH:2]1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)c1cocn1
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NC(=O)c1cocn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
In a 10-mL round bottom flask under N2 were dissolved 4-oxazolecarboxylic acid (500 mg, 4.42 mmol) and oxalyl chloride (1.94 mL, 22.1 mmol) with 2 drop of DMF in 10 mL of DCM. The reaction was stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure and the material was carried forward crude. Under N2, oxazole-4-carbonyl chloride (crude) was dissolved in 10 mL of acetone and treated at 0° C. with a solution of sodium azide (575 mg, 8.84 mmol) in 1.0 mL of water. After 1 h, the reaction mixture was diluted with AcOEt then neutralized with H2O. The aqueous phase was extracted 3× with AcOEt then the organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude oxazole-4-carbonyl azide (590 mg, 4.27 mmol, 97% yield) was carried forward without further purification into the next step. MS (ESI, positive ion) [M+1]+: 139.0.
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][C:3]1[C:4](=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:5]([OH:7])=[O:6].[CH2:14]([O:21][C:22]([NH:24][CH2:25][CH2:26][CH2:27]O)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1C=CC=CC=1.OS(O)(=O)=O>[C:5]([C:4]1[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=1[CH2:2][C:1]([O:13][CH2:27][CH2:26][CH2:25][NH:24][C:22]([O:21][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:23])=[O:12])([OH:7])=[O:6]
Reactant: O=C(O)Cc1ccccc1C(=O)O
Reactant: O=C(NCCCO)OCc1ccccc1
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: O=C(Cc1ccccc1C(=O)O)OCCCNC(=O)OCc1ccccc1
Yield: 88.9 %

Procedure:
Homophthalic acid (18 g, 0.1 mole) and 3-(benzyloxycarbonylamino)-1-propanol (41 g, 0.2 mole) were heated in 150 ml of benzene at 120°-130° C. for 2 hrs in the presence of a few drops of conc. H2SO4. Benzene was evaporated, and 200 ml of ethylacetate was added. The organic solution was washed with 4% NaHCO3 twice (150 ml×2). The aqueous layer which contained the monoester salt was acidified with 5N HCl and extracted with ethylacetate. 33 g of 3-(benzyloxycarbonylamino)propyl 2-carboxyphenylacetate (yield, 89%) was obtained after the solvent was evaporated. Hydrogenation of this monoester (1.86 g, 5 mmole) was performed in methanol containing 0.3 ml of acetic acid and 10% palladium on carbon to give 1 g of 3-aminopropyl 2-carboxphenylacetate.HAc (yield, 67%). This compound was identified by its NMR spectrum and TLC (Butanol:acetic acid:pyridine:water=4:1:1:2). 2 g of 3-aminopropyl 2-carboxyphenylacetate.HAc (3 mmole) was heated with 1.6 g of PCl5 (7.5 mmole) in 50 ml of anhydrous THF at 70°-80° for 2 hrs, a white precipitate formed. This white solid was purified by column chromatography (methylene chloride:methanol=5:1) and crystalline from MeOH-ether to give 0.2 g of 3-(3-aminopropoxy)isocoumarin.HCl (yield, 26%), m.p. 173°-174° C.; mass spectrum, m/e=220 (M + -Cl). Anal. Calc. for C12H14N1O3Cl1 : C, 56.37; H, 5.52; N, 5.48; Cl, 13.87. Found: C, 56.15; H, 5.49; N, 5.44; Cl 13.95.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[C:10]([C@@H:12]([NH:16][C:17]([C:19]2[C:20]3[CH:27]=[N:26][N:25]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[C:21]=3[CH:22]=[N:23][CH:24]=2)=[O:18])[CH2:13][CH:14]=[CH2:15])[CH:9]=[CH:8][N:7]=1)(=[O:5])=[O:4])[CH3:2]>CO.[Pd]>[CH2:1]([S:3]([C:6]1[CH:11]=[C:10]([C@@H:12]([NH:16][C:17]([C:19]2[C:20]3[CH:27]=[N:26][N:25]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[C:21]=3[CH:22]=[N:23][CH:24]=2)=[O:18])[CH2:13][CH2:14][CH3:15])[CH:9]=[CH:8][N:7]=1)(=[O:4])=[O:5])[CH3:2]
Reactant: C=CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(S(=O)(=O)CC)c1
Agent: [Pd]
Solvent: CO
Product: CCC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(S(=O)(=O)CC)c1
Reaction time: 0.33 h

Procedure:
A solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid [(S)-1-(2-ethanesulfonyl-pyridin-4-yl)-but-3-enyl]-amide (136 mg, 0.284 mmol) in MeOH (30 mL) was hydrogenated over 10% Pd/C using a continuous flow hydrogenation apparatus (conditions: full H2 mode, flow rate 1 mL/minute, 30° C., 1 atmosphere). The solution was concentrated in vacuo and purified by reversed-phase HPLC using a 20 minute gradient of 5-95% acetonitrile (0.1% TFA) in water (0.1% TFA) (flow rate=25 mL/min). The desired fractions were combined, neutralized with saturated aqueous sodium bicarbonate and extracted with dichloromethane (3×20 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to afford the title compound as an off white solid.
Reaction SMILES: [Na].[O-][Al]=O.[O-][Al]=O.[Ca+2].[O:9]=[C:10]([CH:12]=[C:13]([CH3:15])[CH3:14])[CH3:11].[CH3:16][C:17]([CH3:19])=O>>[O:9]=[C:10]1[CH2:11][C:17]([CH3:19])([CH3:16])[CH2:14][C:13]([CH3:15])=[CH:12]1
Reactant: CC(=O)C=C(C)C
Reactant: CC(C)=O
Agent: O=[Al][O-]
Agent: [Ca+2]
Agent: [Na]
Product: CC1=CC(=O)CC(C)(C)C1
Yield: 43 %

Procedure:
Numerous conventional, strongly basic heterogeneous catalysts such as magnesium and calcium hydroxide are known. For example, U.S. Pat. No. 2,183,127 describes the vapor phase condensation of acetone in the presence of CaO or Ca(OH)2 catalyst at 350° C. to 400° C. to give isophorone in 25% yield, U.S. Pat. No. 2,393,510 claims the vapor phase condensation of acetone over sodium or calcium aluminate at 424° C. and a liquid hourly space velocity of 0.35 hr.-1 to get 15% acetone conversion and a yield of about 43% isophorone, 32% mesityl oxide and 25% higher boiling products. The use of other bulk oxide and mixed oxide catalysts are described in several references for the condensation of acetone to isophorone, viz., U.S. Pat. No. 4,086,188; U.S. Pat. No. 4,165,339; U.S. Pat. No. 2,549,508; British Pat. No. 909,941; British Pat. No. 1,010,695 and U.S. Pat. No. 2,451,350. Only a few disclosures have been made for the use of Al2O3 or metal oxide(s) supported on Al2O3. These include U.S. Pat. No. 2,429,361; U.S. Pat. No. 2,425,096; U.S. Pat. No. 2,419,142 and H. J. Seebald et al. Archive der Pharmazie, 406, 305(6) (1972). However, the efficencies to a desired product, e.g., isophorone achievable by this process are barely satisfactory and far less satisfactory in respect to the acetone conversion achieved per pass. Also, the above heterogeneous catalyst when employed as vapor phase catalysts either require high temperature (350° to 400° C.), are of short life and/or tend to be fragile which provides a more expensive process. The co-precipitated mixed oxide catalysts have the drawback of exhibiting poor catalyst manufacturing reproducibility and are expensive.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C(=O)=O.CC(C)=O.[CH3:15][C@H:16]([NH:20][C:21](=[O:27])OC(C)(C)C)[C:17](=[O:19])[CH3:18].[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[OH:19][C@:17]1([CH3:18])[C@H:16]([CH3:15])[NH:20][C:21](=[O:27])[CH2:1]1
Reactant: CC(C)NC(C)C
Reactant: CC(=O)[C@H](C)NC(=O)OC(C)(C)C
Agent: O=C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: C[C@@H]1NC(=O)C[C@]1(C)O
Reaction time: 0.33 h
Yield: 48.9 %

Procedure:
A solution of diisopropylamine (3.44 g) in tetrahydrofuran (50 mL) was ice-cooled under a nitrogen atmosphere and 1.6 mol/L n-butyllithium-hexane solution (20.8 mL) was added. The mixture was stirred at the same temperature for 20 min, and the reaction solution was cooled with dry ice/acetone. Ethyl acetate (3.28 mL) was added to the reaction solution, and the mixture was stirred at the same temperature for 30 min. A solution of tert-butyl [(1S)-1-methyl-2-oxopropyl]carbamate (4.48 g) in tetrahydrofuran (10 mL) was added. The mixture was stirred at the same temperature for 5 hr, saturated aqueous ammonium chloride solution (100 mL) was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=0→30%), the obtained oil was dissolved in 4 mol/L hydrogen chloride-ethyl acetate solution (50 mL), and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated under reduced pressure, the residue was dissolved in tetrahydrofuran (150 mL), and diisopropylethylamine (11.5 mL) was added. The reaction solution was refluxed under heating for 4 hr, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methanol/ethyl acetate=0→10%), and the obtained solid was recrystallized from isopropanol/hexane to give the title compound as colorless crystals (yield: 1.51 g, 55%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:11][N:12]([CH:28]1[C:37]2[N:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH2:31][CH2:30][CH2:29]1)[CH2:13][CH2:14][CH2:15][CH2:16][N:17]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>C(O)C>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:11][N:12]([CH:28]1[C:37]2[N:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH2:31][CH2:30][CH2:29]1)[CH2:13][CH2:14][CH2:15][CH2:16][NH2:17]
Reactant: Cn1c(CN(CCCCN2C(=O)c3ccccc3C2=O)C2CCCc3cccnc32)nc2ccccc21
Agent: NN
Solvent: CCO
Solvent: O
Product: Cn1c(CN(CCCCN)C2CCCc3cccnc32)nc2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 32.2 %

Procedure:
To a solution of 2-{4-[(1-Methyl-1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyl}-isoindole-1,3-dione (0.1030 g, 0.21 mmol) in ethanol (1 mL) was added hydrazine monohydrate (0.51 mL, 10.5 mmol), and the reaction mixture was stirred at room temperature for 18 hours. The mixture was concentrated and purified first via column chromatography on silica gel (91:12:1 CH2Cl2-MeOH—NH4OH) and then by radial chromatography on silica (18:1:1 CH2Cl2-MeOH—NH4OH) to yield 0.0246 g (32%) of N1-(1-Methyl-1H-benzoimidazol-2-ylmethyl)-N1-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine. 1H NMR (CDCl3) δ 1.32-1.42 (m, 5H), 1.91-2.02 (m, 2H), 2.05-2.11 (m, 1H), 2.55 (t, 2H, J=6.9 Hz), 2.60-2.64 (m, 3H), 2.76-2.86 (m, 1H), 3.98 (s, 3H), 4.04-4.17 (m, 3H), 7.00-7.04 (m, 1H), 7.21-7.27 (m, 2H), 7.30-7.33 (m, 2H), 7.68-7.72 (m, 1H), 8.47 (d, 1H, J=3.3 Hz).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1[OH:18])[CH:2]=[CH2:3].[H][H]>C(OCC)(=O)C.[Pd]>[CH2:11]([O:10][C:8]1[CH:7]=[CH:6][C:5]([OH:18])=[C:4]([CH2:1][CH2:2][CH3:3])[CH:9]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C=CCc1cc(OCc2ccccc2)ccc1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1cc(OCc2ccccc2)ccc1O
Yield: 56 %

Procedure:
2-Allyl-4-benzyloxyphenol (WO 9728137 A1 19970807, Adams, A. D. et al.) (5.00 g, 20.8 mmol) in ethyl acetate (40 mL) is treated with 5% Pd/C (0.25 g) and hydrogen (1 atm) at ambient temperature for 18 h. The mixture is filtered and concentrated. The crude product is purified on a Biotage medium pressure chromatography system using a 40L normal phase cartridge and eluted with 10% ethyl acetate in hexanes to give a tan solid (2.8 g, 56%). Rf=0.33 (25% EtOAc/Hexanes); 1H NMR (400 MHz, CDCl3) δ 7.44-7.31 (m, 5H), 6.78 (s, 1H), 6.69 (d, J=1.5 Hz, 2H), 5.00 (s, 2H), 4.31 (s, 1H), 2.55 (t, J=7.6 Hz, 2H), 1.64 (q, J=7.5 Hz, 2H), 0.97 (t, J=7.3 Hz, 3H).
Reaction SMILES: S(Cl)(Cl)=O.[CH:5]([C:8]1[O:9][CH:10]=[C:11]([C:13]([OH:15])=O)[N:12]=1)([CH3:7])[CH3:6].[CH:16]1([NH2:19])[CH2:18][CH2:17]1.O>C1(C)C=CC=CC=1.CN(C)C=O.ClCCl>[CH:16]1([NH:19][C:13]([C:11]2[N:12]=[C:8]([CH:5]([CH3:6])[CH3:7])[O:9][CH:10]=2)=[O:15])[CH2:18][CH2:17]1
Reactant: CC(C)c1nc(C(=O)O)co1
Reactant: NC1CC1
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CC(C)c1nc(C(=O)NC2CC2)co1
Temperature: 80 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
At room temperature, 47.6 g (0.40 mol) of thionyl chloride was dripped into a solution of 31.0 g (0.20 mol) of 2-isopropyloxazole-4-carboxylic acid in 200 ml of toluene and 2 ml of dimethylformamide, and the mixture was stirred for one hour at 80° C. The solvents were stripped off under reduced pressure, the residue was dissolved in 300 ml of dichloromethane, and 24.0 g (0.42 mol) of cyclopropylamine in 20 ml of dichloromethane was dripped in at 0° to 10° C. The mixture was stirred for 12 hours at room temperature, 150 ml of water was added, the phases were separated, the organic phase was washed once with saturated sodium bicarbonate solution and dried over magnesium sulfate, and the solvent was removed under reduced pressure. There was obtained 37.2 g (96%) of 2-isopropyl-oxazole-4-carboxylic acid-cyclopropylamide.