Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-]CC.[Na+].[N:5](OCCC(C)C)=O.[NH2:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=1.[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[OH:31]>C(O)C.O>[CH3:20][C:19]1[C:14]([N:13]=[N:5][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][C:22]=2[OH:31])=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1cccnc1N
Reactant: CC(C)CCON=O
Reactant: Oc1ccc2ccccc2c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cccnc1N=Nc1c(O)ccc2ccccc12
Temperature: 25 °C

Procedure:
A reaction flask was loaded with ethanol (25 ml), sodium ethoxide (2.5 g), isopentyl nitrite (4.3 g), and 2-amino-3-methylpyridine (4 g), and they were mixed. The mixture was heated up to the reflux temperature of the solvent with stirring and stirred at the reflux temperature for 3 hours. Then, the heating was stopped and the mixture was cooled to room temperature with stirring. To this, 2-naphthol (3 g) dissolved in ethanol (5 ml) was dropwise added in 1.5 hours. The mixture was heated again and stirred at the reflux temperature for 4 hours. Then, the heating and stirring were stopped and the mixture was left to cool. The reaction mixture was filtrated to remove insoluble components, and the filtrate was condensed. Water was added little by little to the residue for crystallization. The filtrated crystals were put into metanol (20 ml). This was stirred for 30 minutes, followed by recrystallization. The crystals were dried to give intended crystals (1.5 g).
Reaction SMILES: [O:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=O)[CH2:2]1.[CH3:11][O:12][C:13](=[O:34])[CH:14]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:11][O:12][C:13](=[O:34])[CH2:14][C:3]1[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=2[O:1][CH:2]=1
Reactant: O=C1COc2ccccc21
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)Cc1coc2ccccc12
Reaction time: 5 h

Procedure:
A solution of 3-coumaranone (5.0 g, 37 mmol) and methyl(triphenylphosphoranylideneacetate) (13.5 g, 40 mmol) in toluene (70 mL) was heated to reflux for 25 hours. More toluene was added (50 mL), and after a further 5 hours, more methyl(triphenylphosphoranylideneacetate) (0.5 g, 1.5 mmol). After another 19 hours, a further 1.0 g (3.0 mmol) was added, and after a further 21 hours, the solvent was removed in vacuo. Column chromatography (heptane:ethyl acetate 4:1) gave the product as a brown oil, 33 mmol, 89%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1.[NH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[C:22]([O:21][C:20](=[O:26])[NH:19][CH2:18][CH2:17][NH:16][CH:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:10][CH2:11]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: COc1ccccc1N1CCC(=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccccc1N1CCC(NCCNC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 20 (186 mg, 0.906 mmol), 1 (153 mg, 0.955 mmol), and acetic acid (288 mg, 4.80 mmol) in methanol (1 mL) was treated with sodium cyanoborohydride (63 mg, 1.00 mmol) at room temperature. The resulting mixture was stirred at room temperature (2 h). The solvent was removed in vacuo and the residue dissolved in dichloromethane and sodium bicarbonate solution. The aqueous layer was extracted with two additional portions of dichloromethane and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. PCTLC (SiO2, 2 mm, 10% EtOH; 90% CHCl3) afforded the title compound (21).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[CH:20]=[CH2:21]>CN(C)C=O.O>[CH2:21]([O:12][C:3]1[CH:4]=[C:5]([C:8]([F:10])([F:11])[F:9])[CH:6]=[CH:7][C:2]=1[Cl:1])[CH:20]=[CH2:19]
Reactant: C=CCBr
Reactant: Oc1cc(C(F)(F)F)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1cc(C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 2-chloro-5-trifluoromethyl-phenol (10.00 g, 0.05 mol) in N,N-dimethylformamide (500 mL) was added potassium carbonate (28.12 g, 0.209 mol) followed by allyl bromide (7.38 g, 0.061 mol) and the reaction was allowed to stir at room temperature for 12 h. The reaction mixture was diluted with water (500 mL) to dissolve any solids and extracted with ethyl acetate (3×250 mL). The combined organic layers were washed with water (4×500 mL), saturated aqueous sodium chloride (400 mL), dried (magnesium sulfate) and the solvent removed in vacuo to give 2-(allyloxy)-1-chloro-4-(trifluoromethyl)benzene as a colorless oil. The oil was re-dissolved in mesitylene (35 mL) and heated at reflux for 12 h. Removal of the solvent in vacuo provided a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 2:8) provided 9.6 g (96%) of 2-allyl-6-chloro-3-(trifluoromethyl)phenol as a amber oil. Rf=0.66 (silica, ethyl acetate:hexanes 1:4); 1H NMR (DMSO-d6) δH 9.84 (s, 1H); 7.43 (d, 2H); 7.16 (d, 1H); 5.84 (m, 1H); 4.95 (d, 1H); 4.89 (d, 1H); 3.46 (d, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1I.[CH:22]([Sn](CCCC)(CCCC)CCCC)=[CH2:23]>CN(C)C=O.O>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[CH:22]=[CH2:23]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: O
Product: C=Cc1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Temperature: 75 °C
Reaction time: 60 h

Procedure:
To a stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (2 g) in dimethylformamide (10 ml) at room temperature was added vinyltri-n-butyl tin (4.25 g) and tetra-kis-triphenylphosphinepalladium(0) (0.3 g). The mixture was heated at 75° C. for one hour and then cooled and left at room temperature for 60 hours. The reaction mixture was diluted with water and extracted with ether. The organic layer was separated, washed with brine, dried (MgSO4) and evaporated to give the crude product as a black oil (6 g) which was purified by column chromatography on silica gel (200 g) eluted with dichloromethane:hexane (1:1). Combination and evaporation of appropriate fractions gave the title compound as a buff solid, m.p. 186-70° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.[CH3:28][N:29]([C@@H:46]([C:54](=[O:57])[NH:55][CH3:56])[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:30](=[O:45])[CH:31]([NH:43][CH3:44])[CH2:32][C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13](=[O:15])[N:43]([CH3:44])[C@@H:31]([C:30](=[O:45])[N:29]([CH3:28])[C@@H:46]([C:54](=[O:57])[NH:55][CH3:56])[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH2:32][C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)C(Cc1ccc2ccccc2c1)NC
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C/CC(C)(C)NC(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 87.3 %

Procedure:
(2E)-5-(tert-Butyloxycarbonylamino)-5-methylhex-2-enoic acid (200 mg, 0.82 mmol), 1-hydroxy-7-azabenzotriazole (112 mg, 0.82 mmol) and 1-ethyl-3-(3-s dimethylaminopropyl)-carbodiimide hydrochloride (173 mg, 0.90 mmol) were dissolved in a mixture of methylene chloride (10 mL) and N,N-dimethylformamide (1 mL) and strirred for 15 min. N-Methyl-2-methylamino-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-3-(2-naphthyl)propionamide (332 mg, 0.82 mol) dissolved in methylene chloride (5 mL) and diisopropylethylamine (0.14 mL) were added and the mixture was stirred overnight under nitrogen atmosphere. The mixture was diluted with methylene chloride (50 mL), washed with water (50 mL), sodium hydrogen carbonate (30 mL, saturated), and sodium hydrogensulfate (30 mL, 5%). The phases were separated and the organic phase was dried with magnesium sulfate and evaporated in vacuo. The residue was chromatographed (silica, 2×40 cm) to afford 450 mg of ((3E)-1,1dimethyl-4-(N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)but-3-enyl)-carbamic acid tert-butyl ester.
Reaction SMILES: [F:1][C:2]1([F:37])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:22]=[C:21]([C:23]5[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=5)[C:26]([O:28]C(C)(C)C)=[O:27])[C:20]([CH3:36])=[CH:19][N:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.FC(F)(F)C(O)=O>ClCCl>[F:37][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:22]=[C:21]([C:23]5[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=5)[C:26]([OH:28])=[O:27])[C:20]([CH3:36])=[CH:19][N:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: Cc1cnc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)cc1-c1cccc(C(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)cc1-c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 3-(2-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-5-methylpyridin-4-yl)benzoate (40. mg, 0.079 mmol) was dissolved in dichloromethane (1 mL). Trifluoroacetic acid (0.500 mL) was added and the reaction mixture was stirred at room temperature for 1 hour. The crude reaction mixture was evaporated to dryness to yield the pure product. ESI-MS m/z calc. 452.1. found; 453.0 (M+1)+ Retention time 1.64 minutes. 1H NMR (400 MHz, DMSO-d6) δ 1H NMR (400.0 MHz, DMSO-d6) δ 9.01 (s, 1H), 8.22 (s, 1H), 8.03-8.00 (m, 1H), 7.89 (d, J=2.5 Hz, 2H), 7.68-7.64 (m, 2H), 7.58 (d, J=1.6 Hz, 1H), 7.43 (d, J=8.3 Hz, 1H), 7.35 (dd, J=1.7, 8.3 Hz, 1H), 2.18 (s, 3H), 1.54-1.51 (m, 2H), 1.21-1.17 (m, 2H).
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10]Br.[CH:13]1([CH2:19][NH2:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[CH:13]1([CH2:19][N:20]2[CH2:10][C:5]3[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:3]2=[O:12])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COC(=O)c1ccccc1CBr
Reactant: NCC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2CN1CC1CCCCC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 37.1 %

Procedure:
A mixture of 2-bromomethyl-benzoic acid methyl ester (0.230 g, 1 mmol), C-cyclohexyl-methylamine (0.190 g, 1 mmol), and K2CO3 (0.230 g, 1.67 mmol) in toluene (6 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-cyclohexylmethyl-2,3-dihydro-isoindol-1-one (0.085 g, 37%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.18 (m, 5H), 1.72 (m, 6H), 3.46 (d, 2H), 4.38 (s, 2H) 7.42-7.53 (m, 3H), 7.85 (d, 1H). GC-MS: m/z 229 (M)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.O=S(Cl)Cl.[CH2:16](O)[CH2:17][CH3:18]>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:16][CH2:17][CH3:18])=[O:10])=[CH:6][CH:7]=1
Reactant: CCCO
Reactant: O=C(O)Cc1ccc(O)cc1
Solvent: O=S(Cl)Cl
Product: CCCOC(=O)Cc1ccc(O)cc1

Procedure:
A mixture of 4-hydroxyphenylacetic acid (9.12 g, 0.06 mol), n-propanol (40 mL) and SOCl2 (2 mL, 0.028 mol) was refluxed for 3 hours, then evaporated in vacuo. The residue was extracted with ethyl acetate (200 mL), washed with 10% Na2CO3, then water dried (MgSO4), and evaporated in vacuo to give n-propyl 4-hydroxyphenylacetate as an oil. A solution of n-propyl 4-hydroxyphenylacetate (5.8 g, 0.03 mol) in epichlorohydrin (50 mL) was refluxed in the presence of DBU (2 mL, 0.014 mol) for 2 hours. After the excess epichlorohydrin was removed, the residue was refluxed with isopropylamine (20 mL, 0.23 mol) in n-propanol (50 mL), for 4 hours, then was evaporated in vacuo. The residue was crystallized from h-hexane to yield 3.8 g (41%) of n-propyl 4-(2-hydroxy-3-isopropylamino)propoxyphenylacetate, melting at 61°-62° C. and having the structural formula: ##STR28##
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.Cl.[Cl:12][C:13]1[CH:14]=[C:15]([NH:19]N)[CH:16]=[CH:17][CH:18]=1.[CH3:21][N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1>C(N(CC)CC)C>[F:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][N:19]2[C:15]3[CH:16]=[CH:17][CH:18]=[C:13]([Cl:12])[C:14]=3[C:24]3[CH2:23][N:22]([CH3:21])[CH2:27][CH2:26][C:25]2=3)=[CH:5][CH:6]=1
Reactant: CN1CCC(=O)CC1
Reactant: NNc1cccc(Cl)c1
Reactant: Fc1ccc(CCBr)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: CN1CCc2c(c3c(Cl)cccc3n2CCc2ccc(F)cc2)C1

Procedure:
The title compound is prepared by following Method 8 by using 1-(2-bromoethyl)-4-fluorobenzene, 3-chlorophenylhydrazine hydrochloride, triethylamine and N-methyl-4-piperidone
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[Cl:23])[C:17](O)=[O:18].C(N(CC)CC)C.Cl.[CH3:32][NH:33][O:34][CH3:35]>ClCCl.O>[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[Cl:23])[C:17]([N:33]([O:34][CH3:35])[CH3:32])=[O:18]
Reactant: CNOC
Reactant: O=C(O)c1ccc(Cl)c(Br)c1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CON(C)C(=O)c1ccc(Cl)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.5 %

Procedure:
Carbonyldiimidazole (7.2 g, 0.045 mol) was added in portions to a stirred suspension of 3-bromo-4-chlorobenzoic acid (10.0 g, 0.042 mol) in dichloromethane (120 mL). The reaction mixture was stirred at room temperature for 30 minutes then at reflux for 30 minutes. Triethylamine (6.3 mL, 0.045 mol) and N,O-dimethylhydroxylamine hydrochloride (4.2 g, 0.043 mol) were added and the reaction mixture was stirred at room temperature overnight, then diluted with water (75 mL) and the layers separated. The aqueous fraction was extracted with dichloromethane (2×50 mL) and the combined organic extracts were washed with citric acid (10%; 2×50 mL), NaHCO3 (50 mL) and brine (50 mL), dried (sodium sulfate) and concentrated to give 3-bromo-4-chloro-N-methoxy-N-methylbenzamide as a colourless oil (9.3 g, 79%). 1H NMR (300 MHz; DMSO-d6) 7.98 (1H, s, Ar), 7.60 (1H, d, J 7.2, Ar), 7.48 (1H, d, J 7.2, Ar), 3.54 (3H, s, Me), 3.36 (3H, s, Me).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[Br:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH2:17][CH2:18][NH:19][CH2:20]2>>[Br:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH2:17][CH2:18][N:19]([C:11]([C:9]1[CH:10]=[C:5]3[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]3[N:8]=1)=[O:13])[CH2:20]2
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: Brc1cccc2c1CCNC2
Product: O=C(c1cc2ncc(Br)cn2n1)N1CCc2c(Br)cccc2C1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-Bromo-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH3:14])=[CH:11][C:10]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[N:9]2)=[CH:4][CH:3]=1.[C:21]1([CH3:29])[C:22]([CH:27]=O)=[CH:23][CH:24]=[CH:25][CH:26]=1.C([BH3-])#N.[Na+]>CC(O)=O.CO>[CH2:13]([C:12]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][CH2:29][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH3:27])=[CH:3][CH:4]=2)[N:9]=[C:10]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:11]=1)[CH3:14]
Reactant: Cc1ccccc1C=O
Reactant: CCc1cc(-c2cccnc2)nn1-c1ccc(N)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCc1cc(-c2cccnc2)nn1-c1ccc(NCc2ccccc2C)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 1-(4-aminophenyl)-3-(3-pyridyl)-5-ethylpyrazole (300 mg, 1.14 mmol) and o-tolualdehyde (260 mg, 2.25 mmol) in 5% HOAc/MeOH (6 mL) at room temperature under argon, sodium cyanoborohydride (200 mg, 3.18 mmol) was added. The reaction mixture was stirred at room temperature for 4 h and then concentrated, diluted with water, extracted into ethyl acetate, washed with brine. The residue obtained on concentration was chromatographed on silica gel (eluant, gradient of 25-50% EtOAc in hexane) to provide the title compound as an oil that solidified on trituration with ether/petroleum ether (97 mg, 23%), m.p. 117-9° C. NMR (CDCl3, 400 MHz): 9.1 (s, 1H); 8.5 (br, 1H); 8.1 (br, 1H); 7.4-7.2 (overlapping m, 7H), 6.7 (d,2H), 6.5 (s, 1H), 4.4 (s, 2H), 4.1 (br, 1H), 2.7 (q, 2H), 2.4 (s, 3H), 1.3 (t, 3H).
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:13][NH2:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].ClC(Cl)(Cl)C(=N)O[CH2:23][CH:24]=[CH2:25].FC(F)(F)S(O)(=O)=O>C(Cl)Cl.C1CCCCC1.C(Cl)Cl>[C:1]([NH:11][C@H:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:13][NH:14][CH2:25][CH:24]=[CH2:23])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: C=CCOC(=N)C(Cl)(Cl)Cl
Reactant: COC(=O)[C@H](CN)NC(=O)OCc1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCCCC1
Product: C=CCNC[C@H](NC(=O)OCc1ccccc1)C(=O)OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Dissolve Nα -(carbobenzyloxy)-β-(amino)-L-alanine, methyl ester (15.9 g, 63 mmol) in methylene chloride/cyclohexane (1:1, 600 mL). Add allyl trichloroacetimidate (26 g, 128 mmol) and trifluoromethanesulfonic acid (5 mL), 56.6 mmol). Stir at room temperature under a nitrogen atmosphere for 5 hours and dilute with methylene chloride. Wash with saturated aqueous sodium hydrogen carbonate, water, dry (MgSO4) and evaporate the solvent in vacuo. Purify by silica gel chromatography to give Nα -(carbobenzyloxy)-β-(allylamino)-L-alanine, methyl ester.
Reaction SMILES: COC1C=CC(C[S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([OH:29])=O)[CH2:10]2)=CC=1.[CH2:32]([NH2:35])[CH2:33][NH2:34].[N+:36]([C:39]1[CH:51]=[CH:50][C:42]([CH2:43][O:44][C:45]([NH:47][CH:48]=N)=[O:46])=[CH:41][CH:40]=1)([O-:38])=[O:37]>>[SH:8][C@@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=2)=[O:15])[C@H:11]([C:27](=[O:29])[NH:34][CH2:33][CH2:32][NH:35][CH:48]=[N:47][C:45]([O:44][CH2:43][C:42]2[CH:50]=[CH:51][C:39]([N+:36]([O-:38])=[O:37])=[CH:40][CH:41]=2)=[O:46])[CH2:10]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: NCCN
Reactant: N=CNC(=O)OCc1ccc([N+](=O)[O-])cc1
Product: O=C(N=CNCCNC(=O)[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1)OCc1ccc([N+](=O)[O-])cc1
Yield: 27.2 %

Procedure:
Following a procedure similar to that described in Preparation 17, but using 850 mg of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidinecarboxylic acid, 450 mg of ethylenediamine and 400 mg of N-(4-nitrobenzyloxycarbonyl)formamidine, 280 mg of the title compound were obtained as a powder.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8]OS(C1C=CC(C)=CC=1)(=O)=O)[CH:2]=[CH2:3].[OH:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=1.[OH-].[K+]>C(O)C>[CH2:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=1)[CH:2]=[CH2:3]
Reactant: O=Cc1ccc(O)cc1
Reactant: C=CCOCCCCOS(=O)(=O)c1ccc(C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C=CCOCCCCOc1ccc(C=O)cc1

Procedure:
4-allyloxybutyl-p-toluene sulfonate is reacted with p-hydroxybenzaldehyde in the presence of KOH and C2H5OH to form 4-(4-allyloxybutoxy)benzaldehyde which is reacted with malonic acid in the presence of pyridine to form p-(4-allyloxybutoxy)cinnamic acid. The acid is esterified with CH3OH and sulfuric acid to yield the methyl ester, namely methyl p-(4-allyloxybutoxy)cinnamic carboxylate. This methyl ester is then reacted with TosMIC in Et2O/DMSO in the presence of sodium hydride or other strong base to form the substituted pyrrole, represented as follows: ##STR7##
Reaction SMILES: N1C=CC=CC=1.[CH2:7]1[CH2:25][O:24][C:9]2([CH2:15][O:14][C:13]([CH3:23])([CH2:16][CH2:17][CH2:18][CH:19]([CH3:22])[CH2:20][OH:21])[CH2:12][CH2:11][CH2:10]2)[O:8]1>C(Cl)Cl.[O-2].[O-2].[O-2].[Cr+6]>[CH2:25]1[CH2:7][O:8][C:9]2([CH2:15][O:14][C:13]([CH3:23])([CH2:16][CH2:17][CH2:18][CH:19]([CH3:22])[CH:20]=[O:21])[CH2:12][CH2:11][CH2:10]2)[O:24]1
Reactant: CC(CO)CCCC1(C)CCCC2(CO1)OCCO2
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C=O)CCCC1(C)CCCC2(CO1)OCCO2
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 68.6 %

Procedure:
A solution of pyridine (6.8 g, 0.086 mol) and chromium trioxide (4.3 g, 0.043 mol) in methylene chloride (450 ml) at 23° C. in a nitrogen atmosphere is stirred for 45 minutes. The mixture is cooled to -20° C. and celite (20 g) is added followed by 6,6-ethylenedioxy-2-methyl-2-(4'-methyl-5'-hydroxypentyl)-oxepane (1.95 g, 0.00717 mol) in methylene chloride (50 ml). The mixture is stirred for 1 hour at -20° C. and 30 minutes at 0° C. The mixture is then filtered and the celite cake is washed with methylene chloride (10×50 ml). The filtrate and washings are combined and washed with satd. NaHCO3 (2×150 ml). The methylene chloride phase is separated, dried (MgSO4) and the solvents are removed at reduced pressure. The crude product (1.9 g) is chromatographed on SilicAR CC-7 (50 g) in hexane. Elution with 15% ethyl acetate/hexane gives 6,6-ethylenedioxy-2-methyl-2-(4'-methyl-5'-oxopentyl)-oxepane (19) as a clear colorless oil (1.33 g, 68%): nmr (CDCl3) δ1.10 (d, J=6 Hz, 3H, CH3 --CH--CHO), 3.42 (s, 2H, O--CH2 --C), 3.97 (s, 4H, ketal), 9.53 (d, J=2H, 1H, CH--CHO).
Reaction SMILES: CC(C1C=[CH:11][C:10]([CH2:13][CH2:14][C:15]([NH:17][C:18]2[CH:19]=[N:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:16])=CC=1)CCCC.[CH3:28][CH:29]([C:34]1[CH:42]=[CH:41][C:37]([C:38](O)=O)=[CH:36][CH:35]=1)[CH2:30][CH2:31][CH2:32][CH3:33].[CH3:43]CN(CC)CC.NC1C=NC2C(C=1)=CC=CC=2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH3:28][CH:29]([C:34]1[CH:42]=[CH:41][C:37]([C:38]2[CH:43]=[C:14]([CH:13]=[CH:10][CH:11]=2)[C:15]([NH:17][C:18]2[CH:19]=[N:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:16])=[CH:36][CH:35]=1)[CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCC(C)c1ccc(CCC(=O)Nc2cnc3ccccc3c2)cc1
Reactant: CCN(CC)CC
Reactant: CCCCC(C)c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1cnc2ccccc2c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCC(C)c1ccc(-c2cccc(C(=O)Nc3cnc4ccccc4c3)c2)cc1

Procedure:
3-[4-(1-Methyl-pentyl)-phenyl]-N-quinolin-3-yl-propionamide. 4-(1-Methyl-pentyl)-benzoic acid from step B (0.114 g, 0.55 mmol) was dissolved in 5 mL DMF with stirring. To this was added Et3N (0.10 mL, 0.72 mmol), 3-aminoquinoline (0.082 g, 0.57 mmol) and lastly HBTU (0.224 g, 0.59 mmol). The reaction was allowed to stir overnight then poured into 25 mL EtOAc and washed with saturated NaHCO3 solution (25 mL) then brine (25 mL). The organics were dried over Na2SO4, filtered, evaporated in vacuo and the residue chromatographed over silica gel eluting with 0% to 40% EtOAc in hexanes. Evaporation of the proper fractions yielded the title product (0.120 g, 0.36 mmol). 1H NMR (DMSO-d6): 8.93 (d, 1H), 8.86 (d, 1H), 8.09 (m, 2H), 7.88 (m, 3H), 7.67 (dt, 1H), 7.57 (t, 1H), 7.35 (d, 2H), 2.79 (h, 1H), 1.61 (q, 2H), 1.37-1.04 (m, 7H), 0.87 (t, 3H); MS: m/z 333.4 (MH+).