Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.CCCCCC.[CH3:12][C:13]1([CH3:34])[CH2:18][O:17][CH:16](/[CH:19]=[CH:20]/[C:21]2[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=2[CH:29]([CH2:31][CH2:32][CH3:33])[OH:30])[O:15][CH2:14]1.[CH3:35][C:36]([CH3:42])([CH2:40][CH3:41])[C:37](Cl)=[O:38]>C1COCC1>[CH3:12][C:13]1([CH3:34])[CH2:14][O:15][CH:16](/[CH:19]=[CH:20]/[C:21]2[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=2[CH:29]([O:30][C:37](=[O:38])[C:36]([CH3:42])([CH3:35])[CH2:40][CH3:41])[CH2:31][CH2:32][CH3:33])[O:17][CH2:18]1
Reactant: CCCC(O)c1cc(C)cc(C)c1/C=C/C1OCC(C)(C)CO1
Reactant: CCC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC(OC(=O)C(C)(C)CC)c1cc(C)cc(C)c1/C=C/C1OCC(C)(C)CO1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 42.6 %

Procedure:
A 1.4M solution of n-butyllithium in hexane (2.6 mL, 3.61 mmol) was added dropwise under a nitrogen atmosphere to a solution of (E)-2-[2-(5,5-dimethyl-1,3-dioxan-2-yl)ethenyl]-3,5-dimethyl-α-propylbenzenemethanol (956.8 mg, 3.01 mmol) in 100 mL of dry THF. After the addition, the solution was stirred at room temperature for 15 minutes. 2,2-Dimethylbutyryl chloride (500 μl, 3.61 mmol) was then added and the solution stirred at room temperature for 30 minutes. The reaction was partitioned between 1N HCl-EtoAc and extracted. The organic layer was washed with water (two times), dried (anh. K2CO3) and the solvent removed under reduced pressure. Purification of the residual oil on 250 g of silica gel (Merck, 230-400 mesh) using 3:2 CH2Cl2 -hexane as an eluent gave 2,2-dimethylbutanoic acid (E)-1-[2-[2-(5,5-dimethyl-1,3-dioxan-2-yl)ethenyl]-3,5-dimethylphenyl]butyl ester (534 mg, 43%) as an oil: IR (film) 2945, 2860, 1720 and 1605 cm-1 ; NMR (DMSO-d6) δ 0.68-0.80 (6H, m), 0.86 (3H, t, J=6 Hz), 1.07 (3H, s), 1.08 (3H, s), 1.12 (3H, s), 1.14-1.44 (2H, m), 1.46-1.66 (3H, m), 1.68-1.86 (1H, m), 1.18 (3H, s), 2.23 (3H, s), 3.54 (2H, d, J=10 Hz), 3.64 (2H, d, J=10 Hz), 5.09 (1H, d, J=5 Hz), 5.68 (1H, dd, J=5, 15 Hz), 5.74-5.86 (1H, m), 6.78 (1H, d, J=15 Hz), 6.98 (2H, s).
Reaction SMILES: [Br:1][C:2]1[C:17]([OH:18])=[CH:16][C:5]2[CH2:6][CH2:7][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH2:10][C:4]=2[CH:3]=1.[H-].[Na+].[CH3:21][C@@H:22]1[CH2:26]OS(=O)(=O)[N:23]1C(OC(C)(C)C)=O.Cl>CN(C=O)C.O>[NH2:23][C@H:22]([CH3:26])[CH2:21][O:18][C:17]1[C:2]([Br:1])=[CH:3][C:4]2[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6][C:5]=2[CH:16]=1
Reactant: C[C@@H]1COS(=O)(=O)N1C(=O)OC(C)(C)C
Reactant: CCOC(=O)N1CCc2cc(O)c(Br)cc2CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N1CCc2cc(Br)c(OC[C@@H](C)N)cc2CC1
Reaction time: 0.17 h
Yield: 112.5 %

Procedure:
Under an argon atmosphere, to a solution of 1.7 g of ethyl 7-bromo-8-hydroxy-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate in 30 ml of DMF was added 283 mg of sodium hydride under ice-cooling, followed by stirring at the same temperature for 10 minutes. Then, 1.54 g of t-butyl (4R)-4-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylate was added thereto, followed by stirring at room temperature for 18 hours. To the reaction mixture was added water and 1 M aqueous hydrochloric acid sequentially, followed by stirring, and the precipitated solid was collected by filtration. To 20 ml of a suspension of the resulting solid in ethanol was added 10 ml of a 4 M hydrogen chloride-ethyl acetate solution under ice-cooling, followed by stirring at 60° C. for 1 hour. The reaction mixture was evaporated under reduced pressure, and to the residue were added chloroform and saturated aqueous sodium bicarbonate. After extraction with chloroform, the combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 2.26 g of ethyl 7-{[(2R)-2-aminopropyl]oxy}-8-bromo-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate as an opaque cream-colored oily substance.
Reaction SMILES: [CH2:1]1[CH2:10][O:9][CH:8]2[CH:3]([C@:4]3([CH2:22][C@H:21]([OH:23])[C@H:20]4[C@@H:11]([CH2:12][CH2:13][C:14]5[CH:15]=[C:16]([O:24][CH3:25])[CH:17]=[CH:18][C:19]=54)[C@@H:6]3[CH2:7]2)[CH3:5])[O:2]1.N1C=CC=CC=1.ClC(Cl)C(O)=O.C(O)(=O)C(O)=O>CS(C)=O.C1C=CC=CC=1.CO.CCOCC>[CH2:1]1[CH2:10][O:9][CH:8]2[CH:3]([C@:4]3([CH2:22][C:21](=[O:23])[C@H:20]4[C@@H:11]([CH2:12][CH2:13][C:14]5[CH:15]=[C:16]([O:24][CH3:25])[CH:17]=[CH:18][C:19]=54)[C@@H:6]3[CH2:7]2)[CH3:5])[O:2]1
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)C3OCCOC3C[C@@H]12
Agent: O=C(O)C(=O)O
Agent: O=C(O)C(Cl)Cl
Solvent: CO
Solvent: CS(C)=O
Solvent: c1ccncc1
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2C(=O)C[C@]2(C)C3OCCOC3C[C@@H]12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 5.13 g of 17-ethylenedioxy-11β-hydroxy-3-methoxyestra-1,3,5(10)-triene in 25 ml of dimethylsulfoxide and 25 ml of benzene is added 3 ml of pyridine and 9.3 g of N,N-dicyclohexylcarbodiimide. This mixture is then cooled and 1.5 ml of dichloroacetic acid is added. The whole is next stirred at room temperature for 11/2 hours. It is diluted by the addition of 50 ml of ether and a solution of 4 g of oxalic acid in 10 ml of methanol is added dropwise. The resulting suspension is stirred for 40 minutes at room temperature and then filtered. The filtrate is concentrated to dryness and distributed between methylene chloride and a 10% aqueous solution of sodium bicarbonate. The organic phase is washed with water and dried (Na2SO4) before being evaporated to dryness under reduced pressure. The residue is placed on a column of silica-gel and eluted with chloroform containing various percentages of methanol. The fractions eluted with chloroform containing 5 % of methanol are combined and evaporated to yield a residue which is crystallized from hexane/ether (1:1). Thus is obtained 17-ethylenedioxy-3-methoxyestra-1,3,5(10)-trien-11-one, m.p. 122° - 123° C.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][C:9]([CH3:14])=[CH:10][C:11](Cl)=[O:12]>C1COCC1>[CH3:8][C:9]([CH3:14])=[CH:10][C:11]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:12]
Reactant: Oc1ccccc1
Reactant: CC(C)=CC(=O)Cl
Solvent: C1CCOC1
Product: CC(C)=CC(=O)Oc1ccccc1
Reaction time: 2.5 h

Procedure:
To an ice bath cooled solution of 1.29 (54 mmol) of NaH (obtained from a 60% suspension in mineral oil by 3×10 ml hexane wash) in 20 ml of dry THF was added slowly under oxygen a solution of 5 g (53 mmol) of phenol in 50 ml of dry THF. The mixture was then treated with a solution of 7 g (59 mmol) of dimethylacryloyl chloride in 30 ml of dry THF. The cooling bath was then removed and the mixture was stirred for a further 2.5 h. The reaction mixture was then poured into 150 ml of water containing 1 ml of glacial acetic acid. The mixture was extracted with 150 ml ether and the ether extract washed with saturated NaCl solution and then dried (MgSO4). The solvent was removed in vacuo and the residue purified by flash chromatography (silica; 5% ether in hexanes) to give the title compound as a yellow oil. PMR (CDCl3)): & 1 99 (3H, s), 2.24 (3H, s), 5.93 (1H, broad s), 7.10 (2H, d, J~7 8 Hz) 7.22 (1H, t, J~7.8 Hz), 7.38 (2H, t, J~7.8 Hz).
Reaction SMILES: N1C2C(=CN=CC=2)C=CC=1.[N:11]1[C:20]2[CH:19]=[CH:18][NH:17][C:16](=[O:21])[C:15]=2[CH:14]=[CH:13][C:12]=1C=O>>[N:11]1[C:20]2[CH:19]=[CH:18][NH:17][C:16](=[O:21])[C:15]=2[CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ccc2c(=O)[nH]ccc2n1
Agent: c1cnc2ccncc2c1
Product: O=c1[nH]ccc2ncccc12

Procedure:
Reaction Scheme V illustrates the preparation of 1,6-naphthyridin-5(6H)-one compounds. In the initial condensation of N-Boc-protected 2-chloro-4-amino-nicotinaldehyde with the (substituted phenyl)benzyl ketone (V-1) in the presence of an alkoxide, such as, sodium methoxide, there is obtained directly the 1,6-naphthyridine (V-2) substituted at the 5-position with the alkoxide group. Acid catalyzed hydrolysis readily converts the 1,6-naphthyridine to the requisite 1,6-naphthyridin-5(6H)-one aldehyde functionality (V-3) and this material can undergo reductive amination with a diverse array of amines to give the 1,6-naphthyridin-5(6H)-one compounds (V-6).
Reaction SMILES: C([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1C=CN(C)C)[CH:20]([NH:30][C:31]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:19]2=[O:50])=O)(C1C=CC=CC=1)C1C=CC=CC=1.Cl.[C:52]([O:55][CH2:56][CH3:57])(=[O:54])[CH3:53]>>[CH:56]([O:55][C:52]([C:53]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[CH2:17][CH:15]=[O:14])[CH:20]([NH:30][C:31]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:19]2=[O:50])=[O:54])([C:37]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:57]1[CH:39]=[CH:38][CH:31]=[CH:44][CH:45]=1
Reactant: CCOC(C)=O
Reactant: CN(C)C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C2SC1
Agent: Cl
Product: O=CCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C2SC1

Procedure:
A solution of 2-benzhydryloxycarbonyl-3-(2-dimethylaminovinyl)-8-oxo-7-tritylamino-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (E-form) (23.5 g) in ethyl acetate (500 cc) is stirred with 1 N hydrochloric acid (250 cc) for 90 minutes at 25° C. The organic phase is decanted, washed with distilled water (3×250 cc), a saturated sodium bicarbonate solution (100 cc) and a half-saturated sodium chloride solution (250 cc), then dried over sodium sulphate and concentrated to dryness under reduced pressure (40 mm Hg) at 40° C. 2-Benzhydryloxycarbonyl-8-oxo-3-(2-oxo-ethyl)-7-tritylamino-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (21 g) is obtained in the form of an orange-coloured froth.
Reaction SMILES: [OH-].[K+].C([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:9]=1[Cl:18])(=O)C>C(O)C>[C:14]([C:10]1[C:9]([Cl:18])=[C:8]([CH:13]=[CH:12][CH:11]=1)[CH2:7][OH:6])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(=O)OCc1cccc(C(C)(C)C)c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)c1cccc(CO)c1Cl
Temperature: 50 °C
Reaction time: 6 h
Yield: 98.7 %

Procedure:
21.0 g (0.39 mole) of potassium hydroxide are added to a solution of 62.6 g (0.26 mole) of 3-tert-butyl-2-chlorobenzyl acetate in 400 ml of ethanol. The reaction mixture is stirred for 6 hours at 50° C. and evaporated and the residue is taken up with water. The aqueous mixture is extracted with dichloromethane. 51 g (quantitative) of 3-tert-butyl-2-chlorobenzyl alcohol of boiling point 103°-105° C./0.2 mbar are obtained from the organic phase.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:12])[C:10]=1[CH3:11])[N:7]([CH:13]=[O:14])[CH2:6][CH2:5]2.Cl[CH2:16][C:17]([CH3:19])=[CH2:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:11][C:10]1[C:9]([CH3:12])=[C:8]2[C:4]([CH2:5][CH2:6][N:7]2[CH:13]=[O:14])=[CH:3][C:2]=1[O:1][CH2:18][C:17]([CH3:19])=[CH2:16]
Reactant: C=C(C)CCl
Reactant: Cc1c(O)cc2c(c1C)N(C=O)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)COc1cc2c(c(C)c1C)N(C=O)CC2
Temperature: 60 °C
Reaction time: 15 h
Yield: 76.3 %

Procedure:
A suspension of 2,3-dihydro-5-hydroxy-6,7-dimethyl-1H-indole-1-carbaldehyde (21.8 g, 0.11 mol), 3-chloro-2-methyl-1-propene (15 mL, 0.15 mol) and potassium carbonate (23.6 g, 0.17 mol) in DMF (200 mL) was stirred at 60° C. for 15 hours under the nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate four times. The combined organic layers were washed with water and saturated brine, dried over magnesium sulfate, treated with active carbon, filtered, and concentrated under reduced pressure. The residue was recrystallized from diisopropyl ether-hexane to obtain 20.6 g of title compound.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2C#N)[CH2:5][CH2:4]1.[NH4+].[OH-].C[Mg]Br.C([O:24][CH2:25][CH3:26])C.Cl>O.C1(C)C=CC=CC=1>[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[CH:13][CH:14]=[CH:15][C:16]=2[C:25](=[O:24])[CH3:26])[CH2:5][CH2:4]1
Reactant: CN1CCN(c2ccccc2C#N)CC1
Reactant: CCOCC
Agent: C[Mg]Br
Agent: Cl
Agent: [NH4+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)c1ccccc1N1CCN(C)CC1
Temperature: 0 °C
Yield: 81.6 %

Procedure:
A solution of 2-(4-methyl-piperazin-1-yl)-benzonitrile hydrochloride (2.16 g, 9.1 mmol) in H2O was brought to basic conditions with NH4OH and extracted with DCM. The organic phase was dried over Na2SO4, and evaporated in vacuo. The product obtained (1.77 g, 8.80 mmol) was dissolved in 30 ml of toluene and added under nitrogen atmosphere to a solution of 3 M methyl magnesium bromide in diethyl ether (8.79 ml, 26.38 mmol). The resulting suspension was heated under reflux for 4 hours. The reaction was cooled down to 0° C., acidified with 10% HCl, and then heated under reflux for 1 hour. The two phases were separated and the aqueous phase was extracted with AcOEt, then brought to basic conditions with NH4OH and extracted with DCM. The organic phase was dried over Na2SO4 and concentrated in vacuo to dryness. The crude product was purified by flash chromatography (DCM:MeOH:NH3 98:2:0.2) to obtain 1.62 g of 1-[2-(4-methyl-piperazin-1-yl)-phenyl]-ethanone.
Reaction SMILES: C(O)(C(F)(F)F)=O.Cl[C:9]1[CH:14]=[C:13]([N:15]2[CH:24]([CH3:25])[CH2:23][C:22]3[C:17](=[CH:18][C:19]([C:26]4[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=4)=[CH:20][CH:21]=3)[CH2:16]2)[N:12]=[C:11]([NH2:32])[N:10]=1.[N:33]1(C(OC(C)(C)C)=O)[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[CH3:25][CH:24]1[CH2:23][C:22]2[C:17](=[CH:18][C:19]([C:26]3[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=3)=[CH:20][CH:21]=2)[CH2:16][N:15]1[C:13]1[CH:14]=[C:9]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[N:10]=[C:11]([NH2:32])[N:12]=1
Reactant: CC1Cc2ccc(-c3cnn(C)c3)cc2CN1c1cc(Cl)nc(N)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: CC1Cc2ccc(-c3cnn(C)c3)cc2CN1c1cc(N2CCNCC2)nc(N)n1

Procedure:
This compound was prepared as TFA salt by using procedures analogous to those described for the synthesis of Example 118 starting from 4-chloro-6-[3-methyl-7-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl]pyrimidin-2-amine and tert-butyl piperazine-1-carboxylate (Aldrich, Cat. No. 343536). LCMS (M+H)+: m/z=405.2.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:24])[CH2:6][CH:7]([C:11]2[S:12][CH:13]=[CH:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[N:17]=2)[CH2:8][C:9]=1O)(=O)[CH3:2].N1CCCC1.Cl.[NH2:31][C:32]([NH2:34])=[NH:33]>CCO>[NH2:34][C:32]1[N:33]=[C:1]([CH3:2])[C:4]2[C:5](=[O:24])[CH2:6][CH:7]([C:11]3[S:12][CH:13]=[CH:14][C:15]=3[C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[N:17]=3)[CH2:8][C:9]=2[N:31]=1
Reactant: COc1cccc(-c2ccsc2C2CC(=O)C(C(C)=O)=C(O)C2)n1
Reactant: N=C(N)N
Agent: Cl
Solvent: C1CCNC1
Solvent: CCO
Product: COc1cccc(-c2ccsc2C2CC(=O)c3c(C)nc(N)nc3C2)n1
Temperature: 100 °C
Yield: 14.7 %

Procedure:
To a 150 mL pressure vessel was added 2-acetyl-3-hydroxy-5-(3-(6-methoxypyridin-2-yl)thiophen-2-yl)cyclohex-2-enone (30G, 1.72 g, 5.01 mmol, 1.0 eq.), EtOH (50 mL), pyrrolidine (2.13 g, 30.1 mmol, 6.0 eq.), guanidine hydrochloride (1.44 g, 15 mmol, 3.0 eq.). The vessel was sealed and heated overnight at 100° C. LC/MS analysis showed the reaction to be complete whereupon the reaction mixture was concentrated and the residue was taken up in 20% EtOAc/CH2Cl2. An insoluble solid proving not to be product was filtered off. The remaining filtrate was purified via column chromatography (20% EtOAc/CH2Cl2 to 70% EtOAc/CH2Cl2) to yield the product 30H as a light gray solid (270 mg, 15%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.55 (s, 3H) 2.76-2.95 (m, 2H) 3.02-3.22 (m, 2H) 3.70 (s, 3H) 4.62-4.77 (m, 1H) 6.72 (d, J=8.34 Hz, 1H) 7.31 (d, J=7.58 Hz, 1H) 7.41-7.54 (m, 4H) 7.75 (t, J=7.83 Hz, 1H). ESI-MS: m/z 367.3 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=O)=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH2:19][CH2:17][C:9]1[NH:10][C:11]2[C:16]([C:8]=1[NH:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2
Reactant: NC(=O)c1[nH]c2ccccc2c1Nc1ccncc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1[nH]c2ccccc2c1Nc1ccncc1
Temperature: 25 °C
Yield: 16.8 %

Procedure:
At 0° C. stir a solution of 3-(pyridin-4-ylamino)-1H-indole-2-carboxamide (1.26 g, 5 mmol) in THF (10 mL) and add dropwise a 1M solution of LAH in THF (25 mL, 25 mmol). Allow the reaction to warm to room temperature and then reflux overnight. Add aqueous 10% Rochelle salt solution, and extract the aqueous mixture with EtOAc. Concentrate the extract under vacuum and isolate 0.5 g of crude yellow solid. Purify the solid by preparative HPLC and obtain 0.2 g of the title compound as a solid: MS 239(M+H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[N:9]=[C:10]([CH3:16])[NH:11][CH2:12][C:13]=1[C:14]#[N:15]>[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+].O>[NH2:7][C:8]1[C:13]([C:14]#[N:15])=[CH:12][N:11]=[C:10]([CH3:16])[N:9]=1
Reactant: CC1=NC(N)=C(C#N)CN1
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1ncc(C#N)c(N)n1
Temperature: 10 °C

Procedure:
1.6 g. of potassium carbonate and 0.1 g. of potassium ferricyanide are added to a suspension of 1.35 g. of 4-amino-5-cyano-1,6-dihydro-2-methyl-pyrimidine in 25 ml. of water. A moderately strong stream of chlorine gas is bubbled through the mixture, which has been cooled to 10° C. with stirring. Initially, all the reactants are dissolved. Subsequently, a precipitate forms. The reaction is completed when excess chlorine is detectable. The reaction normally takes 3 hours. The 4-amino-5-cyano-2-methyl-pyrimidine obtained after re-precipitation from dilute sulfuric acid/dilute sodium hydroxide, has a melting point of 258°-259° C.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.CCCCCC.[CH3:19][CH:20]([CH2:26][C:27]#[C:28][CH2:29][CH3:30])[C:21](OCC)=[O:22]>C1COCC1.C(O)(=O)C.O>[CH3:19][CH:20]([CH2:26][C:27]#[C:28][CH2:29][CH3:30])[C:21](=[O:22])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: CCC#CCC(C)C(=O)OCC
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCC#CCC(C)C(=O)CP(=O)(OC)OC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
Under argon atmosphere, to a stirred solution of dimethyl methylphosphonate (7.91 ml, 0.074 mol) in anhydrous THF (150 ml) was added dropwise a solution of n-butyl lithium in hexane (1.71N, 43 ml, 0.074 mol) and the mixture was stirred for 30 min at -78° C. A solution of ethyl 2-methyl-4-heptynoate (5.0 g, 0.03 mol) in anhydrous THF (5 ml) was dropwise added into the mixture, and the resulting mixture was stirred for 30 min. at -78° C. The resulting mixture was allowed to room temperature and 30 min. later, to the solution were then added water (10 ml) and acetic acid (45 ml) under ice-cooling, and concentrated. The residue was diluted with water (20 ml) and extracted with ethyl acetate (50 ml×2). The combined ethyl acetate layers were washed with water (20 ml) and with brine (20 ml), dried over anhydrous sodium sulfate, and concentrated. The residue was distilled to give dimethyl 3-methyl-2-oxo-5-octynylphosphonate (6.55 g, 0.027 mol, 88%, B.p.: 118°-121° C./0.35 mmHg). The product was assigned the structure by the following data.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[C:14](=[O:15])[CH2:13][CH2:12][C@H:11]1[CH:16]=[CH:17][C:18]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)=[O:19]>[Pd].C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[C:14](=[O:15])[CH2:13][CH2:12][C@H:11]1[CH2:16][CH2:17][C:18]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)=[O:19]
Reactant: COC(=O)CCCCCC[C@@H]1C(=O)CC[C@H]1C=CC(=O)c1cccc2ccccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)CCCCCC[C@@H]1C(=O)CC[C@H]1CCC(=O)c1cccc2ccccc12
Reaction time: 1.5 h
Yield: 69.5 %

Procedure:
A mixture of trans-7-[2-(3-naphthalen-1-yl-3-oxo-propenyl)-5-oxo-cyclopentyl]-heptanoic acid methyl ester of Step A (143 mg, 0.352 mmol), 10% palladium on carbon (100 mg), and ethyl acetate (10 mL) were hydrogenated on a Parr shaker at 50 psi for 1.5 h. The catalyst was removed via filtration through Celite®. The filtrate was concentrated and the residue was purified by radial chromatography (hexanes to 25% ethyl acetate in hexanes) to provide the title compound of Step B (100 mg) as a clear and colorless oil. MS 426 (M+18).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:43])=[C:5]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][N:32]2C(=O)C3=CC=CC=C3C2=O)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].O.NN>C(O)C>[CH3:43][C:4]1[NH:3][C:2]([CH3:1])=[C:7]([C:8]([O:10][CH3:11])=[O:9])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:5]=1[C:21]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH2:32])=[O:22]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCCCCCN2C(=O)c3ccccc3C2=O)C1c1cccc([N+](=O)[O-])c1
Agent: NN
Solvent: CCO
Solvent: O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCCCCCN)C1c1cccc([N+](=O)[O-])c1
Yield: 48.1 %

Procedure:
A solution of 16 g of methyl 8-phthalimidooctyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate and 6.8 g of hydrazine monohydrate in 160 ml of ethanol was refluxed for 2 hours under heating. Precipitates (solid) thue formed was removed by filtration. The filtrate was concentrated under reduced pressure and after adding chloroform to the residue, precipitates again removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography. The product was eluted with chloroform-methanol (8:2 v/v), and crude crystals were recrystallized from ethanol-petroleum ether to provide 6 g of 8-aminooctyl methyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:27]=[CH:28][CH:29]=1)[CH2:21][CH:22]([C:24]([OH:26])=[O:25])[NH2:23]>CS(C)=O>[C:24]([CH:22]([NH:23][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:21][C:20]1[CH:27]=[CH:28][CH:29]=[C:18]([O:17][CH3:16])[CH:19]=1)([OH:26])=[O:25]
Reactant: COc1cccc(CC(N)C(=O)O)c1
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Solvent: CS(C)=O
Product: COc1cccc(CC(Nc2nc3ccc(Cl)cc3cc2C(=O)O)C(=O)O)c1

Procedure:
In close analogy to the procedure described in Example 32, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 3-methoxy-DL-phenylalanine in DMSO to provide the title compound in good yield.