Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[C@@H:10]([C:21](=[O:23])[CH3:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[C@@H:10]([C@H:21]([OH:23])[CH3:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)c(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)c(F)c1
Reaction time: 1 h
Yield: 42.2 %

Procedure:
To a solution of 1-[(3R,4S)-1-benzyl-4-(3,4-difluoro-phenyl)-pyrrolidin-3-yl]-ethanone (2.31 g, 7.32 mmol) in THF (80 mL) at 0° C. were added portion wise LiAlH4 (0.245 g, 6.44 mmol). Stirring was continued for one hour, and the reaction mixture was carefully quenched by addition of aq. NH4Cl, concentrated under vacuo and the product extracted with EtOAC. The combined organic phases were dried on Na2SO4 and concentrated under vacuo. The two diastereoisomers were separated by column chromatography (SiO2, EtOAc/H, 1:1) to yield (R)-1-[(3R,4S)-1-benzyl-4-(3,4-difluoro-phenyl)-pyrrolidin-3-yl]-ethanol (V-B-3) 0.98 g (42%) as a white solid ES-MS m/e: 318.1 (M+H+) and (S)-1-[(3R,4S)-1-benzyl-4-(3,4-difluoro-phenyl)-pyrrolidin-3-yl]-ethanol (V-A-3) 0.86 g (37%) as a white solid ES-MS m/e: 318.1 (M+H+).
Reaction SMILES: Br[C:2]1[C:3]([CH3:11])=[N:4][C:5]([O:9][CH3:10])=[CH:6][C:7]=1[CH3:8].C([Li])CCC.[B:17](OC)([O:20]C)[O:18]C.[Cl-].[NH4+]>C1COCC1>[CH3:10][O:9][C:5]1[N:4]=[C:3]([CH3:11])[C:2]([B:17]([OH:20])[OH:18])=[C:7]([CH3:8])[CH:6]=1
Reactant: COc1cc(C)c(Br)c(C)n1
Reactant: COB(OC)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(C)c(B(O)O)c(C)n1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
3-bromo-6-methoxy-2,4-dimethylpyridine (150 mg) was added to THF (3 mL). The solution was cooled to −78° C., and n-butyllithium (1.63 M solution in n-hexane, 0.468 mL) was added, followed by stirring at the same temperature for 30 minutes. Trimethyl borate (0.108 mL) was added to the reaction mixture, and the mixture was stirred at −78° C. for 10 minutes and at room temperature for 50 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the reaction mixture was concentrated under reduced pressure. THF was distilled off. The resulting residue was filtered. The solid collected by filtration was washed with water and n-heptane to give the title compound (41 mg).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8]1[N:14]([CH3:26])[C:15](=[O:25])[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)=[CH:17][C:7]2=1)(=[O:3])[CH3:2].CC(O[CH:32](N(C)C)[N:33]([CH3:35])[CH3:34])(C)C>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:16]2[C:15](=[O:25])[N:14]([CH3:26])[C:8]3[N:9]([CH3:13])[C:10]4[C:6]([C:7]=3[CH:17]=2)=[CH:5][C:4]([C:1](=[O:3])[CH:2]=[CH:32][N:33]([CH3:35])[CH3:34])=[CH:12][CH:11]=4)=[CH:23][CH:22]=1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CC(=O)c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3)c(=O)n(C)c1n2C
Product: CN(C)C=CC(=O)c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3)c(=O)n(C)c1n2C

Procedure:
The process is carried out as indicated in preparation 1.9C above, with compound B 6-acetyl-3-(4-chlorophenyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and Bredereck's reagent.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10]Cl)[C:5]=1[NH:12][C:13](=[O:29])[CH2:14][CH:15]1[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:22][C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)([CH3:3])[CH3:2].[O:30]1CCCC1.O>CC(C)=O.[N+]([O-])([O-])=O.[Ag+]>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][OH:30])[C:5]=1[NH:12][C:13](=[O:29])[CH2:14][CH:15]1[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:22][C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)([CH3:3])[CH3:2]
Reactant: C1CCOC1
Reactant: CC(C)c1cccc(CCl)c1NC(=O)CC1c2ccccc2Oc2ccccc21
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)c1cccc(CO)c1NC(=O)CC1c2ccccc2Oc2ccccc21
Temperature: 60 °C
Reaction time: 7 h
Yield: 66 %

Procedure:
4.24 g (25 mmol) of silver nitrate were added to a solution of 10.14 g (25.0 mmol) N-(2-isopropyl-6-chloromethylphenyl)-2-(9H-xanthen-9-yl)acetamide [prepared as described in step (iv) above] in a mixture of 500 ml of acetone, 100 ml of tetrahydrofuran and 200 ml of water, and the resulting mixture was stirred for 7 hours at 60° C. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the concentrate was diluted with ethyl acetate. The diluted mixture was washed with water and with a saturated aqueous solution of sodium chloride, in that order. The organic phase was then dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 3:1 by volume mixture of methylene chloride and ethyl acetate as the eluent, to give 6.41 g (yield 66%) of the title compound as crystals.
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4]([OH:6])=[O:5].[CH2:8](O)[CH3:9]>>[CH3:1][C:2]([CH3:7])=[CH:3][C:4]([O:6][CH2:8][CH3:9])=[O:5]
Reactant: CCO
Reactant: CC(C)=CC(=O)O
Product: CCOC(=O)C=C(C)C

Procedure:
Ten grams 3,3-dimethylacrylic acid was dissolved in 100 ml absolute ethanol and 0.5 ml concentrated (37% approx.) hydrochloric acid added. The reaction mix was refluxed for 24 to 48 hours with a Dean-Stark trap filled with activated molecular sieves inserted between the reaction vessel and the condenser. After cooling, the solvent was removed by rotary evaporation under reduced pressure at 50° C. to yield 6.3 g of a cloudy, yellow oil (ethyl 3-methyl-2-butenoate.)
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[S:31][C:8]2[NH:9][C:10]([C:12]([NH:14][CH:15]3[CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]([CH2:25][C:26]([O:28]C)=O)[C:16]3=[O:30])=[O:13])=[CH:11][C:7]=2[CH:6]=1>CCO>[Cl:4][C:5]1[S:31][C:8]2[NH:9][C:10]([C:12]([NH:14][CH:15]3[CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]([CH2:25][C:26]([NH:2][NH2:3])=[O:28])[C:16]3=[O:30])=[O:13])=[CH:11][C:7]=2[CH:6]=1
Reactant: COC(=O)CN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)CN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21
Yield: 76 %

Procedure:
Hydrazine monohydrate (1 mL, 20.6 mmol) was added to a suspension of methyl [3-{[(2-chloro-6H-thieno[2,3-b]pyrrol-5-yl)carbonyl]amino}-2-oxo-3,4-dihydroquinolin-1(2H)-yl]acetate (Example 1); 221 mg, 0.53 mmol) in EtOH (10 mL) and heated to reflux for 20 hours. On cooling the mixture was concentrated under reduced pressure and H2O (20 mL) added and the white precipitate filtered off and dried in vacuo to give the title product (169 mg, 76%) as an off white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][OH:16])=[CH:9][CH:8]=[C:7]([Br:17])[CH:6]=2.Cl.N1C=[CH:23][CH:22]=[CH:21][CH:20]=1.C(OC)(OC)(OC)CCC>C1(C)C=CC=CC=1>[Br:17][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:12]([CH2:13][CH2:14][CH2:15][OH:16])[C:20]([CH2:21][CH2:22][CH3:23])=[N:1][C:2]=3[CH:3]=[N:4][C:5]=2[CH:6]=1
Reactant: Nc1cnc2cc(Br)ccc2c1NCCCO
Reactant: c1ccncc1
Agent: CCCC(OC)(OC)OC
Agent: Cl
Solvent: Cc1ccccc1
Product: CCCc1nc2cnc3cc(Br)ccc3c2n1CCCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 230.6 %

Procedure:
A mixture of 3-[(3-amino-7-bromoquinolin-4-yl)amino]propan-1-ol (7.2 g, 24 mmol), pyridine hydrochloride (1.05 g, 9.09 mmol) and trimethyl orthobutyrate (4.05 mL, 25.5 mmol) in toluene (240 mL) was heated at reflux for two hours under an atmosphere of nitrogen. The solvent was removed under reduced pressure, and the residue was dissolved in methanol (100 mL). Aqueous sodium hydroxide (15 mL of 6 M) was added to the solution, and the resulting mixture was stirred for two hours at ambient temperature. A portion of the solvent was removed under reduced pressure, and the resulting mixture was adjusted to pH 7 with the addition of 6 N hydrochloric acid. The mixture was then extracted with chloroform (4×150 mL), and the combined extracts were washed sequentially with saturated aqueous sodium bicarbonate (40 mL) and brine (30 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. An analysis by nuclear magnetic resonance spectroscopy indicated the presence of starting material, and the procedure was repeated using 1 mL trimethyl orthobutyrate and heating at reflux for one hour. Following the work-up procedure, the resulting solid was triturated with ethyl acetate and isolated by filtration to provide 7.30 g of 3-(7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propan-1-ol.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][CH2:9][C:8](=[O:12])[C:7]=2[CH:6]=[CH:5][CH:4]=1.[BH4-].[Na+].O.[Cl-].[NH4+]>CO>[CH3:1][O:2][C:3]1[C:11]2[O:10][CH2:9][CH:8]([OH:12])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1OCC2=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: COc1cccc2c1OCC2O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
To a cold (ice water) solution of 7-methoxy-3-(2H)-benzofuranone (846 mg; 5.0 mmol) in methanol (5 mL) is added sodium borohydride (179 mg; 5.0 mmol) is stirred for 15 minutes. Water (5 mL) is added to the solution and stirred 15 minutes. Saturated ammonium chloride (20 mL) is added and the solution is extracted with ethyl acetate. The organics are separated and dried over magnesium sulfate. The solvent is removed to give 831 milligrams of 7-methoxy-2,3-dihydrobenzofuran-3-ol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=O)[CH:12]=2)[CH2:7]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][O:2][C:3]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:15][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:12]=2)[CH2:7]1
Reactant: COc1ccc(CN2Cc3ccc(C(=O)N4CCOCC4)cc3C2)c(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN2Cc3ccc(CN4CCOCC4)cc3C2)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.6 %

Procedure:
A solution of [2-(2,4-dimethoxybenzyl)-2,3-dihydro-1H-isoindol-5-yl]-morpholin-4-yl-methanone (1.05 g; 2.75 mmol) in dry THF (20 ml) under a nitrogen atmosphere was treated with 1M lithium aluminium hydride solution then stirred at room temperature overnight. The reaction was quenched by the cautious addition of saturated sodium sulphate solution, then diluted with EtOAc (40 ml), filtered through Celite™ and evaporated. Purification by flash column chromatography (2% then 5% MeOH/DCM as eluant) gave 340 mg of 2-(2,4-dimethoxybenzyl)-5-morpholin-4-ylmethyl-2,3-dihydro-1H-isoindole as a pale brown gum.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]2[CH2:14][CH:13]=[CH:12][CH2:11][CH:10]([C:15]3[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N:16]=3)[N:9]2C(=O)C(F)(F)F)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl>CO>[CH3:1][C:2]1[C:3]([CH:8]2[CH2:14][CH:13]=[CH:12][CH2:11][CH:10]([C:15]3[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N:16]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1C1CC=CCC(c2ncccc2C)N1C(=O)C(F)(F)F
Agent: Cl
Solvent: CO
Product: Cc1cccnc1C1CC=CCC(c2ncccc2C)N1
Yield: 55.7 %

Procedure:
A solution of 1-[2,7-bis-(3-methyl-pyridin-2-yl)-2,3,6,7-tetrahydro-azepin-1-yl]-2,2,2-trifluoroethanone (73 mg, 0.194 mmol) was dissolved in MeOH (8 mL) and 6N HCl (2 mL) and was heated to 65° C. for 5 hours. The mixture turned black in color. The solvent was removed in vacuo and the residue was basified with 10 N NaOH solution. The mixture was extracted with CH2Cl2 (3×50 mL). The organic extracts were dried (MgSO4), filtered and concentrated. The residue was purified by radial chromatography (1 mm plate, 1:5 EtOAc:hexanes then EtOAc then 10:1 EtOAc/MeOH) to provide 30.2 mg of 2,7-bis-(3-methyl-pyridin-2-yl)-2,3,6,7-tetrahydro-1H-azepine. 1H NMR(CDCl3) δ 2.29-2.36 (m 3H), 2.41 (6H, s), 3.04 (dd, 2H, J=16.2, 10.2 Hz), 5.15 (d, 2H, J=15.6 Hz), 5.81-5.90 (m, 2H), 7.04 (dd, 2H, J=7.5, 4.2 Hz), 7.43 (d, 2H, J=7.5 Hz), 8.35 (d, 2H, J=4.2 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:16][N:15]([C:17]([O:19][CH3:20])=[O:18])[CH2:14]3)[O:10][N:9]=2)=[CH:4][C:3]=1[NH:21][C:22]([C:24]1[N:28]2[CH:29]=[C:30]([CH2:33][CH2:34][C:35](=[O:37])[CH3:36])[CH:31]=[CH:32][C:27]2=[N:26][CH:25]=1)=[O:23].[CH3:38][Mg]Br>C1COCC1>[OH:37][C:35]([CH3:38])([CH3:36])[CH2:34][CH2:33][C:30]1[CH:31]=[CH:32][C:27]2[N:28]([C:24]([C:22]([NH:21][C:3]3[CH:4]=[C:5]([C:8]4[N:12]=[C:11]([CH:13]5[CH2:14][N:15]([C:17]([O:19][CH3:20])=[O:18])[CH2:16]5)[O:10][N:9]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[O:23])=[CH:25][N:26]=2)[CH:29]=1
Reactant: C[Mg]Br
Reactant: COC(=O)N1CC(c2nc(-c3ccc(C)c(NC(=O)c4cnc5ccc(CCC(C)=O)cn45)c3)no2)C1
Solvent: C1CCOC1
Product: COC(=O)N1CC(c2nc(-c3ccc(C)c(NC(=O)c4cnc5ccc(CCC(C)(C)O)cn45)c3)no2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirring solution of methyl 3-(3-(4-methyl-3-(6-(3-oxobutyl)imidazo[1,2-a]pyridine-3-carboxamido)phenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (F65) (10 mg, 0.0199 mmol) in anhydrous THF (1 mL) at −78° C. under a stream of Argon was added methylmagnesium bromide (27 uL, 0.080 mmol). The reaction was stirred to room temperature for 15 minutes then cooled to 0° C. and quenched with 1N HCl. The crude product was purified by reverse phase preparative HPLC to give methyl 3-(3-(3-(6-(3-hydroxy-3-methylbutyl)imidazo[1,2-a]pyridine-3-carboxamido)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (F67). 1H NMR (400 MHz, d6-DMSO) δ 10.10 (s, 1H), 9.34 (s, 1H), 8.63 (s, 1H), 8.10 (d, J=1.6 Hz, 1H), 7.84 (dd, J=1.6, 8.0 Hz, 1H), 7.78 (d, J=9.2 Hz, 1H), 7.56-7.54 (m, 1H), 7.51 (d, J=8.4 Hz, 1H), 4.39-4.34 (m, 2H), 4.31-4.25 (m, 1H), 4.22-4.17 (m, 2H), 3.59 (s, 3H), 2.76-2.72 (m, 2H), 2.37 (s, 3H), 1.71-1.67 (m, 2H), 1.15 (s, 6H). MS m/z 519.23 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]([N:6]1[C:14]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[C:8]([I:15])=[CH:7]1)[CH3:5].CI.[CH3:19]C(C)([O-])C.[K+]>C1COCC1>[I:15][C:8]1[C:9]2[CH:10]=[N:11][CH:12]=[CH:13][C:14]=2[N:6]([C:4]([CH3:19])([CH3:5])[C:3]([O:2][CH3:1])=[O:16])[CH:7]=1
Reactant: COC(=O)C(C)n1cc(I)c2cnccc21
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)n1cc(I)c2cnccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 37 %

Procedure:
To a solution of 2-(3-iodo-pyrrolo[3,2-c]pyridine-1-yl)-propionic acid methyl ester (Preparation 57, 13.1 g, 39.7 mmol) in THF (15 mL) was added methyl iodide (2.96 mL, 47.6 mmol) followed immediately by a 1M solution of potassium tertbutoxide in THF (5.34 g, 47.6 mmol) and the reaction was stirred at room temperature for 15 minutes. The reaction was quenched with water, and the remaining THF removed in vacuo. The residue was extracted with EtOAc, dried and concentrated in vacuo to afford the title compound as a yellow solid (5.1 g, 37%).
Reaction SMILES: [NH3:1].[CH:2]([CH:20]1[CH2:25][C:24](=[O:26])[O:23][C:21]1=[O:22])=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].Cl>C(#N)C>[CH:2]([CH:20]([CH2:25][C:24]([OH:23])=[O:26])[C:21]([NH2:1])=[O:22])=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCCCCCCC=CC1CC(=O)OC1=O
Reactant: N
Agent: Cl
Solvent: CC#N
Product: CCCCCCCCCCCCCCCCC=CC(CC(=O)O)C(N)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
389 g of a 25% aqueous ammonia was mixed with 200 ml of acetonitrile and to the mixture was added 100 g of n-octadecenylsuccinic anhydride, followed by stirring for 2 hours at room temperature. The mixture was neutralized with concentrated hydrochloric acid. The crystals thus-deposited were collected by filtration, washed with water and then with acetonitrile, and dried to obtain 84.5 g of n-octadecenyl-succinic monoamide as colorless crystals.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([I:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]([CH3:14])[CH3:13].[NH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.C(N(CC)CC)C>CC(O)C>[I:11][C:9]1[N:8]=[C:7]2[C:3]([N:4]=[CH:5][N:6]2[CH:12]([CH3:14])[CH3:13])=[C:2]([NH:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[N:10]=1
Reactant: CC(C)n1cnc2c(Cl)nc(I)nc21
Reactant: NCCc1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC(C)n1cnc2c(NCCc3ccc(O)cc3)nc(I)nc21
Temperature: 85 °C

Procedure:
A mixture of 6-chloro-2-iodo-9-isopropyl-9H-purine (a) (1.0 g, 3.1 mmol), tyramine (0.64 g, 4.65 mmol), triethylamine (0.63 g, 6.2 mmol) and 2-propanol (30 mL) was heated at 85° C. for 2 hr. The reaction mixture was concentrated and saturated aqueous sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate (50 ml×3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (25 to 75% ethyl acetate in hexane eluant) to afford the title compound as a solid. MS m/z 424.1 (M+1).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([F:12])[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH:16]1(OB(O)O)[CH2:18][CH2:17]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C>[CH:16]1([C:2]2[CH:11]=[C:10]([F:12])[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH2:18][CH2:17]1
Reactant: OB(O)OC1CC1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(F)cc1Br
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc([N+](=O)[O-])c(F)cc1C1CC1
Temperature: 110 °C
Reaction time: 1.5 h
Yield: 62.2 %

Procedure:
Under a nitrogen atmosphere, to a mixed liquid of 2.58 g of methyl 2-bromo-4-fluoro-5-nitrobenzoate in 50 mL of toluene and 1 mL of water were added 956 mg of cyclopropylboric acid, 360 mg of tricyclohexyl phosphine, 3.95 g of tripotassium phosphate, and 140 mg of palladium acetate, followed by stirring at 110° C. for 1.5 hours. The mixture was poured into a mixed liquid of water and ethyl acetate, and the insoluble materials were removed by filtration. The aqueous layer was separated, the organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (normal hexane/ethyl acetate) to obtain 1.38 g of methyl 2-cyclopropyl-4-fluoro-5-nitrobenzoate.
Reaction SMILES: [Br:1]Br.[CH2:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[OH:12])[CH3:4].OS([O-])=O.[Na+]>C(Cl)(Cl)Cl>[Br:1][C:9]1[CH:8]=[C:7]([CH3:11])[C:6]([OH:12])=[C:5]([CH2:3][CH3:4])[CH:10]=1
Reactant: BrBr
Reactant: CCc1cccc(C)c1O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCc1cc(Br)cc(C)c1O
Reaction time: 2 h

Procedure:
A solution of 12.7 mL (247 mmol) bromine in 10 mL chloroform was added dropwise at RT to a solution of 33.6 g (247 mmol) 2-ethyl-6-methyl-phenol in 350 mL chloroform and the mixture was stirred for 2 h. The reaction mixture was combined with an aqueous NaHSO3 solution and stirred for 20 min. The phases were separated and the organic phase was washed with saturated NaCl solution, dried on Na2SO4 and concentrated by evaporation i.vac. Column chromatography (silica gel, Cyc/EtOAc 9:1) yielded the product.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@@H:5]3[C@@H:21]([C@@:22]4([CH3:28])[CH2:23][CH2:24][C@H:25]([OH:27])[CH2:26][C:2]124)[CH2:20][CH2:19][C@@:18]1([CH3:29])[C@H:6]3[CH2:7][CH2:8][C@@H:9]1[C@H:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15].[NH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:35][CH2:36][CH2:37][CH2:38][NH2:39].C(O)CCC>COC(C)(C)C>[OH:1][C@:2]12[CH2:26][C@@H:25]([OH:27])[CH2:24][CH2:23][C@:22]1([CH3:28])[C@@H:21]1[C@H:5]([C@H:6]3[C@:18]([CH3:29])([CH2:19][CH2:20]1)[C@@H:9]([C@H:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:8][CH2:7]3)[CH2:4][C@H:3]2[NH:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:35][CH2:36][CH2:37][CH2:38][NH2:39]
Reactant: NCCCCNCCCN
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C[C@@H]4OC45C[C@@H](O)CC[C@]5(C)[C@H]3CC[C@]12C
Solvent: CCCCO
Solvent: COC(C)(C)C
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C[C@@H](NCCCCNCCCN)[C@@]4(O)C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Yield: 50.4 %

Procedure:
5,6α-epoxicholestan-3β-ol (8.9 g, 22.1 mmol, 1 eq) and spermidine (6.4 g, 44.1 mmol, 2 eq) were charged in a round-bottomed flask equipped with a magnetic stirrer bar. 1-Butanol (70 ml, 5 vol) was added and the mixture heated to reflux for 40 h. The reaction mixture was cooled at r.t., diluted with methyl-tertbutyl-ether (5 vol) and washed with water (5 vol) and with brine (5 vol). The organic layer was passed through a silica pad (40 g) eluted with methyl-tertbutyl-ether (3 vol) then 10% Methanol/ethyl acetate (60 vol). Fractions of interest were pooled and the solvent was removed under reduced pressure to give 5α-Hydroxy-6β-[4-(3-aminopropylamino)-butylamino]-cholestan-3β-ol as a light yellow solid (6.1 g, 50%). In same conditions, use of ethanol as solvent (40 vol) and Ca(OTf)2 as catalyst gave a 11% yield.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][C:20]=2[CH3:21])[C:12](N(OC)C)=[O:13])[C:5]([CH3:22])=[N:4][C:3]=1[O:23][CH2:24][C:25]1[N:26]=[C:27]([CH3:30])[S:28][CH:29]=1.[C:31]([Mg]Cl)#[CH:32]>O1CCCC1>[Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([C:12](=[O:13])[C:31]#[CH:32])[CH:18]=[CH:19][C:20]=2[CH3:21])[C:5]([CH3:22])=[N:4][C:3]=1[O:23][CH2:24][C:25]1[N:26]=[C:27]([CH3:30])[S:28][CH:29]=1
Reactant: C#C[Mg]Cl
Reactant: CON(C)C(=O)c1ccc(C)c(-n2c(C)nc(OCc3csc(C)n3)c(Br)c2=O)c1
Solvent: C1CCOC1
Product: C#CC(=O)c1ccc(C)c(-n2c(C)nc(OCc3csc(C)n3)c(Br)c2=O)c1

Procedure:
To a solution of 3-[5-bromo-2-methyl-4-(2-methyl-thiazol-4-ylmethoxy)-6-oxo-6H-pyrimidin-1-yl]-N-methoxy-4,N-dimethyl-benzamide from Step C (71 mg, 0.14 mmol) in tetrahydrofuran (2 mL), cooled using an ice water bath, was added ethynylmagnesium chloride, 0.5M in tetrahydrofuran, (0.42 mL, 0.21 mmol) in a drop-wise manner. Additional Grignard reagent was added as necessary to ensure full product formation. After thirty minutes, the reaction was quenched into ice cold water and extracted with ethyl acetate. The organic layer was washed with saturated ammonium chloride, water and brine and dried over magnesium sulfate. The slurry was filtered and concentrated. The crude material was used without any additional purification.
Reaction SMILES: Cl.[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]=1.[CH3:12][C:13]([C:15]1[CH2:19][CH2:18][CH2:17][CH:16]=1)=[O:14]>C(O)C>[CH2:16]1[CH:15]2[CH:19]([N:3]3[CH:2]([CH2:12][C:13]2=[O:14])[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4]3)[CH2:18][CH2:17]1
Reactant: CC(=O)C1=CCCC1
Reactant: C1=NCCc2ccccc21
Agent: Cl
Solvent: CCO
Product: O=C1CC2c3ccccc3CCN2C2CCCC12

Procedure:
A mixture of 16.7 g (0.1 mole) of 3,4-dihydroisoquinoline hydrochloride and 27.0 g (0.02 mole) of 1-cyclopenten-1-yl methyl ketone in 22 ml of ethanol is refluxed overnight then evaporated to dryness. The remaining solid is dissolved in water and washed with ether. The aqueous layer is made basic with concentrated ammonium hydroxide solution with stirring. Upon the formation of an oil, ice is added to the mixture after which a solid is formed. The solid material is washed with water, dried overnight in a vacuum oven, and recrystallized from hexane to give 1,2,3,3a,5,6,10b,11,12,12 a-decahydrobenzo[a]cyclopenta[f]quinolizin-12-one, M.P. 101°-102.5° C.