Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.[C:6]([C:8]1([OH:13])[CH2:12][CH2:11][CH2:10][CH2:9]1)#[CH:7].N1C=CN=C1.[CH2:19]([Si:21]([CH2:25][CH3:26])([CH2:23][CH3:24])Cl)[CH3:20]>CCCCCC>[C:6]([C:8]1([O:13][Si:21]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:19][CH3:20])[CH2:12][CH2:11][CH2:10][CH2:9]1)#[CH:7]
Reactant: C#CC1(O)CCCC1
Reactant: CC[Si](Cl)(CC)CC
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: C#CC1(O[Si](CC)(CC)CC)CCCC1
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
To a dimethylformamide solution (49.5 ml) of 1-ethynyl-1-hydroxycyclopentane (5.45 g, 49.5 mmol) were added imidazole (6.74 g, 99.0 mmol) and triethylchlorosilane (9.97 ml, 59.4 mmol) at room temperature, followed by stirring for 30 minutes. The reaction solution was added to a mixture of n-hexane and a saturated aqueous sodium bicarbonate solution, and the organic layer was separated. The aqueous layer was extracted with hexane, and the organic layers were combined, washed with a saturated aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulfate. After filtration, the filtrate was evaporated under reduced pressure to give the title compound (9.26 g).
Reaction SMILES: [NH2:1][C@H:2]([CH2:10][OH:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H][H]>C(O)C.[Pt]>[CH2:12]([NH:1][C@H:2]([CH2:10][OH:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: [H][H]
Reactant: O=Cc1ccccc1
Reactant: N[C@H](CO)Cc1ccccc1
Agent: [Pt]
Solvent: CCO
Product: OC[C@H](Cc1ccccc1)NCc1ccccc1
Temperature: 60 °C
Yield: 48.1 %

Procedure:
L-Phenylalaninol (5 g, 33 mmoles) and 3.59 g (33.83 mmoles) of benzaldehyde were dissolved in 55 mL of 3A ethanol under inert atmosphere in a Parr shaker and the mixture was warmed to 60° C. for 2.7 hours. The mixture was cooled to approximately 25° C. and 0.99 g of 5% platinum on carbon was added and the mixture was hydrogenated at 60 psi of hydrogen and 40° C. for 10 hours. The catalyst was filtered off, the product was concentrated under reduced pressure and the crude solid product was recrystallized from 150 mL of heptane to give 3.83 g (48% yield) of N-benzyl-L-phenylalaninol as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[N:8][CH:7]=[C:6]2[CH2:13][C:14](O)=O)#[CH:2].CCN(C(C)C)C(C)C.[NH2:26][C:27]1[C:28](=[O:40])[N:29]([CH3:39])[C:30](=[O:38])[N:31]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:32]=1[NH2:33]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[N:8][CH:7]=[C:6]2[CH2:13][C:14]1[NH:26][C:27]2[C:28](=[O:40])[N:29]([CH3:39])[C:30](=[O:38])[N:31]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:32]=2[N:33]=1)#[CH:2]
Reactant: C#Cc1ccc2cncc(CC(=O)O)c2c1
Reactant: CC(C)Cn1c(N)c(N)c(=O)n(C)c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C#Cc1ccc2cncc(Cc3nc4c([nH]3)c(=O)n(C)c(=O)n4CC(C)C)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(6-Ethynyl-isoquinolin-4-yl)-acetic acid (58 mg, 0.28 mmol) is dissolved in DMF (1 ml) and O-(7-azabenzotriazo-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.125 g, 0.33 mmol) and Hunig's base (0.180 ml, 1.03 mmol) are added, followed by a solution of 5,6-diamino-1-isobutyl-3-methyl-1H-pyrimidine-2,4-dione (58 mg, 0.28 mmol) in DMF (0.7 ml). The reaction is stirred at room temperature for 2 hours. The solvent is evaporated and the residue purified by flash column chromatography (30:1 dichloromethane-methanol elution). The intermediate is dissolved in methanol (2 ml) and water (2.75 ml) added, followed by 4M aqueous sodium hydroxide (0.25 ml). The reaction is heated at 40° C. for 2 hours, then stirrred for 16 hours at ambient temperature. The solvent is evaporated and the crude product purified by flash column chromatography (30:1 dichloromethane-methanol elution) to afford 8-(6-ethynyl-isoquinolin-4-ylmethyl)-3-isobutyl-1-methyl-3,7-dihydro-purine-2,6-dione, [MH]+ 388.
Reaction SMILES: [CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]([CH3:4])[CH3:3].[C:25]([O:29][C:30]([NH:32][C@H:33]([C:38](O)=[O:39])[CH2:34][CH2:35][S:36][CH3:37])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[CH3:24][C:21]1[CH:22]=[CH:23][C:18]([S:15]([N:5]([C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:38]([C@@H:33]([NH:32][C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[CH2:34][CH2:35][S:36][CH3:37])=[O:39])[CH2:1][CH:2]([CH3:3])[CH3:4])(=[O:17])=[O:16])=[CH:19][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCN)C(=O)O)cc1
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)NCCCC[C@@H](C(=O)O)N(CC(C)C)S(=O)(=O)c1ccc(C)cc1

Procedure:
The title compound was prepared from Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-L-lysine (100 mg, 0.29 mmol, example 1, step E) as described in general procedure Bc using commercially available Nα-tert-butoxycarbonyl-L-methionine (75 mg, 0.3 mmol). The final product was triturated with ether to yield 170 mg (96%) of the desired material.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH2:6][C:7]1[CH:8]=[C:9]([NH:14][C:15](=[O:24])[C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)[CH:10]=[CH:11][C:12]=1Cl.[CH2:25]([O:27][CH2:28][CH2:29][O:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=1)[CH3:26].N1C=CC=C[CH:41]=1>O>[C:22]([C:19]1[CH:20]=[CH:21][C:16]([C:15]([NH:14][C:9]2[CH:10]=[CH:11][C:12]([CH3:41])=[C:7]([NH:6][C:35](=[O:36])[C:34]3[CH:38]=[CH:39][C:31]([O:30][CH2:29][CH2:28][O:27][CH2:25][CH3:26])=[CH:32][CH:33]=3)[CH:8]=2)=[O:24])=[CH:17][CH:18]=1)#[N:23]
Reactant: c1ccncc1
Reactant: N#Cc1ccc(C(=O)Nc2ccc(Cl)c(N)c2)cc1
Reactant: CCOCCOc1ccc(C(=O)O)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CCOCCOc1ccc(C(=O)Nc2cc(NC(=O)c3ccc(C#N)cc3)ccc2C)cc1
Temperature: -15 °C
Reaction time: 3 h

Procedure:
Phosphoryl chloride (0.03 ml) was added dropwise to a stirred mixture of N-(3-amino-4-chlorophenyl)-4-cyanobenzamide (0.08 g), 4-(2-ethoxyethoxy)benzoic acid (J. Org. Chem., 1973, 38, 3160; 0.062 g) and pyridine (4 ml) which had been cooled to −15° C. The reaction mixture was stirred at −15° C. for 3 hours and then allowed to warm to ambient temperature. The mixture was stirred for 48 hours. The reaction mixture was diluted with water and stirred overnight. The precipitate was isolated, washed with diethyl ether and dried under vacuum at 55° C. to give the title compound (0.024 g); NMR Spectrum: (DMSOd6) 1.15 (t, 3H), 3.49 (m, 2H), 3.73 (m, 2H), 4.19 (m, 2H), 9.86 (s, 1H), 10.62 (s, 1H); Mass Spectrum: M−H− 462.
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[CH:11]([N:12]([CH3:23])S(C2C=CC(C)=CC=2)(=O)=O)[CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:24][CH3:25])=[CH:7][CH:8]=2)[CH:3]1[CH2:26][CH2:27][O:28]C1CCCCO1.N.[Na].[Cl-:38].[NH4+]>CCOCC.O1CCOCC1>[ClH:38].[CH3:1][C:2]1([CH3:35])[CH:11]([NH:12][CH3:23])[CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:24][CH3:25])=[CH:7][CH:8]=2)[CH:3]1[CH2:26][CH2:27][OH:28]
Reactant: [Cl-]
Reactant: COc1ccc2c(c1)C(CCOC1CCCCO1)C(C)(C)C(N(C)S(=O)(=O)c1ccc(C)cc1)C2
Agent: N
Agent: [NH4+]
Agent: [Na]
Solvent: C1COCCO1
Solvent: CCOCC
Product: CNC1Cc2ccc(OC)cc2C(CCO)C1(C)C
Product: Cl
Reaction time: 2 h
Yield: 76 %

Procedure:
A solution of 121.5 g of 2,2-dimethyl-7-methoxy-3-(N-methyl-p-toluenesulphonamido)-1-[2-(tetrahydro-2-pyranyloxy)ethyl]-1,2,3,4-tetrahydronaphthalene in 300 ml of absolute ether and 5 ml of dry dioxane is added dropwise to 1500 ml of liquid ammonia which is stirred mechanically. At the same time small pieces of sodium (total amount 30 g) are added. After completion of the addition, which takes some 2 hours, the colourless reaction mixture is diluted cautiously with 200 ml of ether whereafter 15 g of ammonium chloride is added and the ammonia is allowed to evaporate. Then water is added and the aqueous layer separated from the organic one. The aqueous solution is shaken twice with ether and the combined organic solutions are extracted with an excess of dilute hydrochloric acid. The acidic aqueous solution is heated on a steambath during 1.5 hours. After cooling, the basic reaction product is set free by the addition of 4 N sodium hydroxide and gathered by extraction with ether. The ethereal solution is dried and evaporated. The product is converted into the hydrochloride by means of ethanolic hydrogen chloride. The crystalline precipitate which is formed has a melting point of 240°-244° C. It is not a single isomer but mixed with a lower melting one. Accordingly, from the mother liquor more soluble and lower melting (205°-210° C.) crystallisates can be obtained. No special attempts are made to achieve a separation of the isomers. The total yield is 76%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]([CH3:11])[CH3:10])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.ClCCl>CN(C=O)C.O>[Cl:8][C:6]1[N:5]=[C:4]([N:9]([CH3:11])[CH3:10])[N:3]=[C:2]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:7]=1
Reactant: CN(C)c1nc(Cl)nc(Cl)n1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)c1nc(Cl)nc(N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 55.1 %

Procedure:
The obtained 2,4-dichloro-6-dimethylamino-1,3,5-triazine (1.96 g, 10.2 mmol) was dissolved in DMF (20 ml), added with anhydrous potassium carbonate (1.45 g, 10.5 mmol) and cooled to -5° C.-0° C. This mixture was gradually added dropwise with morpholine (0.96 g, 11.0 mmol) dissolved in DMF (5 ml). The reaction mixture was stirred at room temperature for 17 hours and was evaporated under reduced pressure. The residue obtained was added with dichloromethane and water, and then shaken for mixing. The organic layer was separated from the mixture, sufficiently washed with water, dried over anhydrous magnesium sulfate and evaporated. The residue obtained was purified by silica gel column chromatography, using n-hexane and ethyl acetate (8: 2) as eluant, to obtain 1.37 g (yield: 55.4%) of 2-chloro-4-dimethylamino-6-morpholino-1,3,5-triazine as colorless crystals having melting point of 96° C. -97° C.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C@@H:11]([CH3:23])[CH2:10]1)C1C=CC=CC=1.C([N:38](CC1C=CC=CC=1)[C@@H:39]1[CH2:44][CH2:43][C@@H:42]([NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])[C@H:41]([CH3:53])[CH2:40]1)C1C=CC=CC=1>[OH-].[OH-].[Pd+2].CCO>[NH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])[C@@H:11]([CH3:23])[CH2:10]1.[NH2:38][C@@H:39]1[CH2:44][CH2:43][C@@H:42]([NH:45][C:46](=[O:52])[O:47][C:48]([CH3:50])([CH3:49])[CH3:51])[C@H:41]([CH3:53])[CH2:40]1
Reactant: C[C@H]1C[C@@H](N(Cc2ccccc2)Cc2ccccc2)CC[C@@H]1NC(=O)OC(C)(C)C
Reactant: C[C@@H]1C[C@H](N(Cc2ccccc2)Cc2ccccc2)CC[C@H]1NC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: C[C@@H]1C[C@H](N)CC[C@H]1NC(=O)OC(C)(C)C
Product: C[C@H]1C[C@@H](N)CC[C@@H]1NC(=O)OC(C)(C)C

Procedure:
A mixture of tert-butyl (1S,2S,4S)-4-(dibenzylamino)-2-methylcyclohexylcarbamate/tert-butyl (1R,2R,4R)-4-(dibenzylamino)-2-methylcyclohexylcarbamate (750 mg, 1.836 mmol) and Pearlman's catalyst (290 mg, 2.73 mmol) in EtOH (35 mL) was hydrogenated in a steel bomb under H2-atmosphere (pressure ˜75 psi) for 16 hr. The steel bomb was flushed with Argon, Celite and methanol were added. The mixture was filtered and concentrated in vacuo. The white resulting residue was dissolved in acetonitrile/water (1:1) and lyophilized giving crude tert-butyl (1S,2S,4S)-4-amino-2-methylcyclohexylcarbamate/tert-butyl (1R,2R,4R)-4-amino-2-methylcyclohexylcarbamate, which was directly used in the next step without further purification. Yield: 412 mg. LCMS (m/z): 173.2/229.3 [M+H]+; Retention time=0.54 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:26]([F:29])([F:28])[F:27])[O:14][N:13]=[C:12]([C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[C:17]([CH3:25])[CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].[OH-].[Na+].Cl>C1COCC1.O.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:26]([F:28])([F:29])[F:27])[O:14][N:13]=[C:12]([C:15]3[CH:24]=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[C:17]([CH3:25])[CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8]
Reactant: COC(=O)c1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.4 %

Procedure:
A mixture of methyl 4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoate (4.1 g, 8.8 mmol) and NaOH (3.5 g, 88 mmol) in THF—H2O-MeOH (1:1:1, 90 mL) was stirred at rt for 18 h. The mixture was acidified with 2 N HCl and extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give 4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid (3.8 g; yield 95%) as a white solid. MS: m/z=451.7 (M+1, ESI+).
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:19][C@H:18]([OH:20])[CH2:17][C@H:13]2[C:14]([OH:16])=[O:15])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[CH3:30][O:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Cl)=[CH:34][CH:33]=1>CN(C)C=O.C(OCC)(=O)C>[CH3:30][O:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][O:15][C:14](=[O:16])[C@@H:13]2[CH2:17][C@@H:18]([OH:20])[CH2:19][N:12]2[C:10]([O:9][CH2:8][C:7]2[CH:21]=[CH:22][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:11])=[CH:34][CH:33]=1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(CCl)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)[C@@H]2C[C@@H](O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 70 °C
Reaction time: 10 h

Procedure:
15.0 g of trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-proline and 13.5 ml of triethylamine were dissolved in 150 ml of dried dimethylformamide, and 12.66 ml of p-methoxybenzyl chloride was added dropwise to the solution under a nitrogen stream, followed by stirring at 70° C. for 10 hours. The reaction mixture was diluted with 500 ml of ethyl acetate, washed with water, dried over sodium sulfate and distilled off to remove the solvent. Recrystallization of the residue from diethyl ether gave trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-proline p-methoxybenzyl ester.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[N:23]=1.[C:24](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C)C=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:24])[C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH2:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:6]=2[N:23]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1Nc2cnc(Cl)nc2N(CCc2ccccc2)CC1(F)F
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)C(F)(F)CN(CCc2ccccc2)c2nc(Cl)ncc21
Reaction time: 4 h
Yield: 61.2 %

Procedure:
To a solution of 0.64 g (0.0019 mole) of 2-chloro-7,7-difluoro-9-phenethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-275) in 15 mL of dimethylformamide was added 0.92 g (0.0029 mole) of cesium carbonate, followed by 0.35 mL (0.0057 mole) of iodomethane. After stirring four hours, the mixture filtered and then concentrated under reduced pressure. Ice water and dichloromethane were added. The mixture was extracted with dichloromethane twice. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 0.41 g of 2-chloro-7,7-difluoro-5-methyl-9-phenethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-275) as a yellow solid.
Reaction SMILES: [CH2:1]([NH2:11])[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.[CH2:12]1[CH2:18][S:15](=[O:17])(=[O:16])[O:14][CH2:13]1>CC(C)=O>[CH2:1]([NH:11][CH2:13][CH2:12][CH2:18][S:15]([OH:17])(=[O:16])=[O:14])[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: O=S1(=O)CCCO1
Solvent: CC(C)=O
Product: O=S(=O)(O)CCCNCc1ccc2c(c1)OCO2
Temperature: 25 °C

Procedure:
To a solution of piperonylamine (2.5 mL, 19.8 mmol) in acetone (30 mL) was added 1,3-propane sultone (2.52 g, 20.8 mmol). The mixture stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid material was collected by filtration, washed with acetone (2×25 mL) and dried in vacuo. The product was suspended in 90% Acetone/MeOH (75 mL). The suspension was stirred at reflux for 30 sec., the solid was collected by filtration and dried in vacuo. This allowed the isolation of compound AW, 2.56 g (45%).
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[CH3:7][N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1>C1CCCCC1>[CH3:7][N:8]1[CH2:13][CH2:12][CH:11]([NH:1][N:2]2[CH:6]=[CH:5][CH:4]=[CH:3]2)[CH2:10][CH2:9]1
Reactant: Nn1cccc1
Reactant: CN1CCC(=O)CC1
Solvent: C1CCCCC1
Product: CN1CCC(Nn2cccc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.1 %

Procedure:
A solution of 1-aminopyrrole (4.2 g, 0.05 mol) and 1-methyl-4-piperidone (6.9 g, 0.06 mol) in cyclohexane was refluxed overnight (about 16 hours) over 4 Å molecular sieves. After 3 hours, an additional 1 g of 1-methyl-4-piperidone was added. The molecular sieves were filtered off and the cyclohexane removed by evaporation under reduced pressure. The resulting oil was dissolved in isopropanol and 5 g of sodium borohydride added. The mixture was stirred at reflux for three hours, then methanol was added, the heat was removed, and stirring continued until the mixture had cooled to room temperature. The solvent was removed by evaporation under reduced pressure to give a residue to which water was added. This mixture was extracted with dichloromethane, the dichloromethane solution was dried with saturated sodium chloride solution and magnesium sulfate, and the dichloromethane evaporated in vacuo to give 7 g (78%) of 1-methyl-4-(1H-pyrrol-1-yl)aminopiperidine. To a cooled solution of 1-methyl-4-(1H-pyrrol-1-yl)aminopiperidine (5.4 g, 0.03 mol) and triethylamine (3.35 g, 0.033 mol) in CHCl3 (100 ml) was added dropwise a solution of propionyl chloride (3.07 g, 0.033 mol) in CHCl3 (100 ml). The reaction mixture was stirred at ice bath temperature for one hour, then at room temperature overnight (about 16 hours). The chloroform solution was washed with water, dried with saturated sodium chloride and magnesium sulfate, and the chloroform removed to give 4.8 g of an oil. The oxalate was formed by adding ethereal oxalic acid but did not crystallize. The resultant oil was basified, extracted with dichloromethane and dried to give 3.2 g of an oil. This oil was chromatographed on a high pressure liquid chromatograph (HPLC) using 11/2% diethylamine in acetonitrile. The resultant 1.5 g of free base was converted to the maleate (1.9 g) by adding ethereal maleic acid and recrystallized from absolute ethanol/ether to give 1.8 g, m.p. 146°-147° C. of N-(1-methylpiperidin-4-yl)-N-(1H-pyrrol-1-yl)propanamide maleate. The recovered starting material was reacted again with propionyl chloride (0.7 g) in CH2Cl2 (20 ml) with sodium bicarbonate (1 g) at room temperature overnight. Work-up gave an oil which was dissolved in ether, and an ether solution of maleic acid added to give the maleate salt. Recrystallization from absolute ethanol/ether gave an additional 1.5 g of product of N-(1-methylpiperidin-4-yl)-N-(1H-pyrrol-1-yl)propanamide maleate, mp 146°-147° C., combined yield 3.3 g (9.39 mmole), 31.3% yield from 1-methyl-4-(1H-pyrrol-1-yl)aminopiperidine.
Reaction SMILES: [OH:1][CH:2]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([O:21][CH3:22])[CH:15]=1)[C:3](=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CN(C(C#N)CCCCCCCCC)C>>[OH:13][CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:2]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([O:21][CH3:22])[CH:15]=1)=[O:1]
Reactant: CCCCCCCCCC(=O)C(O)c1ccc(O)c(OC)c1
Agent: CCCCCCCCCC(C#N)N(C)C
Product: CCCCCCCCCC(O)C(=O)c1ccc(O)c(OC)c1

Procedure:
Similar procedure was used to synthesise 1-hydroxy-1-(4-hydroxy-3-methoxyphenyl)undecan-2-one where 1-(N,N-dimethylamino)-1-decylcyanide was formed instead and reacted with vanillin-THP.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Br.Br.[C:23]12[CH2:30][NH:29][CH2:28][C:27]=1[CH2:26][NH:25][CH2:24]2.N12CCCN=C1CCCCC2>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:25]4[CH2:26][C:27]5[CH2:28][NH:29][CH2:30][C:23]=5[CH2:24]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: C1NCC2=C1CNC2
Agent: Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CC4=C(CNC4)C3)c(F)cc2c1=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
0.4 g of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 0.8 g of 3,7-diazabicyclo[3.3.0]oct-1(5)-ene dihydrobromide and 0.8 ml of 1,8-diazabicyclo[5.4.0] undec-7-ene (DBU) were suspended in 30 ml of acetonitrile and the suspension was refluxed in 100° C. oil bath for 8 hours. The reaction mixture was kept overnight at room temperature. The produced precipitate was filtered and washed with methanol. 0.35 g of the title compound was obtained (yield 67%)
Reaction SMILES: Br[CH2:2][C:3]1N=[CH:7][C:6]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH:13]=2)=[O:10])=[CH:5][CH:4]=1.[C:25]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)(=[O:27])[CH3:26].[CH3:34]S(C)=O>>[C:25]([N:28]1[CH2:33][CH2:32][N:31]([CH2:2][C:3]2[CH:34]=[CH:7][C:6]([C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[CH:13]=3)=[O:10])=[CH:5][CH:4]=2)[CH2:30][CH2:29]1)(=[O:27])[CH3:26]
Reactant: CS(C)=O
Reactant: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(CBr)nc1
Reactant: CC(=O)N1CCNCC1
Product: CC(=O)N1CCN(Cc2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)cc2)CC1

Procedure:
6-(bromomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)pyridine-3-carboxamide (85 mg) was dissolved in DMSO (1 mL) and stirred for 1 h with N-acetylpiperazine. The reaction mixture was concentrated, and the crude residue was purified by revered phase HPLC to yield 4-((4-acetylpiperazin-1-yl)methyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl) benzamide. MS (Q1) 449.1 (M)+.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=1[N+:17]([O-:19])=[O:18].C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C>[CH2:1]([O:16][C:13]1[CH:14]=[CH:15][C:10]([Cl:9])=[C:11]([N+:17]([O-:19])=[O:18])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 93.4 %

Procedure:
This was prepared as follows:- A solution of benzyl bromide (10.26 g; 60 mmol) and 4chloro-3-nitrophenol (8.7 g; 50 mmol) in DMF (250 ml) was treated with Na2CO3 (10.6 g; 0.1 mol) and the mixture was stirred at room temperature for 3 days. The mixture was poured into water and extracted with Et2O. The organic phase was washed with brine and dried over MgSO4. The residue was purified by flash chromatography eluting with CH2Cl2 to give 5-benzyloxy-2-chloro-nitrobenzene as a pale yellow solid (12.32 g).