Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl.[C:16]1([C:22]2[N:26]=[C:25]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[S:24][N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:16]1([C:22]2[N:26]=[C:25]([N:27]3[CH2:32][CH2:31][N:30]([C:8]([NH:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[O:15])[CH2:29][CH2:28]3)[S:24][N:23]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C(Nc1ccccn1)OCC(Cl)(Cl)Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(Nc1ccccn1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Yield: 55.5 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl pyridin-2-ylcarbamate (270 mg, 0.610 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and diisopropylethylamine (0.129 ml, 0.738 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 3 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:7) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 124 mg (55.4%) of the desired product as a solid.
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][C@H:8]3[N:13]([CH2:14][CH:15]4[CH2:17][CH2:16]4)[CH2:12][CH2:11][C@:10]45[C@H:18]([C:20]([CH2:22][CH2:23][C@@:9]34[OH:24])=[O:21])[O:19][C:4]([C:5]=25)=[C:3]([OH:25])[CH:2]=1.Cl.N1C=CN=C1.[C:32]([Si:36]([CH3:39])([CH3:38])Cl)([CH3:35])([CH3:34])[CH3:33].O>C(OCC)C>[Si:36]([O:25][C:3]1[CH:2]=[CH:1][C:6]2[CH2:7][C@H:8]3[N:13]([CH2:14][CH:15]4[CH2:17][CH2:16]4)[CH2:12][CH2:11][C@:10]45[C:5]=2[C:4]=1[O:19][C@H:18]4[C:20](=[O:21])[CH2:22][CH2:23][C@@:9]35[OH:24])([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:39])[CH3:38]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Agent: Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 76 %

Procedure:
3.49 g of naltrexone hydrochloride was suspended in 10.5 ml of N,N-dimethylfonnamde. After adding 3.46 g of imidazole, 3.48 g of tert-butyldimethylchlorosilane was added followed by stirring for 35 minutes at room temperature. 30 ml of water and 50 ml of diethyl ether were added to the reaction system followed by separation. The aqueous layer was extracted twice with 30 ml of diethyl ether. The combined extracts were dried over anhydrous sodium sulfate and concentrated. The resulting residue was recrystallized from ethanol to obtain 3.2 g of the target compound (yield: 76%).
Reaction SMILES: C(OC([N:8]([C:24]1[N:25]([CH2:38][CH2:39][CH3:40])[N:26]=[C:27]2[C:36]=1[C:35]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N:29]=[C:28]2[Cl:37])[CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1)=O)(C)(C)C.[ClH:41].[NH3:42]>CO.C(O)C>[ClH:37].[ClH:41].[NH:14]1[CH2:13][CH2:12][CH:11]([CH2:10][CH2:9][NH:8][C:24]2[N:25]([CH2:38][CH2:39][CH3:40])[N:26]=[C:27]3[C:36]=2[C:35]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[N:29]=[C:28]3[NH2:42])[CH2:16][CH2:15]1
Reactant: N
Reactant: CCCn1nc2c(Cl)nc3ccccc3c2c1N(CCC1CCN(C(=O)OC(C)(C)C)CC1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: CCO
Product: CCCn1nc2c(N)nc3ccccc3c2c1NCCC1CCNCC1
Temperature: 150 °C

Procedure:
A solution of tert-butyl 4-{2-[(tert-butoxycarbonyl)(4-chloro-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)amino]ethyl}piperidine-1-carboxylate (1.41 g) in 7N ammonia in methanol (25 mL) was placed in a stainless steel pressure vessel and heated at 150° C. for 18 hours. The reaction mixture was cooled to ambient temperature and then concentrated under reduced pressure to provide a brown residue. The residue was suspended in anhydrous ethanol (20 mL). Hydrochloric acid (4 mL of 3M) was added and the reaction mixture was heated at reflux for 4 hours. The reaction mixture was concentrated under reduced pressure. The residue was triturated with diethyl ether and the resulting solid was isolated by filtration to provide 0.7 g of N1-(2-piperidin-4-ylethyl)-2-propyl-2H-pyrazolo[3,4-c]quinoline-1,4-diamine dihydrochloride as a brown solid. MS (APCI) m/z 353.30 (M+H)+. The experiment was repeated using 5.75 g of tert-butyl 4-{2-[(tert-butoxycarbonyl)(4-chloro-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)amino]ethyl}piperidine-1-carboxylate in 70 mL of 7N ammonia in methanol followed by treatment with 16.75 mL of 3M hydrochloric acid to provide 4.1 g of product as a brown solid. MS (APCI) m/z 353.26 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:16])[CH2:10]2)=[N:6][C:7]=1[NH2:8].[CH3:22][C:23]1[N:28]([C:29](O)=[O:30])[C:27](=[O:32])[CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>CN(C)C=O>[NH2:8][C:7]1[C:2]([NH:1][C:29]([N:28]2[C:23]([CH3:22])=[CH:24][CH:25]=[CH:26][C:27]2=[O:32])=[O:30])=[CH:3][CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:16])[CH2:10]2)[N:6]=1
Reactant: Cc1cccc(=O)n1C(=O)O
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cccc(=O)n1C(=O)Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Into a vial were added (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (100 μmol), 6-methyl-2-oxopyridine-1(2H)-carboxylic acid and N,N-dimethylformamide (1.5 mL) followed by O-(7-Azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (HATU) (200 μmol) and triethylamine (250 μmol). The vial was shaken for 16 h at room temperature. The mixture was concentrated via Speedvac. The residue was partitioned between dichloromethane and water. The organics were evaporated under vacuum to afford (R)—N-(2-amino-6-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)-6-methyl-2-oxopyridine-1(2H)-carboxamide which was used without further purification.
Reaction SMILES: [Cl:1][C:2](O[CH:5]([CH3:7])[CH3:6])=O.[C:8]([Cl:14])(=O)[CH2:9][CH:10](C)C>>[CH3:6][CH2:5][CH2:7][CH2:8][CH2:9][CH3:10].[Cl:14][CH2:2][Cl:1]
Reactant: CC(C)OC(=O)Cl
Reactant: CC(C)CC(=O)Cl
Product: CCCCCC
Product: ClCCl
Yield: 87 %

Procedure:
This compound was prepared according to the method described in Example 7, except that isopropyl chloroformate was replaced by an equivalent portion of isovaleryl chloride. The product was purified by recrystallization from a mixture of hexane/dichloromethane as colourless crystals mp 97°-80° C., yield 87%.
Reaction SMILES: [NH2:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([O:13][CH:14]([C:16]#[C:17][CH3:18])[CH3:15])[CH:3]=1.O.Cl>CO>[NH2:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:13][CH:14]([C:16]#[C:17][CH3:18])[CH3:15])[CH:3]=1
Reactant: CC#CC(C)Oc1cc(N)c(Cl)cc1C(=O)OC
Agent: Cl
Solvent: CO
Solvent: O
Product: CC#CC(C)Oc1cc(N)c(Cl)cc1C(=O)O
Temperature: 50 °C
Reaction time: 6 h
Yield: 97 %

Procedure:
To the suspension of methyl 4-amino-5-chloro-2-{(3-pentyn-2-yl)oxy}benzoate (56.0 g) in methanol (1.3 l) aqueous sodium hydroxide (SN) solution (140 ml) was added. -The resultant mixture was stirred for 6 hours at 50° C., and then 3 days at room temperature. To the obtained mixture, water (1 l) was added, followed by acidification with 2N hydrochloric acid. Crystal thus precipitated was recovered by filtration, washed with water and dried to obtain 51.5 g of the title compound as colorless crystal.
Reaction SMILES: O.[NH2:2][NH2:3].[NH2:4][C:5]1[C:6]([C:12]([O:14]C)=O)=[N:7][C:8]([Br:11])=[CH:9][N:10]=1.NN>CCO>[NH2:4][C:5]1[C:6]([C:12]([NH:2][NH2:3])=[O:14])=[N:7][C:8]([Br:11])=[CH:9][N:10]=1
Reactant: COC(=O)c1nc(Br)cnc1N
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)c1nc(Br)cnc1N
Temperature: 50 °C
Reaction time: 16 h
Yield: 101 %

Procedure:
Hydrazine hydrate (23.59 mL, 480.75 mmol) was added dropwise to a stirred mixture of methyl 3-amino-6-bromopyrazine-2-carboxylate (100 g, 418.04 mmol) in EtOH (2 L). The mixture was heated at 50° C. under nitrogen. The resulting thick suspension was stirred at 50° C. for 16 hours. Further hydrazine (2.5 mL) was added in one portion and the suspension was stirred at 50° C. for a further 24 hours. Ethanol (500 mL) was charged to the thick reaction mixture and the mixture was allowed to cool to room temperature. The resulting suspension was filtered and the solid washed with ethanol (1 L) and dried in vacuo to give 3-amino-6-bromopyrazine-2-carbohydrazide (98 g, quantitative) as a cream solid: 1H NMR Spectrum; (DMSO-d6) 4.52 (2H, s), 7.59 (2H, s), 8.30 (1H, s), 9.74 (1H, s); Mass Spectrum [M+H]+=232.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[N:17][C:18]=3[NH:28][NH2:29])[N:13]=2)=[CH:8][CH:7]=1.C(N(CC)CC)C.[C:37](Cl)(Cl)=[O:38]>C(Cl)Cl.C1(C)C=CC=CC=1>[O:3]1[CH2:4][CH2:5][O:1][CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][C:19]3[C:18]4=[N:28][N:29]=[C:37]([OH:38])[N:17]4[CH:16]=[CH:15][C:14]=3[N:13]=2)=[CH:8][CH:7]=1
Reactant: NNc1nccc2nc(-c3ccc(C4OCCO4)cc3)c(-c3ccccc3)cc12
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Oc1nnc2c3cc(-c4ccccc4)c(-c4ccc(C5OCCO5)cc4)nc3ccn12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of [2-(4-[1,3]dioxolan-2-yl-phenyl)-3-phenyl-[1,6]naphthyridin-5-yl]-hydrazine (3-4, 5.3 g, 13.8 mmol) in CH2Cl2 (anhydrous, 40 mL) at 0° C. was added triethylamine (9.7 mL, 68.9 mmol) followed by a rapid addition of phosgene in toluene (2M, 7.6 mL). After stirring for 10 min at room temperature, the mixture was concentrated and water (30 mL) was added. The solid was collected and dried with toluene azeotropically to give the title compound which was used for the next step without further purification. LRMS m/z (M+1) Calcd: 411.1. Found 411.2.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][CH:6]1[OH:7])(=[O:3])[CH3:2].N1C=CC=CC=1.[C:22](Cl)(=[O:38])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>CN(C)C=O>[C:1]([NH:4][C@@H:5]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][O:15][C:22](=[O:38])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[O:8][C@@H:6]1[OH:7])(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCC(=O)OC[C@H]1O[C@H](O)[C@H](NC(C)=O)[C@@H](O)[C@@H]1O
Temperature: 70 °C
Reaction time: 4 h

Procedure:
To 1 g of N-acetylglucosamine, 5 mL of pyridine and 15 mL of N,N-dimethylformamide were added, and the mixture was heated to 70° C. under stirring and 1.37 mL of palmitoyl chloride was dropwise added, and the reaction was carried out for 4 hours. On completion of the reaction, after extracting with ethyl acetate and washing with 2 mol/L hydrochloric acid, the ethyl acetate layer was dried over anhydrous magnesium sulfate and then the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent; chloroform:methanol=15:1) to obtain 710 mg of 2-acetamido-2-deoxy-6-O-palmitoyl-α-D-glucopyranose as a white crystal.
Reaction SMILES: [Sn:1]([Cl:3])[Cl:2].[C:4]([CH2:7][C:8](=[O:10])[CH3:9])(=O)[CH3:5].C([Cl:14])(=O)C>CCCCC>[CH3:5][C:4]([Sn:1]([Cl:14])([Cl:3])[Cl:2])=[CH:7][C:8](=[O:10])[CH3:9]
Reactant: CC(=O)CC(C)=O
Reactant: CC(=O)Cl
Reactant: Cl[Sn]Cl
Solvent: CCCCC
Product: CC(=O)C=C(C)[Sn](Cl)(Cl)Cl
Reaction time: 2 h
Yield: 90.9 %

Procedure:
94.8 g (0.5 mol) of tin(II) chloride and 50 g (0.5 mol) of acetylacetone were placed in a reactor at room temperature. 39.3 g (0.5 mol) of acetyl chloride were metered in over 45 min, the temperature rising to 45° C. The highly viscous, partially crystalline reaction mixture was stirred for 2 h, 50 ml of n-pentane were added and the solid formed was separated off. After washing with 100 ml of n-pentane and drying, 140 g (92% of theory) of 1-methylbut-1-en-3-onyltin trichloride were isolated.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([CH2:11][CH3:12])=[CH:9][N:8]([C@@H:13]3[O:19][C@H:18]([CH2:20][OH:21])[C@@H:16]([OH:17])[C@H:14]3[OH:15])[C:6]=2[N:7]=1.Cl.[OH-:24].[Na+]>>[NH2:1][C:2]1[NH:3][C:4](=[O:24])[C:5]2[C:10]([CH2:11][CH3:12])=[CH:9][N:8]([C@@H:13]3[O:19][C@H:18]([CH2:20][OH:21])[C@@H:16]([OH:17])[C@H:14]3[OH:15])[C:6]=2[N:7]=1
Reactant: [OH-]
Reactant: CCc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2nc(N)nc(Cl)c12
Agent: Cl
Agent: [Na+]
Product: CCc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2nc(N)[nH]c(=O)c12

Procedure:
A mixture of the compound from Step B (104 mg, 0.32 mmol) in 2N aqueous NaOH (10 mL) was stirred at reflux temperature for 15 min. The solution was cooled in ice bath, neutralized with 2 N aqueous HCl, and evaporated to dryness. The residue was suspended in MeOH, mixed with silica gel, and evaporated. The solid residue was placed onto a silica gel column (packed in a solvent mixture of CH2Cl2/MeOH: 10/1) which was eluted with a solvent system of CH2Cl2/MeOH: 10/1 and 5/1. The fractions containing the product were collected and evaporated to dryness to yield the title compound (48 mg) as a white solid.
Reaction SMILES: O1[CH:5]=[CH:4][C:3]([C:6]2([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:8][CH2:7]2)=[CH:2]1.[N:17]#[N:18].C([O-])(O)=O.[Na+].BrN1C(=O)CCC1=O>CC(C)=O.C1COCC1.O>[N:17]1[CH:5]=[CH:4][C:3]([C:6]2([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:8][CH2:7]2)=[CH:2][N:18]=1
Reactant: N#N
Reactant: CC(C)(C)OC(=O)NC1(c2ccoc2)CC1
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC1(c2ccnnc2)CC1
Temperature: -20 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl 1-(furan-3-yl)cyclopropylcarbamate (2.15 g, 9.64 mmol, 1.0 eq), in acetone (86 ml) and water (86 ml) at r.t. was purged with N2 and cooled to −20° C. NaHCO3 (1.62 g, 19.28 mmol, 2.0 eq) and N-bromosuccinimide (2.23 g, 12.52 mmol, 1.3 eq) were added to the mixture at −20° C. and the stirring was continued at the same temperature for 2 hr. To the reaction mixture at −20° C. was added THF (4.3 ml) and the temperature raised to 0° C. over 30 min. Acetone was removed from the reaction mixture with a stream of N2, and to the residue at 0° C. was added isopropanol (86 ml) followed by hydrazine hydrate (12.9 ml). The reaction mixture was stirred at r.t. overnight. Product formation was confirmed by LCMS. The solvent was evaporated under reduced pressure, and the residue diluted with water and then extracted with EtOAC. The organic was washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by silica gel (60-120) column chromatography using 4% MeOH/CHCl3 as an eluent. Yield: 1.3 g (57.5%). 1H NMR (400 MHz, CDCl3): δ 9.04 (d, J=5.6, 1H), 8.95 (d, J=2.8, 1H), 7.19 (s, 1H), 5.25 (bs, 1H), 1.42 (s, 9H), 1.25 (bs, 4H). LCMS: (ES+) m/z=236.2 (M+H)+
Reaction SMILES: [C:1]([N:4]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[C:5](=[O:27])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:8][CH:7]=1)(=[O:3])[CH3:2].[CH2:35]([Br:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(#N)C>[Br-:42].[C:1]([N:4]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N+:30]=1[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:5](=[O:27])[C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)N(Cc2ccccn2)C(C)=O)cc1
Solvent: CC#N
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)N(Cc2cccc[n+]2Cc2ccccc2)C(C)=O)cc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 17.5 h
Yield: 50.2 %

Procedure:
A mixture of 0.75 g of product from Example 5, 0.412 g of benzyl bromide and 3 ml of acetonitrile is stirred at room temperature for 17.5 hours then heated, in a sealed tube, at 100° C. for 21.25 hours. The cooled reaction mixture is concentrated in vacuo and the residue purified by column chromatography (silica gel:10% methyl alcohol/chloroform) to give 0.515 g of the desired product.
Reaction SMILES: [N+](=C)=[N-].[CH3:4][O:5][C:6]([CH:8]1[CH2:12][S:11][CH2:10][C:9]1=[O:13])=[O:7].[CH:14](Cl)(Cl)Cl>CCOCC>[CH3:4][O:5][C:6]([C:8]1[CH:9]([O:13][CH3:14])[CH2:10][S:11][CH:12]=1)=[O:7]
Reactant: ClC(Cl)Cl
Reactant: COC(=O)C1CSCC1=O
Agent: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)C1=CSCC1OC
Temperature: 0 °C
Reaction time: 21 h
Yield: 86 %

Procedure:
15 Parts by volume of an 0.5 molar solution of diazomethane in ether are added in the course of about 10 minutes to a solution, cooled to 0° C., of 1.6 parts of 3-oxo-tetrahydrothiophene-4-carboxylic acid methyl ester in 10 parts by volume of dry chloroform. The solution is stirred for 21 hours at 0° C., flushed with nitrogen to remove excess diazomethane and concentrated under reduced pressure. The residue is recrystallized from methylene chloride/petroleum ether. 1.5 parts (86% of theory) of 3-methoxy-dihydrothiophene-4-carboxylic acid methyl ester of melting point 79°-81° C. are obtained.
Reaction SMILES: [CH2:1]([C:6]1[CH:31]=[CH:30][C:9]([CH:10]=[CH:11][C:12]([NH:14][C:15]2[C:20]3[O:21][CH:22]([C:25]4[NH:29][N:28]=[N:27][N:26]=4)[CH2:23][O:24][C:19]=3[CH:18]=[CH:17][CH:16]=2)=[O:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].CO.C(O)C.[H][H]>[C].[Pd].C(OCC)(=O)C>[CH2:1]([C:6]1[CH:31]=[CH:30][C:9]([CH2:10][CH2:11][C:12]([NH:14][C:15]2[C:20]3[O:21][CH:22]([C:25]4[NH:29][N:28]=[N:27][N:26]=4)[CH2:23][O:24][C:19]=3[CH:18]=[CH:17][CH:16]=2)=[O:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(C=CC(=O)Nc2cccc3c2OC(c2nnn[nH]2)CO3)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CO
Product: CCCCCc1ccc(CCC(=O)Nc2cccc3c2OC(c2nnn[nH]2)CO3)cc1
Yield: 93.1 %

Procedure:
8- (p-pentylcinnamoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane (216 mg; synthesized in example 2(1)) and palladium-carbon (50 mg; content 5%) were suspended in a mixed solvent (6 ml) of methanol, ethanol and ethyl acetate (1:1:1). In an atmosphere of hydrogen, the suspension was stirred for 90 min at room temperature. After stirring, the suspension was filtered through celite. The filtrate was condensed under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride: methanol=19:1) to give the title compound (202 mg) having the following physical data:
Reaction SMILES: CON(C)[C:4](=[O:18])[CH:5]([O:16][CH3:17])[C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[N:11]2.[Br:20][C:21]1[C:26]([O:27][CH3:28])=[CH:25][C:24]([C:29]2[O:30][CH:31]=[CH:32][CH:33]=2)=[CH:23][C:22]=1[O:34][CH3:35]>>[Br:20][C:21]1[C:22]([O:34][CH3:35])=[CH:23][C:24]([C:29]2[O:30][C:31]([C:4](=[O:18])[CH:5]([O:16][CH3:17])[C:6]3[CH:15]=[CH:14][CH:13]=[C:12]4[C:7]=3[CH:8]=[CH:9][CH:10]=[N:11]4)=[CH:32][CH:33]=2)=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: COC(C(=O)N(C)OC)c1cccc2ncccc12
Reactant: COc1cc(-c2ccco2)cc(OC)c1Br
Product: COc1cc(-c2ccc(C(=O)C(OC)c3cccc4ncccc34)o2)cc(OC)c1Br
Yield: 46 %

Procedure:
1-(5-(4-Bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(quinolin-5-yl)ethanone was synthesized from N,2-dimethoxy-N-methyl-2-(quinolin-5-yl)acetamide and 2-(4-bromo-3,5-dimethoxyphenyl)furan following the procedure used for the synthesis of Example 12. Purification by chromatography (EtOAc-hexanes) provided 1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(quinolin-5-yl)ethanone as a light yellow foam (0.102 g, 46% yield). MS: m/z 482.1 [M+H]+.
Reaction SMILES: N1CCCC1.[N:6]1([CH2:12][C:13](=[CH2:17])[C:14](=[O:16])[CH3:15])[CH2:11][CH2:10]C[CH2:8][CH2:7]1.N1(CC(CN2CCCCC2)C(C)=O)CCCCC1>>[CH2:7]([N:6]([CH2:12][C:13](=[CH2:17])[C:14](=[O:16])[CH3:15])[CH2:11][CH3:10])[CH3:8]
Reactant: C=C(CN1CCCCC1)C(C)=O
Agent: CC(=O)C(CN1CCCCC1)CN1CCCCC1
Solvent: C1CCNC1
Product: C=C(CN(CC)CC)C(C)=O

Procedure:
The intermediate olefinic ketone is prepared by the procedure of H.M.E. Cardwell [J. Chem. Soc., 1058 (1950)]. The ketone obtained from A., 22.8 g., in 25 ml. of ethanol was added to a solution of 25 g. of anhydrous oxalic acid in 75 ml. of ethanol. The mixture was cooled to 0° C., filtered to remove diethylamine hydrogen oxalate and the mother liquor evaporated to dryness under reduced pressure. The residue was dissolved in a little water, treated with potassium carbonate and extracted with ether. The ether was dried over anhydrous sodium sulphate and the residue distilled. After re-distillation the product was obtained as an oil, b.p. 82° C./18 mm. Similarly, the other 1,1-bis-(di-substituted aminomethyl)acetones obtained as in A. can be converted to the corresponding 3-disubstituted aminomethylbut-3-en-2-ones. The di-substituted amino term as previously indicated also comprises pyrrolidine and piperidine alicyclic ring analogs. For example, 3-(piperidinomethyl)but-3-en-2-one boils at 135°-139° C./15 mm. and is synthesized following the same procedure from 1,1-bis(piperidinomethyl)acetone.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:16]=[CH:15][C:6]([O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])=[C:5]([O:17][CH2:18][CH3:19])[CH:4]=1.[CH:20]1[CH:25]=[CH:24][C:23]([P:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[Br-:1].[Si:8]([O:7][C:6]1[CH:15]=[CH:16][C:3]([CH2:2][P+:26]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:23]2[CH:22]=[CH:21][CH:20]=[CH:25][CH:24]=2)=[CH:4][C:5]=1[O:17][CH2:18][CH3:19])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: CCOc1cc(CBr)ccc1O[Si](C)(C)C(C)(C)C
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOc1cc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)ccc1O[Si](C)(C)C(C)(C)C
Product: [Br-]
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.8 %

Procedure:
To a solution of (4-(bromomethyl)-2-ethoxyphenoxy)(tert-butyl)dimethylsilane (14.5 g, 41.8 mmol, 1.0 equiv.) in toluene (84 mL), PPh3 (11.0 g, 41.8 mmol, 1.0 equiv.) was added. The mixture was stirred at 25° C. for 20 h and concentrated to yield 25.1 g (99%) of (4-(tert-Butyldimethylsilyloxy)-3-ethoxyphenyl)methyltriphenylphosphonium bromide as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:26]CCl>FC(F)(F)C(O)=O>[ClH:26].[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([S:21][C:22]([F:24])([F:23])[F:25])=[CH:19][CH:20]=2)[CH2:10][CH2:9]1.[ClH:26]
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(SC(F)(F)F)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: FC(F)(F)Sc1ccc(NC2CCNCC2)cc1
Reaction time: 1.5 h

Procedure:
4-(4-Trifluoromethylsulfanyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (200 mg; 0.53 mmol, prepared in accordance with Example 46) is dissolved in a 1 to 1 mixture of dichloromethane and trifluoroacetic acid (2 mL), and stirred for 90 minutes. The mixture is concentrated under reduced pressure and co-evaporated with dichloromethane (2×10 mL). The resulting residue is diluted in ethylacetate (5 mL) and a 4N solution of hydrochloric acid in dioxane (5 mL) is added. A precipitate is obtained which is filtered and dried under high vacuum to afford the desired product as hydrochloride (168 mg; 0.53 mmol).