Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[C:4]([N:6]1[CH2:9][C:8]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[CH2:7]1)=[O:5].[CH3:31][C:32]1[N:36]=[CH:35][NH:34][C:33]=1[CH2:37][CH2:38][C:39](Cl)=[O:40].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C)C=O.O>[CH2:18]([O:17][C:8]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[CH2:7][N:6]([C:4](=[O:5])[C@H:3]([NH:2][C:39](=[O:40])[CH2:38][CH2:37][C:33]2[NH:34][CH:35]=[N:36][C:32]=2[CH3:31])[CH2:22][C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[CH2:9]1)[CH2:19][CH2:20][CH3:21]
Reactant: Cc1nc[nH]c1CCC(=O)Cl
Reactant: CCCCOC1(c2ccccc2C)CN(C(=O)[C@H](N)Cc2ccc(OC)cc2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCOC1(c2ccccc2C)CN(C(=O)[C@@H](Cc2ccc(OC)cc2)NC(=O)CCc2[nH]cnc2C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
146 mg (0.34 mmol) of (R)-2-amino-3-(4-methoxy-phenyl)-1-(3-butyloxy-3-o-tolylazetidin-1-yl)propan-1-one hydrochloride in solution in 2 ml of dimethylformamide are added to a solution of 64 mg (0.34 mmol) of 3-(5-methyl-3H-imidazol-4-yl)propanoic acid chloride, 119 mg (2.34 mmol) of TBTU and 0.15 ml (1.1 mmol) of triethylamine in 2 ml of dimethylformamide. The reaction mixture is stirred for 2 hours at ambient temperature. The reaction is stopped by adding 10 ml of water and then extracted with ethyl acetate. The organic phases are combined, washed with a 1N solution of sodium hydroxide and then a saturated solution of sodium chloride, and dried over sodium sulphate. After filtration, the solvents are evaporated off and the residue is then purified by silica gel chromatography (eluent 90/10 dichloromethane/methanol). 154 mg of N—[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(5-methyl-3H-imidazol-4-yl)propionamide are obtained in the form of a white powder with a yield of 86%.
Reaction SMILES: [CH3:1][C:2]1([CH:17]=[O:18])[CH2:6][CH:5]2[CH:7]([CH3:16])[C:8]([N+:13]([O-:15])=[O:14])=[C:9]([CH3:12])[C:10]([CH3:11])=[C:4]2[O:3]1.CC(=CC)C.Cl([O-])=[O:25].[Na+].[Na].[H][H]>C(O)(C)(C)C.O>[CH3:1][C:2]1([C:17]([OH:25])=[O:18])[CH2:6][CH:5]2[CH:7]([CH3:16])[C:8]([N+:13]([O-:15])=[O:14])=[C:9]([CH3:12])[C:10]([CH3:11])=[C:4]2[O:3]1
Reactant: CC1=C2OC(C)(C=O)CC2C(C)C([N+](=O)[O-])=C1C
Reactant: [H][H]
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: [Na+]
Agent: [Na]
Solvent: CC(C)(C)O
Solvent: O
Product: CC1=C2OC(C)(C(=O)O)CC2C(C)C([N+](=O)[O-])=C1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.2 %

Procedure:
2.39 g of 2,4,6,7-tetramethyl-5-nitrodihydrobenzofuran-2-aldehyde and 31 g of 2-methyl-2-butene were dissolved in 190 ml of t-butanol and a solution prepared by dissolving 7.77 g of sodium chlorite and 10.1 g of sodium dihydrogen phospahte dehydrate in 78 ml of water was added dropwise under ice cooling, followed by stirring at room temperature for 2 hours. After 2-methyl-2-butene and t-butanol were distilled off under reduced pressure, water was added and the reaction solution was extracted with ether. The solution was washed with saturated saline and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure and the residue was crystallized from ether-hexane to obtain 1.20 g of the objective product.
Reaction SMILES: C(OCCCCC#N)(=S)C.C[O-].[Na+].CS(O[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]1[C:37]2[C:32](=[CH:33][C:34]([O:38][CH3:39])=[CH:35][CH:36]=2)[S:31][CH2:30][C:29]1([C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=1)[CH3:40])(=O)=O.[C:49]([CH2:51][CH2:52][CH2:53][CH2:54][SH:55])#[N:50]>CO.O1CCCC1.O>[C:49]([CH2:51][CH2:52][CH2:53][CH2:54][S:55][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]1[C:37]2[C:36](=[CH:35][C:34]([O:38][CH3:39])=[CH:33][CH:32]=2)[S:31][CH2:30][C:29]1([C:41]1[CH:42]=[CH:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=1)[CH3:40])#[N:50]
Reactant: N#CCCCCS
Reactant: COc1ccc(C2(C)CSc3cc(OC)ccc3C2CCCCCCCCCOS(C)(=O)=O)cc1
Agent: CC(=S)OCCCCC#N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C2(C)CSc3cc(OC)ccc3C2CCCCCCCCCSCCCCC#N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-cyanobutyl thioacetate (613 mg, 3.90 mmol) in methanol (10 ml) and was added 1M sodium methoxide (3.06 ml) and stirred at room temperature for 1 h. Then (3RS,4RS)-4-(9-methansulfonyloxynonyl)-7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman (290 mg, 0.557 mmol) dissolved in dry tetrahydrofuran (5 ml) was added dropwise thereto at room temperature and stirred overnight. When the reaction was completed, water was added to the reaction solution which was then extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The residue was concentrated under reduced pressure and flash chromatographed on silica gel (n-hexane:ethyl acetate=8:2) to give 495 mg (165%, contains the 4-cyanobutan-1-thiol) of the title compound as a colorless oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([OH:10])=[N:2]1.[CH2:11]([N:13]1C(=O)O[C:16](=[O:17])[C:15]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:14]12)[CH3:12]>>[CH2:11]([NH:13][C:14]1[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=1[C:16]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([OH:10])=[N:2]1)=[O:17])[CH3:12]
Reactant: Oc1n[nH]c2ccccc12
Reactant: CCn1c(=O)oc(=O)c2ccccc21
Product: CCNc1ccccc1C(=O)n1nc(O)c2ccccc21
Yield: 47.7 %

Procedure:
1H-Indazol-3-ol was reacted with N-ethylisatoic anhydride according to the general procedure A above and afforded the desired amine as a canary yellow solid, in 47.7% yield; m.p. 163°-165° C.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([C:10]([O:12]CC)=O)[C:3]1=[O:15].[NH2:16][C:17]1[S:18][C:19]([CH2:22][CH3:23])=[N:20][N:21]=1.BrC1C=CC=CC=1>>[CH2:22]([C:19]1[S:18][C:17]([NH:16][C:10]([C:4]2[C:3](=[O:15])[N:2]([CH3:1])[C:7]([CH3:8])=[CH:6][C:5]=2[OH:9])=[O:12])=[N:21][N:20]=1)[CH3:23]
Reactant: CCc1nnc(N)s1
Reactant: CCOC(=O)c1c(O)cc(C)n(C)c1=O
Solvent: Brc1ccccc1
Product: CCc1nnc(NC(=O)c2c(O)cc(C)n(C)c2=O)s1
Temperature: 25 °C
Reaction time: 5 h
Yield: 75 %

Procedure:
212 mg of ethyl 1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxyl ate and 117 mg of 2-amino-5-ethyl-1,3,4-thiadiazole were added to 2.5 ml of bromobenzene, then, the mixture was stirred for 5 hours under heat refluxing condition. The reaction mixture was cooled to room temperature. The resulting solid was collected by filtration, and washed with a mixed solvent of t-butyl methyl ether and hexane and dried to obtain 200 mg of N-(5-ethyl-1,3,4-thiadiazol-2-yl)-1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxamide (hereinafter, referred to as present compound 17) represented by the formula:
Reaction SMILES: [F-].[K+].[O:3]1CCOCCOCCOCCOCCOCC1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH2:30][CH:31]2[NH:37][C:36](=[O:38])[C:35]3[CH:39]=[CH:40][CH:41]=[CH:42][C:34]=3[N:33]3[C:43](=[O:51])[C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][C:49]=4[N:50]=[C:32]23)=[CH:22]1.[N+](C1C=CC([C@@:61]([NH:69][C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])([CH2:65][CH:66]([CH3:68])[CH3:67])[C:62]([O-])=[O:63])=CC=1)([O-])=[O:53].C(N(C(C)C)CC)(C)C>CN(C)C=O.C(#N)C>[OH2:3].[CH3:75][C:73]([CH3:76])([O:72][C:70]([NH:69][C@@H:61]([CH2:65][CH:66]([CH3:67])[CH3:68])[C:62]([N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH2:30][CH:31]2[NH:37][C:36](=[O:38])[C:35]3[CH:39]=[CH:40][CH:41]=[CH:42][C:34]=3[N:33]3[C:43](=[O:51])[C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][C:49]=4[N:50]=[C:32]23)=[CH:22]1)=[O:63])=[O:71])[CH3:74].[OH2:53].[OH2:3].[CH3:75][C:73]([CH3:76])([O:72][C:70]([NH:69][C@@H:61]([CH2:65][CH:66]([CH3:67])[CH3:68])[C:62]([N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH2:30][CH:31]2[NH:37][C:36](=[O:38])[C:35]3[CH:39]=[CH:40][CH:41]=[CH:42][C:34]=3[N:33]3[C:43](=[O:51])[C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][C:49]=4[N:50]=[C:32]23)=[CH:22]1)=[O:63])=[O:71])[CH3:74]
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: O=C1NC(Cc2c[nH]c3ccccc23)c2nc3ccccc3c(=O)n2-c2ccccc21
Reactant: CC(C)C[C@@](NC(=O)OC(C)(C)C)(C(=O)[O-])c1ccc([N+](=O)[O-])cc1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)n1cc(CC2NC(=O)c3ccccc3-n3c2nc2ccccc2c3=O)c2ccccc21
Product: O
Reaction time: 60 h

Procedure:
Potassium fluoride (117 mg, 2.02 mmole) was added to 10 ml of dry acetonitrile containing 1,4,7,10,13,16-hexaoxacyclooctadecane (266 mg, 1.01 mmole). To this solution were added 7-[(1H-indol-3-yl)methyl]quinazolino-(3,2-A)-1,4-benzodiazepin-5,13-(6H,7H)-dione (492 mg, 1.01 mmole), p-nitrophenyl-2(S)-((1,1-dimethyl)ethoxycarbonyl)amino-4-methylpentanoate (441 mg, 1.25 mmole) and 218 μl (1.25 mmole) of diisopropylethylamine under nitrogen. The reaction mixture was stirred rapidly, 10 ml of dimethylformamide was added, and one equivalent of each of the above reagents was added. After 60 hours, the reaction mixture was partitioned between ethyl acetate and water; the phases were separated and the organic layer was washed in succession with saturated sodium bicarbonate solution, 10% citric acid solution, and brine. Rotoevaporation of the dried (MgSO4) extracts gave a solid which was purified by silica gel chromatography (1:1 hexaneethyl acetate v/v).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[C:7]2[CH2:8][N:9]([C:12](=[O:14])[CH3:13])[CH2:10][CH2:11][N:6]2[N:5]=1)([O-:3])=[O:2].[CH3:16]CN(CC)CC.C(Cl)(=O)CC>ClCCl>[N+:1]([C:4]1[CH:15]=[C:7]2[CH2:8][N:9]([C:12](=[O:14])[CH2:13][CH3:16])[CH2:10][CH2:11][N:6]2[N:5]=1)([O-:3])=[O:2]
Reactant: CCN(CC)CC
Reactant: CC(=O)N1CCn2nc([N+](=O)[O-])cc2C1
Agent: CCC(=O)Cl
Solvent: ClCCl
Product: CCC(=O)N1CCn2nc([N+](=O)[O-])cc2C1
Reaction time: 0.08 h

Procedure:
To a solution of 2-nitro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine 209a (200 mg, 1.19 mmol) in dichloromethane (8 mL) was added Et3N (240 mg, 2.38 mmol). After stirring for 5 minutes, a solution of propionyl chloride (121 mg, 1.31 mmol) in dichloromethane (2 mL) was added and the reaction mixture was stirred at room temperature for 1 h. Analysis of the reaction mixture by LCMS showed complete conversion to the desired product. The mixture was washed with water and brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to afford 265a (260 mg, 98%) as white solid, which was used in the next step without further purification. MS-ESI: [M+H]+ 225.0
Reaction SMILES: C(N)CCC.NO.Cl.[CH:9]#[C:10][CH2:11][C@@H:12]([OH:22])[C@H:13]([OH:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].Br[C:24]#[C:25][C@@H:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[OH:27]>C(Cl)Cl.[Cu]Cl>[C:28]1([C@@H:26]([OH:27])[C:25]#[C:24][C:9]#[C:10][CH2:11][C@@H:12]([OH:22])[C@H:13]([OH:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O[C@@H](C#CBr)c1ccccc1
Reactant: C#CC[C@@H](O)[C@H](O)CCCCCCC
Agent: Cl[Cu]
Agent: Cl
Agent: NO
Solvent: ClCCl
Solvent: CCCCN
Product: CCCCCCC[C@@H](O)[C@H](O)CC#CC#C[C@H](O)c1ccccc1
Temperature: 25 °C
Yield: 78.4 %

Procedure:
Copper(I) chloride (6.4 mg, 64.6 μmol, 20 mol %) was added to a stirred solution of n-BuNH2 (0.32 mL) and distilled water (0.74 mL) at 0° C., which resulted in a deep blue solution. A few crystals of NH2OH.HCl were added to get a colorless solution which is indicative of the presence of the required Cu(I) salt. At the same temperature was added (4R,5R)-1-dodecyne-4,5-diol (64.1 mg, 0.323 mmol) by cannula as a solution in CH2Cl2 (0.6 mL). Then a freshly prepared solution of (R)-3-bromo-1-phenyl-2-propyn-1-ol (75.0 mg, 0.355 mmol, 1.1 equiv) in CH2Cl2 (2.4 mL) was slowly added over 60 min by help of syringe pump under a flow of argon in order to prevent the solution from turning to green or blue (NH2OH.HCl can be added as necessary throughout the reaction). The reaction mixture was allowed to warm up to room temperature. After stiffing for 10˜20 minutes, the brownish orange colored solution was extracted three times with CH2Cl2, washed with brine, dried over Na2SO4, filtered and concentrated. The reaction procedure in Cho, E. J.; Kim, M.; Lee, D. Org. Lett. 2006, 8, 5413-54169 and supporting information, both of which are incorporated herein by reference in their entireties, can also be followed. Purification of the crude mixture by gradient flash chromatography on silica gel (hexanes/EtOAc=2.5:1→2:1→1.5:1→1:1) afforded the title compound (83.2 mg, 78%) as a white solid: 1H-NMR (CDCl3, 500 MHz) δ 7.51-7.38 (m, 2H), 7.40-7.32 (m, 3H), 5.50 (s, 1H), 3.63-3.60 (m, 2H), 2.62-2.53 (m, 3H), 2.17 (br s, 1H), 1.68 (br s, 1H), 1.50-1.28 (m, 12H), 0.88 (t, J=7.0 Hz, 3H); 13C-NMR (CDCl3, 75 MHz) δ 139.68, 128.71, 128.62, 126.60, 78.40, 75.64, 73.07, 72.11, 71.23, 66.52, 64.86, 33.49, 31.78, 29.52, 29.20, 25.55, 24.92, 22.62, 14.09.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([C:15]([OH:17])=O)=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[Br:18][C:19]1[CH:20]=[N:21][C:22]([NH:25][C@@H:26]2[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]2)=[N:23][CH:24]=1>>[Br:18][C:19]1[CH:20]=[N:21][C:22]([NH:25][C@@H:26]2[CH2:31][CH2:30][CH2:29][N:28]([C:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:4]3[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=3)=[O:17])[CH2:27]2)=[N:23][CH:24]=1
Reactant: Brc1cnc(N[C@@H]2CCCNC2)nc1
Reactant: Cc1ccc(-c2ccccc2C(=O)O)cc1C
Product: Cc1ccc(-c2ccccc2C(=O)N2CCC[C@@H](Nc3ncc(Br)cn3)C2)cc1C

Procedure:
prepared by reaction of 3′,4′-dimethyl-biphenyl-2-carboxylic acid with (R)-(5-bromo-pyrimidin-2-yl)-piperidine-3-yl-amine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#N)=[CH:5][CH:4]=1.[CH3:12]I.Cl.C[N:16]([CH3:19])C=O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:10])([CH3:12])[C:19]#[N:16])=[CH:5][CH:4]=1
Reactant: CI
Reactant: CN(C)C=O
Reactant: COc1ccc(CC#N)cc1
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(C(C)(C)C#N)cc1
Reaction time: 1.5 h

Procedure:
To a suspension of sodium tert-butylate (21.54 g, 217.4 mmol) in dimethylformamide (37 mL) and tetrahydrofuran (37 mL) was added (4-methoxyphenyl)acetonitrile (8.00 g, 54.36 mmol) at 5° C. At the same temperature methyl iodide (13.54 mL) was added dropwise resulting in the formation of a light brown solid. The reaction mixture was diluted with dimethylformamide (15 mL) and tetrahydrofuran (15 mL). Stirring was continued at 10° C. for 1.5 h. The reaction mixture was cooled in a ice bath and 2N aqueous hydrochloric acid (100 mL) was added. The reaction mixture was extracted with ethyl acetate (3×100 mL). The combined extracts were washed with aqueous saturated NaHCO3 solution (2×50 mL) and brine (50 mL). The extracts were dried (MgSO4) and the solvent was evaporated in vacuo. The crude product was purified by flash chromatography (silica, n-heptane:dichloromethane=1:1). Yield: 7.6 g (43.4 mmol, 79.8%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[CH:7][C:6]([C:14]#[N:15])=[C:5]2[NH:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Cl:24])[CH:18]=1.[O:25]1[C:29]2([CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[O:28][CH2:27][CH2:26]1>>[Cl:24][C:19]1[CH:18]=[C:17]([NH:16][C:5]2[C:4]3[C:9](=[CH:10][C:11]([O:12][CH3:13])=[C:2]([NH:1][C:11](=[O:12])[CH:2]=[CH:3][CH2:4][N:32]4[CH2:33][CH2:34][C:29]5([O:28][CH2:27][CH2:26][O:25]5)[CH2:30][CH2:31]4)[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:14]#[N:15])[CH:22]=[CH:21][C:20]=1[F:23]
Reactant: C1CC2(CCN1)OCCO2
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1N
Product: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCN1CCC2(CC1)OCCO2
Yield: 73.4 %

Procedure:
By using the method of Example 89, 1.05 g (3.06 mmol) of 6-amino-4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinoline-3-carbonitrile and 2.6 g (18.4 mmol) of 1,4-dioxa-8-azaspiro[4.5]decane were converted to 0.62 g the title compound. The free base obtained as a yellow foam: mass spectrum (electrospray, m/e): M+H 552.0, (M+2H)+2270.5.
Reaction SMILES: [CH3:1][CH2:2]C([O-])(C)C.[K+].[CH2:8]([O:10][C:11]([C:13]1[C:18]([CH2:19][S:20]([CH2:23][C:24]2[C:29]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:34])(=[O:22])=[O:21])=[N:17][CH:16]=[CH:15][N:14]=1)=[O:12])[CH3:9].ICC>CN(C)C=O>[CH2:8]([O:10][C:11]([C:13]1[C:18]([CH:19]([S:20]([CH2:23][C:24]2[C:29]([C:30]([F:32])([F:31])[F:33])=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:34])(=[O:21])=[O:22])[CH2:1][CH3:2])=[N:17][CH:16]=[CH:15][N:14]=1)=[O:12])[CH3:9]
Reactant: CCOC(=O)c1nccnc1CS(=O)(=O)Cc1c(Cl)cccc1C(F)(F)F
Reactant: CCC(C)(C)[O-]
Agent: [K+]
Solvent: CCI
Solvent: CN(C)C=O
Product: CCOC(=O)c1nccnc1C(CC)S(=O)(=O)Cc1c(Cl)cccc1C(F)(F)F
Reaction time: 0.33 h

Procedure:
Potassium tert-pentoxide (0.155 ml, ˜1.7M solution in toluene, Aldrich 60435) was added drop wise to a cooled (0 to 5° C.) solution of 3-(2-chloro-6-trifluoromethyl-phenylmethanesulfonylmethyl)-pyrazine-2-carboxylic acid ethyl ester (Compound B13 of Table B) (0.1 g) in N,N-dimethylformamide (1 ml) under nitrogen atmosphere and stirred cold for 20 minutes. Iodoethane (0.021 ml) was added to the cool dark red solution and stirred at this temperature for a further hour. The reaction mixture was partitioned between ether and 2M aqueous hydrochloric acid. The aqueous layer was extracted with further diethyl ether. The combined organic layers were washed further with water and brine, dried over magnesium sulfate and concentrated to give 3-[1-(2-chloro-6-trifluoromethyl-phenylmethanesulfonyl)-propyl]-pyrazine-2-carboxylic acid ethyl ester Compound No. D1 of Table D (0.106 g). MH+=451, RT=1.58 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:14])[CH2:10][C:11](=[O:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].[CH3:21][N:22]([CH3:25])[CH:23]=O.COC(OC)N(C)C>O>[CH3:21][N:22]([CH:25]=[C:10]([C:11](=[O:13])[CH3:12])[C:9]([NH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])=[O:14])[CH3:23]
Reactant: CC(=O)CC(=O)Nc1ccccc1C
Reactant: CN(C)C=O
Agent: COC(OC)N(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(=O)C(=CN(C)C)C(=O)Nc1ccccc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of N-(2-methylphenyl)-3-oxobutanamide (10.0 g), potassium carbonate (7.23 g) and N,N-dimethylformamide (130 mL) was added dropwise 1,1-dimethoxy-N,N-dimethylmethanamine (12.5 g) over 30 min at room temperature, and the reaction mixture was stirred at room temperature for 2 hr. The reaction mixture was slowly poured into water, and the mixture was extracted with dichloromethane. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (10.2 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=O)[CH3:16])[C:10]=2[OH:18])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[NH:19]([C:21]([NH:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1)=[S:22])[NH2:20].CN(C)C=O>Cl.O>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=[N:20][NH:19][C:21]([NH:23][C:24]3[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)=[S:22])[CH3:16])[C:10]=2[OH:18])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: NNC(=S)Nc1ccc(C(=O)O)cc1
Reactant: CC(=O)c1nn(C)c(-c2cc(C)cc(C)c2)c1O
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(=NNC(=S)Nc1ccc(C(=O)O)cc1)c1nn(C)c(-c2cc(C)cc(C)c2)c1O
Yield: 65 %

Procedure:
1-[5-(3,5-Dimethylphenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethanone (0.122 mmol, 29.9 mg) and 4-hydrazinocarbonothioylaminobenzoic acid (0.122 mmol, 25.9 mg) were stirred with dimethylformamide (2 mL) and two drops of concentrated hydrochloric acid at room temperature for 24 hours. After addition of water, the precipitated yellow solid was recovered by filtration, washed with water and dried by means of a vacuum pump. The resulting solid was stirred with chloroform/n-hexane for a while, then recovered by filtration and dried by means of a vacuum pump to give the desired product as a pale yellow solid (34.7 mg, yield 65%).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]1[NH:12][C:11]2[C:6](=[C:7]([CH3:23])[CH:8]=[C:9]([C:13]3[N:21]([CH3:22])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[CH:10]=2)[N:5]=1.[CH3:24]S(C)=O.[OH-].[K+].C[O:31][C:32]([C:34]1[C:35]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[CH:36][CH:37]=[C:38](CBr)[CH:39]=1)=[O:33]>C(O)(=O)C.O>[CH2:3]([C:4]1[N:12]([CH2:24][C:45]2[CH:44]=[CH:43][C:42]([C:35]3[C:34]([C:32]([OH:31])=[O:33])=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:47][CH:46]=2)[C:11]2[CH:10]=[C:9]([C:13]3[N:21]([CH3:22])[C:20]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[N:14]=3)[CH:8]=[C:7]([CH3:23])[C:6]=2[N:5]=1)[CH2:2][CH3:1]
Reactant: COC(=O)c1cc(CBr)ccc1-c1ccccc1
Reactant: CCCc1nc2c(C)cc(-c3nc4ccccc4n3C)cc2[nH]1
Reactant: CS(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CCCc1nc2c(C)cc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Temperature: 27.5 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
50 gm of [1H-Benzimidazole-2-n-propyl-4-methyl-6-(1′methyl benzimidazole-2′-yl)] was added to 200 ml dimethyl sulfoxide and 50 gm of potassium hydroxide. To this was added 60 gm of methyl-4-(bromomethyl)biphenyl-2-carboxylate at ambient temperature. The contents were stirred for 2 hours at 25-30° C., then heated to 40-50° C. and maintained for 2 hours. About 500 ml water was added to the reaction mixture at room temperature and acidified to pH 4 with acetic acid. The reaction mixture was filtered and washed with purified water, dried under reduced pressure at 50-60° C. to give 80 gm (88%) of the title product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH2:9]([CH2:11][NH2:12])[OH:10]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:12][CH2:11][CH2:9][OH:10])[CH:5]=[CH:4][N:3]=1
Reactant: NCCO
Reactant: Clc1ccnc(Cl)n1
Product: OCCNc1ccnc(Cl)n1
Yield: 16 %

Procedure:
Prepared in analogy to example 98a), using 2,4-dichloro-pyrimidine and ethanolamine. The title compound was isolated as a colorless solid in a yield of 16%. MS ISP (m/e): 174.3 & 172.1 (100 & 40) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=7.90 (s broad, 1H), 7.84 (d, 1H), 6.48 (d, 1H), 4.77 (t, 1H), 3.52 (qa, 2H), 3.26 (qa broad, 2H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].O[N:8]=[C:9]1[CH2:14][CH2:13][N:12]([CH:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][O:18][C:17]3[CH:26]=[CH:27][C:28]([Br:30])=[CH:29][C:16]2=3)[CH2:11][CH2:10]1.O>C1COCC1.CCOCC>[NH2:8][CH:9]1[CH2:14][CH2:13][N:12]([CH:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][O:18][C:17]3[CH:26]=[CH:27][C:28]([Br:30])=[CH:29][C:16]2=3)[CH2:11][CH2:10]1
Reactant: ON=C1CCN(C2c3ccccc3COc3ccc(Br)cc32)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: NC1CCN(C2c3ccccc3COc3ccc(Br)cc32)CC1
Temperature: 0 °C
Yield: 69.1 %

Procedure:
Step 4): LiAlH4 (0.14 g, 3.7 mmol) was added to a solution of 11-(4-hydroxyiminopiperidin-1-yl)-2-bromo-6,11-dihydrodibenz[b,e]oxepin (1.5 g, 3.7 mmol) in dry THF (50 ml) under nitrogen atmosphere. The reaction mixture was heated at 60°-70° C. for 3 hours. After cooled at 0° C., the reaction mixture was hydrolyzed with water and diluted with ether, then filtered. The filtrate was concentrated to give 11-(4-aminopiperidin-1-yl)-2-bromo-6,11-dihydrodibenz[b,e]oxepin (69.1%): mp 142°-144° C.