Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[NH:9][N:8]=[N:7][C:6]=1[CH2:10][N:11]1[CH2:16][CH2:15][O:14][C@H:13]([O:17][C@@H:18]([C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([S:30][CH3:31])[CH:21]=2)[CH3:19])[C@@H:12]1[C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)[CH3:3].FC(F)(F)C(OO)=[O:42].C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O>[CH3:1][N:2]([CH2:4][C:5]1[NH:9][N:8]=[N:7][C:6]=1[CH2:10][N:11]1[CH2:16][CH2:15][O:14][C@H:13]([O:17][C@@H:18]([C:20]2[CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[C:22]([S:30]([CH3:31])=[O:42])[CH:21]=2)[CH3:19])[C@@H:12]1[C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)[CH3:3]
Reactant: O=C(OO)C(F)(F)F
Reactant: CSc1cc([C@@H](C)O[C@H]2OCCN(Cc3nn[nH]c3CN(C)C)[C@H]2c2ccc(F)cc2)cc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](O[C@H]1OCCN(Cc2nn[nH]c2CN(C)C)[C@H]1c1ccc(F)cc1)c1cc(S(C)=O)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The thioether of Example 76 (155 mg, 0.28 mmol) was dissolved in trifluoroacetic acid (800 μl) cooled to 0° C. and treated with a 2.0M solution of trifluoroperacetic acid in trifluoroacetic acid (153 μl, 0.308 mmol), with stirring for 30 minutes. The reaction mixture was poured into 0.5M sodium bicarbonate solution (50 ml), extracted with dichloromethane (3×15 ml), dried (MgSO4) and concentrated in vacuo. The resulting crude solid (200 mg) was purified by flash silica gel chromatography in 8% methanol:dichioromethane to yield the title compound as unresolved stereoisomers as a white foam (81 mg, 51%). 1H NMR (360 MHz, CDCl3) δ 1.44 and 1.46 (3H total, 2×d, J=6.6 Hz), 2.24 (6H, s), 2.56 (1H, m), 2.59 and 2.62 (3H total, 2×s), 2.88 (1H, d, J=11.9 Hz), 3.23 and 3.26 (1H total, 2×d, J=13.9 Hz), 3.42-3.55 (3H, m), 3.62 (1H, br d, J=11.3 Hz), 3.75 and 3.79 (1H total, 2×d, J=14.4 Hz), 4.22 (1H, m), 4.32 and 4.35 (1H total, 2×d, J=2.7 Hz), 4.89 (1H, m), 6.85 (1/2H, s), 7.04-7.13 (3H, m), 7.24 (1/2H, s), 7.50 (2H, br s), 7.73 and 7.75 (1H total, 2×s); MS (ES+) m/z 570 (M+1, 100%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][C:4]([NH2:14])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:3]1.C(N(C(C)C)C(C)C)C.[CH3:24][O:25][C:26]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[C:27]=1[C:28](Cl)=[O:29]>ClCCl>[CH3:24][O:25][C:26]1[CH:34]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:32]=[C:31]([C:39]([F:40])([F:41])[F:42])[C:27]=1[C:28]([NH:14][C:4]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][CH2:6][CH2:7][N:2]([CH3:1])[CH2:3]1)=[O:29]
Reactant: CN1CCCC(N)(c2ccccc2)C1
Reactant: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)NC1(c2ccccc2)CCCN(C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.6 %

Procedure:
To a solution of 205 mg (1.077 mmol) rac-1-methyl-3-phenyl-piperidin-3-ylamine (Example A.1) and 369 ul (2.154 mmol) N-ethyldiisopropylamine in dichloromethane (2.5 ml) was added dropwise a solution of 430 mg (1.4 mmol) 2-methoxy-4,6-bis-trifluoromethyl-benzoyl chloride (CAS: 886503-47-5) in dichloromethane (2.0 ml) at room temperature. The mixture was stirred at room temperature for 16 hours. The solvent was removed in vacuo. The crude product was purified on silica gel (Eluent: Heptane/ethyl acetate 0 to 100%) to provide 340 mg (69%) of the title compound as a light yellow foam. MS (m/e): MS (m/e): 461.4 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[OH:10])[CH3:2].[Br-:11].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)(Cl)Cl>[Br:11][C:7]1[CH:6]=[C:5]([CH3:9])[C:4]([OH:10])=[C:3]([CH2:1][CH3:2])[CH:8]=1
Reactant: CCc1cccc(C)c1O
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClC(Cl)Cl
Product: CCc1cc(Br)cc(C)c1O
Temperature: 0 °C
Yield: 182.7 %

Procedure:
Then, 16 g of 2-ethyl-6-methylphenol was dissolved in 200 ml of chloroform, which was stirred at 0° C., and 56.6 g of tetrabutylammonium tribromide was added in small portions to this solution. After stirring at room temperature for 1 hour, the solvent was distilled out under reduced pressure. The residue was dissolved in 300 ml of diethyl ether, successively washed with 10% hydrochloric acid and water, dried over anhydrous magnesium sulfate, and then concentrated to give a crude product. The crude product was subjected to silica gel chromatography, which afforded 23 g of 4-bromo-2- ethyl-6-methylphenol (92% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][N:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH2:28](S(Cl)(=O)=O)[CH2:29][CH2:30]C>>[CH2:26]([S:23]([N:20]1[CH2:21][CH2:22][C@H:18]([NH:17][C:15]2[C:14]([F:27])=[CH:13][N:12]=[C:11]([C:10]3[C:4]4[C:5](=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[NH:8][CH:9]=3)[N:16]=2)[CH2:19]1)(=[O:24])=[O:25])[CH2:28][CH2:29][CH3:30]
Reactant: CS(=O)(=O)N1CC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Reactant: CCCCS(=O)(=O)Cl
Product: CCCCS(=O)(=O)N1CC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Yield: 45 %

Procedure:
According to the procedure for compound 398 using 1-butanesulfonyl chloride (90 mg, 0.57 mmol) afforded 21 mg (45% yield) of 402, as a solid.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH:3]([O:5][CH2:6][CH2:7][C:8]([F:32])([F:31])[C:9]([F:30])([F:29])[C:10]([F:28])([F:27])[C:11]([F:26])([F:25])[C:12]([F:24])([F:23])[C:13]([F:22])([F:21])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])O.S(Cl)([Cl:37])=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:37][CH:3]([O:5][CH2:6][CH2:7][C:8]([F:32])([F:31])[C:9]([F:30])([F:29])[C:10]([F:28])([F:27])[C:11]([F:26])([F:25])[C:12]([F:24])([F:23])[C:13]([F:22])([F:21])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])[C:2]([F:34])([F:33])[F:1]
Reactant: O=S(Cl)Cl
Reactant: OC(OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: FC(F)(F)C(Cl)OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 3 h
Yield: 63 %

Procedure:
A 1.0 M hexane solution (34 ml) of diisobutylaluminum hydride (hereinafter, referred to as DIBAL) was added, dropwise, at −70° C., to a tetrahydrofuran solution (60 ml) of 3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecyl trifluoroacetate ester (18.3 g) obtained by reaction of trifluoroacetic anhydride and 3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecanol, followed by stirring at −70 to −50° C. for 2 hours. The resultant reaction solution was allowed to warm gradually to 0° C., and 1-mol/L aqueous hydrochloric acid (5 ml) was added thereto, followed by stirring at the same temperature for 5 minutes. After extraction with ethyl acetate/1 mol/L-hydrochloric acid, the organic layer was washed with water and an aqueous sodium chloride solution, and then dried over magnesium sulfate. The solvent was concentrated under reduced pressure, to give crude 2,2,2-trifluoro-1-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecyloxy)ethanol. The resultant crude alcohol was dispersed in toluene (50 ml), and thionyl chloride (3.5 ml) and pyridine (4.0 ml) were added thereto, dropwise, at room temperature, followed by stirring for 3 hours. After the reaction solution was extracted with ethyl acetate/1 mol/L-aqueous hydrochloric acid, the organic layer was washed with water and an aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The concentrated residue was purified by column chromatography (developing solvent: ethyl acetate/hexane=1/9), to give 10-(1-chloro-2,2,2-trifluoroethoxy)-1,1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8-heptadecafluorodecane (11.9 g, 63%).
Reaction SMILES: CC([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:6][CH:7]([CH2:16][CH2:17][CH2:18][CH:19]=[CH:20][C:21]#[C:22][CH2:23][CH:24]([O:50][CH2:51][O:52][CH3:53])[CH:25]1[O:29][CH:28]([CH:30]2[CH2:34][CH2:33][CH:32]([CH:35]([O:46][CH2:47][O:48][CH3:49])[CH2:36][C:37]#[C:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[O:31]2)[CH2:27][CH2:26]1)[CH2:8][C:9]1[C:10](=[O:15])[O:11][CH:12]([CH3:14])[CH:13]=1)(C)C.[H][H].O>C1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[OH:6][CH:7]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]([O:50][CH2:51][O:52][CH3:53])[CH:25]1[O:29][CH:28]([CH:30]2[CH2:34][CH2:33][CH:32]([CH:35]([O:46][CH2:47][O:48][CH3:49])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[O:31]2)[CH2:27][CH2:26]1)[CH2:8][C:9]1[C:10](=[O:15])[O:11][CH:12]([CH3:14])[CH:13]=1
Reactant: CCCCCCCC#CCC(OCOC)C1CCC(C2CCC(C(CC#CC=CCCCC(CC3=CC(C)OC3=O)O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)OCOC)O2)O1
Reactant: [H][H]
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCCCCCCCCCC(OCOC)C1CCC(C2CCC(C(CCCCCCCCC(O)CC3=CC(C)OC3=O)OCOC)O2)O1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of {2R-[2α[2′R*, 5′R*(R*)],5β[1(S*), 2R*, 11R*]}-3-{2-[(1,1-dimethylethyl)diphenylsilyloxy]-11-methoxymethyloxy-11-[octahydro-5′-(1-(methoxymethyloxy)undec-3-ynyl) [2.2′-bifuran]-5-yl]-6-undecen-8-ynyl}-5-methyl-2-(5H)-furanone (64 mg, 70 mmole) in benzene (0.5 mL) is stirred at room temperature under a flow of nitrogen while tris(triphenylphosphine)rhodium chloride (14 mg, 15 mmole) is added. The mixture is charged with hydrogen gas and stirred at room temperature for two days. Water is added, and the layers are separated. The aqueous extracted with ethyl acetate (3×2 mL) and the combined organic fractions are washed (1×20 mL water) dried (saturated aqueous NaCl, sodium sulfate), filtered, and concentrated. Chromatography (hexane-2:1 hexane:ethyl acetate gradient over silica gel 230-400 mesh) affords the desired product.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl.[NH2:8][C:9]1[CH:15]=[CH:14][C:12]([OH:13])=[CH:11][C:10]=1[OH:16].Cl[CH2:18][C:19](Cl)=[O:20]>O.C1(C)C=CC=CC=1>[OH:13][C:12]1[CH:14]=[CH:15][C:9]2[NH:8][C:19](=[O:20])[CH2:18][O:16][C:10]=2[CH:11]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(O)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1COc2cc(O)ccc2N1
Temperature: 2.5 °C
Reaction time: 8 h

Procedure:
K2CO3 (250 g, 1.8 mol, 4 eq) was dissolved in water (1100 mL) in a 3 L round bottomed flask, vacuum degassed 3 times, then cooled to 0 to 5° C. 4-Amino resorcinol HCl (73 g, 0.45 mol, 1 eq) was added though a strong nitrogen purge, and the blue solution was again degassed 3×. Choroacetyl chloride (45 mL, 64 g, 0.57 mol, 1.25 eq) was dissolved in toluene (225 mL), and was added over 1 h maintaining the temperature below 5° C. the ice bath was removed, and the mixture (biphasic with suspended crystalline product) was stirred overnight. The intermediate 2 was then isolated via filtration giving 53 g (71%) after a water wash (550 mL) and drying.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[C:11]([O:15][C:16]([N:18]1[CH2:25][CH:24]2[O:26][CH:20]([CH2:21][NH:22][CH2:23]2)[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH:20]2[O:26][CH:24]([CH2:23][N:22]([CH2:2][C:3]3[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=3)[CH2:21]2)[CH2:25]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C1)O2
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC2CN(Cc3ccc(C#N)cc3)CC(C1)O2
Temperature: 60 °C
Reaction time: 8 h
Yield: 66.3 %

Procedure:
A suspension of 4-bromomethylbenzonitrile (10 g, 0.054 mol), 9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (11.5 g, 0.0439 mol; see WO 01/28992) and dry K2CO3 (21.2 g, 0.153 mol) in 200 μL of dry acetonitrile was stirred at 60° C. overnight under a N2 atmosphere. The reaction mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography over silica gel using 10% ethyl acetate in petroleum ether as eluent to yield 10 g of the sub-title compound as colourless liquid.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=1.Cl[CH:19]([CH:25]=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(O)C>[F:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][N:12]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: Nc1ncccc1OCc1c(F)cccc1F
Reactant: CCOC(=O)C(Cl)C=O
Solvent: CCO
Product: CCOC(=O)c1cnc2c(OCc3c(F)cccc3F)cccn12

Procedure:
1.93 g of 3-[(2,6-difluorobenzyl)oxy]pyridine-2-amine (Example 4A; 8.2 mmol, 1 equivalent) were initially charged in 50 ml of ethanol, and 8.2 g of ethyl 2-chloro-3-oxopropanoate (75% pure, crude product from Example 29A, 40.8 mmol, 5 equivalents) were added. The resulting reaction mixture was heated at reflux overnight. The reaction solution was concentrated and the crude product obtained was chromatographed on 340 g of silica gel (Biotage Isolera) (mobile phase: cyclohexane:ethyl acetate gradient; Rf value of the product in cyclohexane:ethyl acetate 2:1=0.36). The product fractions were combined and concentrated and the residue obtained was triturated with diisopropyl ether. The solid was filtered off and dried under high vacuum. This gave 2.02 g of the title compound (71% of theory).
Reaction SMILES: [CH3:1][NH2:2].[Br:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7]([CH2:11]I)=[CH:6][C:5]=1[CH3:13]>CN(C=O)C>[Br:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7]([CH2:11][NH:2][CH3:1])=[CH:6][C:5]=1[CH3:13]
Reactant: CN
Reactant: Cc1cc(CI)cc(C)c1Br
Solvent: CN(C)C=O
Product: CNCc1cc(C)c(Br)c(C)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 99.8 %

Procedure:
Methylamine (12.3 ml, 24.60 mmol, 2.0 M solution in methanol) was added dropwise to a solution of 2-bromo-5-iodomethyl-1,3-dimethyl-benzene (400 mg, 1.23 mmol) in anhydrous DMF (12 ml), and the mixture was stirred at room temperature for two days. The reaction solution was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The organic layer was then sequentially washed with water and saturated brine and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane-methanol) to give 1-(4-bromo-3,5-dimethylphenyl)-N-methylmethanamine (280 mg, 100%).
Reaction SMILES: C1N=CN([C:6]([N:8]2C=N[CH:10]=[CH:9]2)=[S:7])C=1.[CH3:13][O:14][CH2:15][CH2:16][C@@H](N)C.Cl.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(OC)(C)(C)C.C1COCC1>[N:8]([C@@H:9]([CH3:10])[CH2:16][CH2:15][O:14][CH3:13])=[C:6]=[S:7]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: COCC[C@H](C)N
Agent: Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: COCC[C@H](C)N=C=S
Temperature: -5 °C
Reaction time: 0.38 h
Yield: 83.2 %

Procedure:
Under a nitrogen atmosphere N,N-thiocarbonyldiimidazole (97.0 g, 0.55 mol) and THF (470 mL) are added and the mixture is stirred for 15-30 min. The mixture is cooled to −10 to 0° C., a solution of (S)-4-methoxybutan-2-amine (46.9 g, 0.455 mol) in methyl tert-butyl ether (389 mL) is added, and the reaction mixture is warmed to 10-20° C. The reaction mixture is stirred at this temperature for 15-20 h, and then is cooled to 0-10° C. Hydrochloric acid (275 mL, 4 N in water) is added to arrive at a pH of 1 to 2. The reaction mixture is warmed to RT and the layers are separated. The aqueous layer is extracted with ethyl acetate (235 mL) and the organic layers are combined and washed with water (140 mL). The organic solution is concentrated under reduced pressure below 45° C., ethyl acetate (211.5 mL) is added, and the solution is concentrated under reduced pressure below 45° C. twice, and ethyl acetate (235 mL) is added. Sodium thiosulfate (32.3 g, 227.0 mmol) is added, the solution is filtered, and the filtercake is washed with ethyl acetate (104 mL). The filtrate is concentrated under reduced pressure below 45° C. to furnish the title compound as a yellow oil (55.0 g, 77%).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6]NC(C)C)[C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]1=2.[N+:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])([O-:17])=[O:16]>C1(C)C(C)=CC=CC=1>[CH2:22]([O:21][C:19](=[O:20])[CH:18]([N+:15]([O-:17])=[O:16])[CH2:6][C:4]1[C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]=2[S:1][CH:5]=1)[CH3:23]
Reactant: CCOC(=O)C[N+](=O)[O-]
Reactant: CC(C)NCc1csc2ccccc12
Solvent: Cc1ccccc1C
Product: CCOC(=O)C(Cc1csc2ccccc12)[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 5 h
Yield: 74.8 %

Procedure:
In 50 ml of dry xylene were dissolved 10.97 g of (benzo[b]thiophen-3-ylmethyl)isopropylamine and 13.3 g of ethyl nitroacetate and the temperature of the solution was raised to 100° C. with stirring under nitrogen gas stream. After 5 hours. insoluble matter was filtered off, the solvent was distilled off under reduced pressure from the filtrate, and the residue was dissolved in 500 ml of ethyl acetate. The solution was washed thrice with 100 ml of an aqueous 5% citric acid solution, thrice with 100 ml of an aqueous 5% sodium hydrogencarbonate solution, and then twice with 100 ml of a saturated aqueous sodium chloride solution and after drying with sodium sulfate, ethyl acetate was distilled off under reduced pressure from the solution. After removing excess ethyl nitroacetate by means of a vacuum pump, the residue was subjected to silica gel column chromatography to provide 11.17 g (yield of 80%) of 3-(benzo[b]thiophen-3-yl)-2-nitropropionic acid ethyl ester.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11][C:12]#N)[CH:2]=1.[Cl:14][C:15]1[CH:16]=[C:17]([N+:23]([O-:25])=[O:24])[CH:18]=[C:19]([Cl:22])C=1Cl.[H-].[Na+]>>[Cl:14][C:15]1[CH:16]=[C:17]([N+:23]([O-:25])=[O:24])[CH:18]=[C:19]([Cl:22])[C:12]=1[CH2:11][C:3]1[CH:2]=[N:1][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: N#CCc1cnc2ccccc2c1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Product: O=[N+]([O-])c1cc(Cl)c(Cc2cnc3ccccc3c2)c(Cl)c1

Procedure:
3-(2,6-Dichloro-4-nitro-benzyl)-quinoline was synthesized (71%) from quinolin-3-yl-acetonitrile (228, 1.41 g, 8.4 mmol), 3,4,5-trichloronitrobenzene (Acros, 1.90 g, 8.4 mmol) and NaH (Aldrich, 740 mg, 60%, 18.5 mmol) in a similar manner in two steps as described in Example 222. 1H NMR (400 MHz, DMSO-d6) δ 8.88 (s, 1H), 8.42 (d, J=0.9 Hz, 1H), 8.00 (d, J=8.4 Hz, 1H), 7.92-7,86 (m, 2H), 7.72 (td, J=7.0, 1.3 Hz, 1H), 7.58 (td, J=8.0, 1.0 Hz, 1H), 4.59 (s, 2H). MS (EI): m/z 333 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)[N:3]=1.[CH3:16][C@H:17]1[NH:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1.C(N(CC)CC)C>CN1CCCC1=O>[C:26]([O:25][C:23]([N:19]1[CH2:20][CH2:21][N:22]([C:2]2[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][N:11]=3)[N:3]=2)[C@H:17]([CH3:16])[CH2:18]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1nc(-c2ccncn2)cc(=O)n1C
Yield: 74.4 %

Procedure:
A solution of 2-chloro-3-methyl-6-(pyrimidin-4-yl)-3H-pyrimidin-4-one (5.3 g, 24 mmol), tert-butyl (3R)-3-methylpiperazine-1-carboxylate (5.0 g, 25 mmol) and triethylamine (7.6 g, 75 mmol) in N-methyl-2-pyrrolidone (25 ml) was stirred for 6 hours at 90° C. The solution was partitioned between water and ethyl acetate, and the organic layer was washed with water, brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; ethyl acetate) to afford (3R)-3-methyl-4-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (6.9 g, 71%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([C:15]2[CH:16]=[C:17]([CH:27]=[CH:28][CH:29]=2)[C:18]([O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])=[O:19])(=[O:14])=[O:13])=[CH:7][CH:6]=1)=[O:4].[C:30](#N)[CH3:31].C(=O)([O-])[O-].[K+].[K+].ICC>O>[CH2:30]([N:11]([C:8]1[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][CH:9]=1)[S:12]([C:15]1[CH:16]=[C:17]([CH:27]=[CH:28][CH:29]=1)[C:18]([O:20][CH2:21][CH2:22][Si:23]([CH3:24])([CH3:25])[CH3:26])=[O:19])(=[O:14])=[O:13])[CH3:31]
Reactant: CC#N
Reactant: COC(=O)c1ccc(NS(=O)(=O)c2cccc(C(=O)OCC[Si](C)(C)C)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCI
Product: CCN(c1ccc(C(=O)OC)cc1)S(=O)(=O)c1cccc(C(=O)OCC[Si](C)(C)C)c1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
To a mixture of 320 mg of 2-(trimethylsilyl)ethyl 3-{[4-(methoxycarbonyl)phenyl]sulfamoyl}benzoate and 5 mL of acetonitrile were added 203 mg of potassium carbonate and 0.119 mL of iodoethane. After stirring at 70° C. for 5 hours, 102 mg of potassium carbonate and 0.059 mL of iodoethane were added thereto, followed by stirring at 70° C. for 10 hours. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 334 mg of a 2-(trimethylsilyl)ethyl 3-{ethyl[4-(methoxycarbonyl)phenyl]sulfamoyl}benzoate as a colorless oily substance. ESI+: 464
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([O:11][CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][C:19]4[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=4)[CH2:14][CH2:13]3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH2:25][OH:26].[CH2:27]([O:29][CH2:30][C:31]1[O:32][C:33]2[CH:39]=[CH:38][C:37](O)=[CH:36][C:34]=2[CH:35]=1)[CH3:28].N(C(N(C)C)=O)=NC(N(C)C)=O.C(P(CCCC)CCCC)CCC>C1COCC1.C(OCC)(=O)C>[CH2:27]([O:29][CH2:30][C:31]1[O:32][C:33]2[CH:39]=[CH:38][C:37]([O:26][CH2:25][C:3]3[O:4][C:5]4[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH:12]5[CH2:17][CH2:16][N:15]([CH2:18][C:19]6[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=6)[CH2:14][CH2:13]5)[C:6]=4[C:2]=3[CH3:1])=[CH:36][C:34]=2[CH:35]=1)[CH3:28]
Reactant: Cc1c(CO)oc2cccc(OC3CCN(Cc4cccnc4)CC3)c12
Reactant: CCOCc1cc2cc(O)ccc2o1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOCc1cc2cc(OCc3oc4cccc(OC5CCN(Cc6cccnc6)CC5)c4c3C)ccc2o1
Temperature: -30 °C
Reaction time: 8 h
Yield: 61.6 %

Procedure:
To a cooled (−30° C.) solution of [3-methyl-4-(1-pyridin-3-ylmethyl-piperidin-4-yloxy)-benzofuran-2-yl]-methanol (30 mg), 2-ethoxymethyl-benzofuran-5-ol (16 mg) and 1,1′-azobis(N,N-dimethylformamide) (37 mg) in THF (1 ml) was added tributylphosphine (53 μl) and the resulting solution was stirred overnight at −30° C. The resulting suspension was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by preparative thin layer chromatography (using dichloromethane:MeOH=20:1 as a developing solvent) to give 3-[4-[2-(2-ethoxymethyl-benzofuran-5-yloxymethyl)-3-methyl-benzofuran-4-yloxy]-piperidin-1-ylmethyl]-pyridine (27 mg) as a colorless oil. FAB-MS: m/z 527 (MH+); 1H-NMR (CDCl3): δ 1.26 (3H, t, J=7 Hz), 1.99 (4H, m), 2.41 (3H, s), 2.42 (2H, m), 2.70 (2H, m), 3.55 (2H, s), 3.61(2H, q, J=7 Hz), 4.52 (1H, m), 4.58 (2H, s), 5.10 (2H, s), 6.60 (1H, d, J=8 Hz), 6.63 (1H, s), 6.97 (1H, dd, J1=9 Hz, J2=2.5 Hz), 7.03 (1H, d, J=8 Hz), 7.15 (1H, t, J=8 Hz), 7.15 (1H, d, J=2.5 Hz), 7.26 (1H, dd, J1=8 Hz, J2=5 Hz), 7.37 (1H, d, J=9 Hz), 7.68 (1H, dt, J1=8 Hz, J2=2 Hz),8.51 (1H, dd, J1=5 Hz, J2=2 Hz), 8.56 (1H, d, J=2 Hz).