Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH2:11][CH:12]([CH3:14])[CH3:13])[C:5]([OH:7])=O.O[NH:16][C:17](=[NH:26])[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][CH:19]=1.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:7][N:26]=[C:17]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][CH:19]=3)[N:16]=2)[CH:8]=[CH:9][C:10]=1[CH2:11][CH:12]([CH3:14])[CH3:13]
Reactant: N=C(NO)c1ccc(CO)cc1
Reactant: CC(C)Cc1ccc(C(=O)O)cc1Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Cc1ccc(-c2nc(-c3ccc(CO)cc3)no2)cc1Cl
Temperature: 122.5 °C

Procedure:
N,N-Dicyclohexylcarbodiimide (1.07 g, 0.0052 mol) is added to a solution of 3-chloro-4-isobutylbenzoic acid (0.74 g, 0.0035 mol), N-hydroxy-4-hydroxymethylbenzamidine (0.867 g, 0.0052 mol) and N-hydroxybenzotriazole monohydrate (0.798 g, 0.0052 mol) in N,N-dimethylformamide (15 mL). The reaction mixture is heated at 120-125° C. for 2 hrs. It is then cooled to 0-5° C., filtered and washed with dichloromethane (2×20 mL). The filtrate is evaporated under reduced pressure and the residue is treated with demineralized water (20 mL). It is extracted with ethyl acetate (2×30 mL) and the combined extract is dried over sodium sulfate. Removal of solvent under reduced pressure gives a crude residue which is purified by column chromatography (silica gel 230-400, ethyl acetate:toluene, 15:85) to give {4-[5-(3-chloro-4-isobutylphenyl)-[1,2,4]-oxadiazol-3-yl]-phenyl}methanol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8](OC(=O)CC)(=O)[CH2:9][CH3:10].[CH2:17]([N:20]1[C@H:25]([CH3:26])[CH2:24][N:23]([C@H:27]([C:42]2[CH:43]=[C:44]([CH:48]=[CH:49][CH:50]=2)[C:45](Cl)=[O:46])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][Si](C(C)(C)C)(C)C)[CH:29]=2)[C@@H:22]([CH3:51])[CH2:21]1)[CH:18]=[CH2:19]>>[CH2:8]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][CH3:10].[CH2:17]([N:20]1[C@H:25]([CH3:26])[CH2:24][N:23]([C@H:27]([C:42]2[CH:43]=[C:44]([CH:48]=[CH:49][CH:50]=2)[C:45]([N:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:8][CH2:9][CH3:10])=[O:46])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[CH:29]=2)[C@@H:22]([CH3:51])[CH2:21]1)[CH:18]=[CH2:19]
Reactant: Nc1ccccc1
Reactant: C=CCN1C[C@H](C)N([C@@H](c2cccc(O[Si](C)(C)C(C)(C)C)c2)c2cccc(C(=O)Cl)c2)C[C@H]1C
Reactant: CCC(=O)OC(=O)CC
Product: C=CCN1C[C@H](C)N([C@@H](c2cccc(O)c2)c2cccc(C(=O)N(CCC)c3ccccc3)c2)C[C@H]1C
Product: CCCNc1ccccc1

Procedure:
N-Propylaniline was prepared from aniline and propionic anhydride, coupled with 3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)benzoyl chloride, deprotected and purified by the methods described in Example 10 to give (+)-3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-phenyl-N-propylbenzamide as a light yellow solid. NMR (200 MHz, DMSO-d6): δ0.87 (t, J=7.4 Hz, 3H); 0.91 (d, J=5.9 Hz, 3H); 0.98 (d, J=6.0 Hz, 3H); 1.51 (m, 2H); 1.69 (dd, J1 =7.2 Hz, J2 =10.9 Hz, 1H); 2.06 (dd, J1 =7.0 Hz, J2 =10.5 Hz, 1H); 2.30 (d, J=10.3 Hz, 1H); 2.39-2.54 (m, 2H); 2.65 (br d, J=10.3 Hz, 1H); 2.85 (dd, J1 =7.4 Hz, J2 =14.5 Hz, 1H); 3.16 (dd, J1 =5.1 Hz. J2 =14.2 Hz, 1H); 3.79 (t, J=7.6 Hz, 2H); 4.77 (s, 1H); 5.12 (d, J=10.2 Hz, 1H); 5.18 (d, J=16.0 Hz, 1H); 5.71-5.84 (m, 1H); 6.43 (d, J=7.6 Hz, 1H); 6.57 (s, 1H); 6.64 (d, J=8.0 Hz, 1H); 7.02-7.33 (m, 10H); 9.32 (s, 1H). Mass spectrum (CI--CH4) m/e: 498 (M+1,100%), 344 (23%), 153 (80%), [α]D20 =+8.9° (ethanol, c=1.1). The free amine (0.585 g) was dissolved in ethanol and titrated with ethanolic hydrogen chloride to pH 4.0 followed by precipitation with diethyl ether from dichloromethane to give 0.479 g of the monohydrochloride salt as a hygroscopic off-white powder. Calc. for C32H39N3O2HCl 0.75 H2O: C, 70.18; H, 7.64; N, 7.67; Cl, 6.47. Found: C, 70.16; H, 7.73; N, 7.59; Cl, 6.51.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)#[N:2].[OH:9]F>CC#N>[C:1]([C:3]1[CH:8]=[CH:7][N+:6]([O-:9])=[CH:5][CH:4]=1)#[N:2]
Reactant: OF
Reactant: N#Cc1ccncc1
Solvent: CC#N
Product: N#Cc1cc[n+]([O-])cc1
Yield: 59 %

Procedure:
4-cyanopyridine was reacted with 1 equivalent of HOF.MeCN to yield 59% of 4-cyanopyridine-N-oxide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([C:17]([OH:19])=[O:18])=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20](=O)([O-])[O-].[K+].[K+].CI.C(OCC)(=O)C>CN(C)C=O>[CH3:20][O:18][C:17]([C:15]1[S:14][C:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][C:10]=2[CH:16]=1)=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCc2sc(C(=O)O)cc2C1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: COC(=O)c1cc2c(s1)CCN(C(=O)OC(C)(C)C)C2

Procedure:
5-t-Butoxycarbonyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine-2-carboxylic acid (300 mg, 1.1 mmol), potassium carbonate (150 mg, 1.1 mol) and methyl iodide (150 mg, 1.1 mmol) were stirred at room temperature for 4.5 hours in anhydrous N,N-dimethylformamide (3 ml). The reaction solution was mixed with ethyl acetate, washed with water and saturated brine and then dried with anhydrous sodium sulfate to obtain crude 5-t-butoxycarbonyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine-2-carboxylic acid methyl ester. This was mixed with hydrochloric acid-saturated methanol (4 ml) and stirred at room temperature for 14 hours. By evaporating the solvent from the reaction solution under a reduced pressure, crude 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine-2-carboxylic acid methyl ester hydrochloride was obtained. This compound and triethylamine (0.59 ml, 4.2 mmol) and 2a-(4-bromobutyl)-2a,3,4,5-tetrahydro-1H-benz[cd]indol-2-one (310 mg, 1.0 mmol) were stirred at room temperature for 24 hours in anhydrous N,N-dimethylformamide (10 ml). The reaction solution was mixed with ethyl acetate, washed with water and saturated brine and then dried with anhydrous sodium sulfate. The solvent was removed by evaporation under a reduced pressure, and the thus obtained material was separated and purified by a silica gel column chromatography to obtain 240 mg (0.56 mmol, 56% in yield) of the title compound.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[C:19]([O:22][CH2:23][CH3:24])(=[O:21])[CH3:20].[C:25]([NH:32][C@H:33]([CH:38]=[O:39])[CH2:34][CH:35]([CH3:37])[CH3:36])([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].Cl>O1CCCC1>[CH2:23]([O:22][C:19](=[O:21])[CH2:20][CH:38]([OH:39])[CH:33]([NH:32][C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:34][CH:35]([CH3:37])[CH3:36])[CH3:24]
Reactant: CCOC(C)=O
Reactant: CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)CC(O)C(CC(C)C)NC(=O)OC(C)(C)C
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 38.8 %

Procedure:
To diisopropylamine (7.7 g, 0.077 mol) in dry tetrahydrofuran (26 mL) cooled to -20 degrees C. under argon was added dropwise n-butyllithium in hexane (1.46M, 52.4 mL, 0.077 mol). The solution was stirred 15 min, the temperature lowered to -78 degrees C. and dry ethyl acetate (6.7 g, 0.077 mol) added dropwise while maintaining the temperature below -75 degrees C. The solution was stirred 10 min and a precooled (-78 degrees C.) tetrahydrofuran solution of Boc-L-leucinal (11 g, 0.051 mol) was added. After 30 min, 2M HCl (40 mL) was added and the mixture was slowly warmed to 10 degrees C. and extracted with ether (3×200 mL). The combined ethereal extract was washed with saturated sodium chloride and dried with magnesium sulfate and filtered. Evaporation of the filtrate in vacuo gave 14 g of crude product which was purified by flash chromatography (20% ethyl acetate in hexane) to give 6 g of desired product.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:11][C:12]#[N:13]>CN(C)C=O>[C:1]([O:9][CH2:11][C:12]#[N:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCBr
Reactant: O=C(O)c1ccccc1
Solvent: CN(C)C=O
Product: N#CCOC(=O)c1ccccc1
Temperature: 0 °C
Yield: 94.7 %

Procedure:
To a suspension of 50.0 g (0.41 mol) benzoic acid in 150 mL N,N-dimethylformamide 70.0 g (0.50 mol) potassium carbonate was added and the mixture was stirred until the evolution of gas has ceased. The reaction mixture was cooled to 0° C. and a solution of 29.0 mL (0.41 mol) bromoacetonitrile in 50 mL N,N-dimethylformamide was added dropwise. The reaction mixture was stirred overnight at room temperature. The solvent was evaporated and the residue was dissolved in 500 mL ethyl acetate. It was washed with water (3×150 mL), saturated aqueous sodium hydrogencarbonate (150 mL) and brine. The organic layer was separated and dried over anhydrous sodium sulfate. The drying agent was filtered off and the solvent was evaporated. The resulting crude product was purified by column chromatography (hexane-ethyl acetate 9:1 to 4:1) to yield cyanomethyl benzoate 62.6 g (95%). 1H-NMR (400 MHz; DMSO-d6): 7.98 (m, 2H), 7.69 (m, 1H), 7.54 (m, 2H), 5.20 (s, 2H); GCMS for C9H7NO2: 161 (MH+).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=C.N1C(C)=CC=CC=1C.C(Cl)Cl.[O:23]1CCOCC1>O.[Os](=O)(=O)(=O)=O>[O:23]=[CH:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: C=CCCCCC(=O)OCC
Reactant: C1COCCO1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CCOC(=O)CCCCC=O
Temperature: 25 °C
Reaction time: 13.5 h

Procedure:
A colorless solution of commercially available ethyl hept-6-enoate (7.000 g; 44.80 mmol) in dioxane (330 ml) and water (110 ml) was treated successively with 2,6-lutidine (9.603 g; 89.61 mmol), a solution of osmium tetroxide (2.5 wt. % in 2-methylpropan-2-ol; 0.56 ml), and NaIO4 (38.335 g; 179.23 mmol). The resulting beige heterogeneous reaction mixture was further stirred at rt, under nitrogen, for 13.5 h. The resulting milky mixture was treated with water (100 ml) and DCM (500 ml). The layers were separated, and the aq. layer was further extracted with DCM (200 ml/150 ml). The mixed slightly yellow organic layers were then washed with brine (200 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure to give crude ethyl 6-oxohexanoate as a dark-yellow/brown oil which was directly used for the next step without additional purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:39]1([CH3:48])[CH:44]=[CH:43][C:42]([CH2:45][CH2:46][NH2:47])=[CH:41][CH:40]=1>>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:10]=[CH:11][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](=[O:22])[NH:47][CH2:46][CH2:45][C:42]3[CH:43]=[CH:44][C:39]([CH3:48])=[CH:40][CH:41]=3)=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:13][CH:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(CCN)cc1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Product: Cc1ccc(CCNC(=O)c2ccc(Sc3ccc(NC(=O)OC(C)(C)C)cc3)c(Nc3ncnc4nc(C(C)C)ccc34)c2)cc1

Procedure:
According to the procedure in Example 385F, the title compound was prepared using 4-(4-tert-butoxycarbonylamino-phenylsulfanyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzoic acid (prepared in Example 385E) and 2-(p-tolyl)ethylamine.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.[NH2:34][C@@H:35]([CH2:47][OH:48])[C@H:36]([C:38]1[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=1)[OH:37]>>[C:28]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:29]=[CH:30][C:31]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:34][C@@H:35]([CH2:47][OH:48])[C@@H:36]([OH:37])[C:38]2[CH:39]=[CH:40][C:41]([N+:44]([O-:46])=[O:45])=[CH:42][CH:43]=2)=[O:18])=[O:7])=[CH:32][CH:33]=1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: N[C@@H](CO)[C@@H](O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Product: CON=C1C[C@@H](C(=O)N[C@@H](CO)[C@@H](O)c2ccc([N+](=O)[O-])cc2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-carbonyl chloride, and (1S,2S)-2-amino-1-(4-nitrophenyl)-1,3-propanediol, the title compound was obtained in 70% purity by HPLC. MS(ESI+): m/z=533.
Reaction SMILES: [Li+].C[O-].[CH3:4][C:5]1([CH3:14])[C@H:7]([CH:8]=O)[C@H:6]1[C:10]([O:12][CH3:13])=[O:11].[C:15]1([C:21]2(C3C=CC=CC=3)COC(C3C=CC=CC=3)(CBr)[O:22]2)C=CC=CC=1.CN(C)C=O>CO>[CH3:4][C:5]1([CH3:14])[C@H:7](/[CH:8]=[CH:15]/[CH:21]=[O:22])[C@H:6]1[C:10]([O:12][CH3:13])=[O:11]
Reactant: BrCC1(c2ccccc2)OCC(c2ccccc2)(c2ccccc2)O1
Reactant: COC(=O)[C@@H]1[C@@H](C=O)C1(C)C
Agent: C[O-]
Agent: [Li+]
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1[C@@H](/C=C/C=O)C1(C)C
Temperature: 75 °C
Reaction time: 5 h
Yield: 68.9 %

Procedure:
A solution of 17.1 ml of lithium methylate in methanol was added over 21/2 hours at ≃75° C. to a solution of 46.8 g of methyl (1R,trans) 2,2-dimethyl-3-formyl-cyclopropane-1-carboxylate, 193.2 g of the product of Step A and 750 ml of dimethylformamide and the mixture was stirred at ≃75° C. for 5 hours and then stood overnight at room temperature. The mixture was poured with stirring into an ice-water mixture and the resulting mixture was extracted with ether. The organic phase was washed with aqueous saturated sodium chloride solution and dried under reduced pressure at 50° C. The residue was dissolved in a solution of 750 ml of tetrahydrofuran and 750 ml of N hydrochloric acid and the solution was stirred at room temperature for 3 hours and was poured into water. The mixture was extracted with ether and the organic phase was washed with aqueous solution bicarbonate solution, with aqueous saturated sodium chloride solution, was dried and evaporated to dryness. The residue was taken up in an 8-2 petroleum ether (b.p.=60°-80° C.)-ethyl acetate mixture and the mixture was vacuum filtered. The filtrate was evaporated to dryness and the residue was chromatographed over silica gel. Elution with an 8-2 petroleum ether-ethyl acetate mixture yielded 37.6 g of methyl (1R,trans) 2,2-dimethyl-3[(E)-2-formylethenyl]-cyclopropane-1-carboxylate with a refractive index of nD28 =1.5018.
Reaction SMILES: [CH3:1][N:2]([CH3:36])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:35])/[C:14](/[C:25]2[CH:30]=[CH:29][C:28]([O:31]COC)=[CH:27][CH:26]=2)=[C:15](/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)\[CH2:16][CH2:17][CH3:18])=[CH:8][CH:7]=1.Cl.C([O-])(O)=O.[Na+]>CO.CCOC(C)=O.O>[CH3:36][N:2]([CH3:1])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:35])/[C:14](/[C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[C:15](/[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)\[CH2:16][CH2:17][CH3:18])=[CH:10][CH:11]=1
Reactant: CCC/C(=C(\C(=O)Nc1ccc(OCCN(C)C)cc1)c1ccc(OCOC)cc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CCC/C(=C(\C(=O)Nc1ccc(OCCN(C)C)cc1)c1ccc(O)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To a solution of 5a (45 mg, 0.0921 mmol) in MeOH (1 ml) was added 3N HCl in AcOEt (0.5 ml) under ice cooling, and the mixture was stirred at room temperature for 1 h. A solution of NaHCO3 (139 mg) in H2O was poured into the reaction mixture under ice cooling, and the whole was extracted with AcOEt and a little MeOH. The organic layer was washed with brine, dried over Na2SO4, and then concentrated. The residue was crystallized with Et2O to give 6a (83%). 6a: colorless powder; 1H-NMR (CD3OD) δ 0.87 (3H, t, J=7.4 Hz), 1.38 (2H, m), 2.46 (6H, s), 2.59 (2H, m), 2.91 (2H, t, J=5.1 Hz), 4.14 (2H, t, J=5.1 Hz), 6.51 (2H, d, J=8.6 Hz), 6.92-6.96 (4H, m), 7.10-7.24 (5H, m), 7.53 (2H, d, J=8.8 Hz). HRMS calcd for C28H33N2O3 [M+H]+: 445.2491. Found: 445.2510.
Reaction SMILES: [I-:1].N[S+]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH:7]1[OH:19])(=C)C.[C:20](=O)([O-])[O-].[NH4+:24].[NH4+:25]>CO>[I-:1].[C:20]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH:7]1[OH:19])(=[NH:25])[NH2:24]
Reactant: C=[S+](C)(N)C1CCN(C(=O)OC(C)(C)C)CC1O
Reactant: [NH4+]
Reactant: O=C([O-])[O-]
Agent: [I-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(C(=N)N)C(O)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
A solution of 2.76 g (7.09 mmol) of (3RS,4SR)-[amino-(1-tert-butoxycarbonyl-3-hydroxy-piperidine-4-yl)-methylene-methyl-sulphonium iodide in 15 ml of methanol was treated with 0.41g (3.55 mmol) of ammonium carbonate and stirred at room temperature for 18 hours. For the working-up, the reaction mixture was evaporated under reduced pressure. 2.5 g (95% of theory) of tert-butyl (3RS,4RS)-4-carbamimidoyl-3-hydroxy-piperidine-1-carboxylate iodide were obtained as a colourless foam. A solution of 715 mg (1.92 mmol) of tert-butyl (3RS,4RS)-4-carbamimidoyl-3-hydroxy-piperidine-1-carboxylate iodide in 20 ml of methanol was stirred at room temperature for 1 hours with 321 mg (1.92 mmol) of silver acetate. The precipitated silver iodide was filtered off and washed with 20 ml of methanol. The light yellow filtrate obtained was evaporated under reduced pressure. There were obtained 538 mg (92% of theory) of tert-butyl (3RS,4RS)-4-carbamimidoyl-3-hydroxy-piperidine-1-carboxylate acetate as a colourless foam.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4]([CH:7]([NH:15][CH3:16])[CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:3][CH:2]=1.[CH3:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][C:33]=1C)[N:30]([CH2:35][C:36]([OH:38])=O)[C:29](=[O:39])[CH:28]=[CH:27]2.[CH:40](N(C(C)C)CC)(C)C>CN(C)C=O>[C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:2]=[CH:3][C:4]([CH:7]([N:15]([CH3:16])[C:36](=[O:38])[CH2:35][N:30]2[C:31]3[C:26](=[C:25]([CH3:40])[C:24]([CH3:23])=[CH:33][CH:32]=3)[CH:27]=[CH:28][C:29]2=[O:39])[CH2:8][N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)=[CH:5][CH:6]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1cc2ccc(=O)n(CC(=O)O)c2cc1C
Reactant: CNC(CN1CCOCC1)c1ccc(-c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc2c(ccc(=O)n2CC(=O)N(C)C(CN2CCOCC2)c2ccc(-c3ccccc3)cc2)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 19.6 %

Procedure:
[1-(4-biphenylyl)-2-(4-morpholinyl)ethyl]methylamine (80 mg, 0.26 mmol) was added to a solution of (6,7-dimethyl-2-oxo-1(2H)-quinolinyl)acetic acid (50 mg, 0.22 mmol), (benzotriazol-1-yloxy) tris(dimethylamino) phosphonium-hexafluorophosphate (BOP) (110 mg, 0.26 mmol) and diisopropylethylamine (140 mg, 1.1 mmol) in dimethylformamide (DMF) (5 mL). The reaction mixture was stirred at room temperature for 3 h, filtered and washed with DMF. The crude was purified by preparative HPLC (YMC CombiPrep ODS-A, 50×20 mm, 20 mL/min, A: acetonitrile B: water, A: 10 to 90% over 10 min, UV detection at 214 nm) to give the title compound (22 mg, 17%), MS (ES) m/e 510 [M+H]+.
Reaction SMILES: [CH2:1]([CH:4]([NH2:8])[CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3].[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br>CO>[Br-:9].[Br-:9].[CH2:1]([CH:4]([NH2+:8][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH2+:8][CH:4]([CH2:5][CH:6]=[CH2:7])[CH2:1][CH:2]=[CH2:3])[CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3]
Reactant: BrCCCCCCCCCCBr
Reactant: C=CCC(N)CC=C
Solvent: CO
Product: C=CCC(CC=C)[NH2+]CCCCCCCCCC[NH2+]C(CC=C)CC=C
Product: [Br-]
Temperature: 65 °C
Reaction time: 1 h
Yield: 220.5 %

Procedure:
To a 1 L Morton flask was added diallylmethylamine (86.1 g), 1,10-dibromodecane (112 g), and methanol (100 mL). The mixture was heated to 65° C. for 24 h, and then allowed to cool to room temperature. The solvent was removed by rotary vacuum evaporation. Diethylether (400 mL) was added and the mixture was stirred for 1 hr. The mixture was allowed to settle and the top layer was decanted and discarded. The remaining oil was dried by rotary vacuum evaporation to yield 215 g of product.
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][NH:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C(OCC)(=O)C>CN(C=O)C>[CH2:29]([N:2]1[CH2:3][CH2:4][CH2:5][C:6]2[CH:11]=[C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:9]=[CH:8][C:7]=2[CH2:1]1)[CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCCNC3)nc1
Reactant: CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCN1CCCc2cc(Oc3ccc(C(N)=O)cn3)ccc2C1
Temperature: 70 °C

Procedure:
Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Example 447, Part E, 0.300 g, 1.06 mmol), K2CO3 (0.366 g, 2.65 mmol), and 1-bromopentane (0.176 g, 1.16 mmol) in DMF (5.3 mL). Heat at 70° C. overnight and then increase the temperature to 100° C. for additional two hours. Cool the reaction mixture to room temperature and add ethyl acetate (150 mL). Wash with 1.0 N NaOH (1× 50 mL), brine (1× 50 mL), dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography eluting with 7% to 15% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound: MS ES+ 354.2 (M+H)+, HRMS calcd for C21H28N3O2 354.2182 (M+H)+, found 354.2188, time 0.53 min; Anal. Calcd for C21H27N3O2: C, 71.36; H, 7.70; N, 11.89. Found: C, 71.14; H, 7.60; N, 11.79.
Reaction SMILES: [NH2:1][NH2:2].C([O:5][C:6](=O)[CH:7]([C:21](=O)[C:22]([F:25])([F:24])[F:23])[CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)C.CO>C1(C)C=CC=CC=1>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][CH:8]([C:7]2[C:6]([OH:5])=[N:1][NH:2][C:21]=2[C:22]([F:25])([F:24])[F:23])[CH2:9][CH2:10]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: NN
Reactant: CCOC(=O)C(C(=O)C(F)(F)F)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2c(O)n[nH]c2C(F)(F)F)CC1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
Anhydrous hydrazine (0.040 mL, 41 mg, 1.27 mmol) was added to a stirred solution of 1-(tert-butoxycarbonyl)-α-(trifluoroacetyl)-4-piperidineacetic acid ethyl ester (275 mg, 0.75 mmol, from Step B) in toluene (2.0 mL) at RT. The mixture was warmed to 60° C. for 4 h, followed by 16 h at 80° C. The mixture was allowed to cool to RT, transferred to another flask with CH3OH, and evaporated to give the title compound as a white solid. For the title compound: 1H NMR (500 MHz, CD3OD) δ 4.15 (bd, J=13, 2H), 2.86–2.70 (m, 3H), 1.88 (bq, J=12, 2H), 1.62 (bd, J=13, 2H), 1.47 (s, 9H); ESI-MS 280.3 (M+H−56) and 236.3 (M+H−100); HPLC A: 3.0 min.