Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[N:2]1(C(OCC2C=CC=CC=2)=O)[CH2:7][CH2:6][CH:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H][H].CO>CCOC(C)=O.[Pd]>[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)C1CCNCC1
Reaction time: 8 h
Yield: 91.3 %

Procedure:
To a 3 L florentine under nitrogen was charged Pd on C, wet, Degussa (10% Pd, 50% WATER) (8.120 g, 76.30 mmol) then EtOAc (1.706 L). The mixture was degassed via N2/vacuum cycles (3×), then a solution of O1-benzyl O4-tert-butyl piperidine-1,4-dicarboxylate 21 (243.7 g, 763.0 mmol) in EtOAc (243.7 mL) was added. Mixture was stirred under a hydrogen atmosphere overnight. Hydrogen was replenished and mixture was stirred for a further 3.5 h. Methanol (60 mL) was added to aid dissolution of precipitate then filtered through celite, washing through with methanol. Filtrate concentrated in vacuo to leave a brown oil with a slight suspension of a white solid, 138.6 g. Solid removed by filtration, and washed with minimal EtOAc. Filtrate was concentrated in vacuo to leave desired product as a light brown oil (129 g, 91%). 1H NMR (500 MHz, DMSO-d6) δ 2.88 (dt, 2H), 2.44 (td, 2H), 2.23 (tt, 1H), 1.69-1.64 (m, 2H) and 1.41-1.33 (m, 11H).
Reaction SMILES: C([N:8](O)[C@H:9]([CH3:21])[C@@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:11][CH3:12])C1C=CC=CC=1>[OH-].[OH-].[Pd+2].CO>[NH2:8][C@H:9]([CH3:21])[C@@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:11][CH3:12]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)[C@@H](C)N(O)Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC[C@H](NC(=O)OC(C)(C)C)[C@@H](C)N
Yield: 105.5 %

Procedure:
An MeOH (20 ml) solution containing tert-butyl ((3S,4R)-4-(benzyl (hydroxy)amino)pentan-3-yl)carbamate (39 mg) was subjected to a hydrogenation reaction (45° C.; 100 bar; flow rate: 1 ml/min; 20% Pd(OH)2/C) using H-Cube™. Then, the solvent was distilled away under reduced pressure. Colorless oily matter of tert-butyl ((3S,4R)-4-aminopentan-3-yl)carbamate (27 mg) was thus obtained.
Reaction SMILES: [CH2:1]([C:3]1([CH2:16][CH3:17])[CH2:8][C:7](=O)[C:6]2[CH:10]=[C:11]([C:14]#[N:15])[CH:12]=[CH:13][C:5]=2[O:4]1)[CH3:2]>C(O)C>[CH2:16]([C:3]1([CH2:1][CH3:2])[CH:8]=[CH:7][C:6]2[CH:10]=[C:11]([C:14]#[N:15])[CH:12]=[CH:13][C:5]=2[O:4]1)[CH3:17]
Reactant: CCC1(CC)CC(=O)c2cc(C#N)ccc2O1
Solvent: CCO
Product: CCC1(CC)C=Cc2cc(C#N)ccc2O1

Procedure:
13,7 g of this 4-chromanone are dissolved in 420 ml ethanol and the obtained solution is mixed with 1,14 g of sodiumborhydride. After 5 hours at room temperature the reaction solution is partitioned between water and dichloromethane, the organic phases are dried over sodiumsulphate and concentrated. 15 g of the obtained residue are taken up in 600 ml of toluene and are refluxed for 5 hours together with 570 mg of p-toluene-sulphonic acid in a Dean Stark apparatus. Washing of the reaction solution with 2N aq. sodium hydroxide solution and water yields after drying over sodiumsulphate and concentration a residue that is purified by flash-chromatography (silica gel/dichloromethane, hexane 1:2). Concentration of the eluate gives 2,2-diethyl-1-benzopyran-6-carbonitrile as colorless oil.
Reaction SMILES: [NH2:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[OH-].[Na+].Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>O>[C:23]1([CH2:22][O:21][C:19]([NH:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][CH:5]=2)=[O:20])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 102.1 %

Procedure:
To a suspension of tryptophan (20.08 g; 98.32 mmol) in H2O, cooled to 0° C., was added 1N NaOH (98 mL; 98 mmol) and the solution became clear. Maintaining the temperature at 0° C., 1N NaOH (108 mL; 108 mmol) and benzyl chloroformate (CBZCl, commercial product) (15.38 mL; 107.7 mmol) were simultaneously dropped in the reaction mixture. After the addition the mixture was kept at 0° C. for 30 min and then allowed to rise to r. t. The reaction was monitored by HPLC (Chromatographic method of Example 3, A). After further 3 h the pH was corrected to 9.5 by addition of 1N NaOH and the mixture was washed with Et2O (200 mL). The aqueous layer was acidified to pH 2 using 2N HCl and the precipitate was filtered through a G3 septum, washed with cold water (2×200 mL) and dried over P2O5 under vacuum (2 kPa). N-[(Phenylmethoxy)carbonyl]-L-tryptophan (33.96 g) was obtained and used in the following step without further purification.
Reaction SMILES: C([N:8]1[C:16]2[C:15]3=[N:17][CH:18]([CH2:20]OS(C)(=O)=O)[CH2:19][N:14]3[C:13](=[O:26])[N:12]([CH2:27][CH2:28][CH3:29])[C:11]=2[N:10]=[C:9]1[CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)C1C=CC=CC=1.[NH:35]1[CH:39]=[CH:38][CH:37]=[N:36]1.C(=O)([O-])[O-].[Cs+].[Cs+].C([O-])=O.[NH4+]>CN(C)C=O.[OH-].[OH-].[Pd+2]>[CH:30]1([C:9]2[NH:8][C:16]3[C:15]4=[N:17][CH:18]([CH2:20][C:39]5[CH:38]=[CH:37][NH:36][N:35]=5)[CH2:19][N:14]4[C:13](=[O:26])[N:12]([CH2:27][CH2:28][CH3:29])[C:11]=3[N:10]=2)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CCCN1C(=O)N2CC(COS(C)(=O)=O)N=C2c2c1nc(C1CCCC1)n2Cc1ccccc1
Reactant: c1cn[nH]c1
Agent: [Pd+2]
Agent: O=C([O-])[O-]
Agent: O=C[O-]
Solvent: CN(C)C=O
Product: CCCN1C(=O)N2CC(Cc3cc[nH]n3)N=C2c2[nH]c(C3CCCC3)nc21
Temperature: 120 °C
Reaction time: 2 h
Yield: 51.8 %

Procedure:
Compound 17 (100 mg, 0.21 mmol) obtained in Example 17 was dissolved in N,N-dimethylformamide (1 mL), to the solution were added pyrazole (28 mg, 0.42 mmol, 2.0 equivalents), and cesium carbonate (137 mg, 0.42 mmol, 2.0 equivalents) and the mixture was stirred at 120° C. for 2 hours. The reaction mixture was partitioned with ethyl acetate and water, and the organic layer was washed with water and dried over anhydrous magnesium sulfate. After the organic layer was concentrated, diethyl ether and hexane were added to the concentrate and the resulting white solid (66 mg) was collected by filtration. The resulting product was dissolved in methanol (1 mL), to the solution were added ammonium formate (132 mg, 2.10 mmol) and 20% palladium hydroxide/carbon (30 mg), and then the mixture was stirred under reflux with heating for 3 hours. The reaction mixture was filtered by using Celite and concentrated, then to the concentrate were added ammonium formate (150 mg) and 20% palladium hydroxide/carbon (50 mg), and the mixture was stirred under reflux with heating for 4 hours. The reaction mixture was filtered by using Celite and concentrated, and the residue was purified by silica gel column chromatography (chloroform:methanol=10:1) to obtain the title compound (40 mg, 52%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:5][CH:4]=1.Cl[C:23]1[CH:24]=[CH:25][C:26]2[N:27]([C:29]([C:32]([F:35])([F:34])[F:33])=[N:30][N:31]=2)[N:28]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:10]2[CH2:11][CH2:12][N:13]([C:23]3[CH:24]=[CH:25][C:26]4[N:27]([C:29]([C:32]([F:33])([F:35])[F:34])=[N:30][N:31]=4)[N:28]=3)[CH2:14][CH2:15]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Product: COc1ccc(C(c2ccccc2)N2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
A mixture of 1-[(4-methoxyphenyl)-phenylmethyl]piperazine and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 3. The crude product was purified by hplc using a Waters XTerra C18 column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(4-methoxyphenyl)-phenylmethyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:27][CH3:28]>O>[CH2:27]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[CH:4][CH:3]=1)[CH3:28]
Reactant: CC(C)(C)OC(=O)Nc1cccc2ccc(O)cc12
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: CCOc1ccc2cccc(NC(=O)OC(C)(C)C)c2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 67.5 %

Procedure:
Next, to a mixture of tert-butyl (7-hydroxy-1-naphthyl)carbamate (64.0 g, 247 mmol) and cesium carbonate (161 g, 493 mmol) in 300 mL anhydrous DM was added iodoethane (42.3 g, 272 mmol) at room temperature. The mixture was stirred at 60° C. for 2 hours. Water was added to the mixture, and the product was extracted with ethylacetate. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. To the obtained residue was added diisopropyl ether and the precipitate was collected and dried to afford tert-butyl (7-ethoxy-1-naphthyl)carbamate (47.9 g, 67.5% yield).
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[S:15]([OH:18])(=[O:17])=[O:16].O>ClCCl>[C:1]1([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([S:15]([OH:18])(=[O:17])=[O:16])=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(O)Cl
Reactant: c1ccc(Cc2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: O=S(=O)(O)c1ccc(Cc2ccccc2)cc1

Procedure:
To 33.6 g (0.2 mol) of diphenylmethane in 100 g of dichloromethane at room temperature, 23.4 g (0.2 mol) of chlorosulfonic acid was added dropwise. The solution was ripened for 2 hours, whereupon 50 g of water was added. This reaction mixture was used in the subsequent reaction without isolation.
Reaction SMILES: I[C:2]1[N:9]2[C:5]([O:6][CH:7]=[CH:8]2)=[N:4][C:3]=1[C:10]1[CH:15]=[C:14]([F:16])[C:13]([F:17])=[CH:12][C:11]=1[F:18].C([Mg]Cl)(C)C.I[C:25]1[CH:26]=[CH:27][C:28]2[N:29]([C:31]([CH:34]([CH3:36])[CH3:35])=[N:32][N:33]=2)[N:30]=1.CN(C=O)C>C1COCC1.[Cl-].[Zn+2].[Cl-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:34]([C:31]1[N:29]2[N:30]=[C:25]([C:2]3[N:9]4[C:5]([O:6][CH:7]=[CH:8]4)=[N:4][C:3]=3[C:10]3[CH:15]=[C:14]([F:16])[C:13]([F:17])=[CH:12][C:11]=3[F:18])[CH:26]=[CH:27][C:28]2=[N:33][N:32]=1)([CH3:36])[CH3:35]
Reactant: Fc1cc(F)c(-c2nc3occn3c2I)cc1F
Reactant: CC(C)c1nnc2ccc(I)nn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)c1nnc2ccc(-c3c(-c4cc(F)c(F)cc4F)nc4occn34)nn12
Temperature: -65 °C
Reaction time: 1.75 h
Yield: 3.7 %

Procedure:
A 50-mL round bottom flask was charged with 5-iodo-6-(2,4,5-trifluorophenyl)imidazo[2,1-b]oxazole (0.65 g, 1.8 mmol) and THF (4.5 mL) to give a white suspension. The mixture was cooled to about −65° C. followed by the addition of a 2.0 M solution of i-PrMgCl (1.1 mL, 2.1 mmol). The resulting suspension was stirred at about −55° C. for about 30 min and at about −30° C. for about 1.75 h. To the reaction mixture was added dropwise a prepared solution of zinc chloride (0.32 g, 2.3 mmol) in THF (3.0 mL) and the resulting suspension was stirred at about −30° C. for about 30 min. In a separate flask were mixed 6-iodo-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine (0.49 g, 1.7 mmol, Preparation #H.1), Pd(PPh3)4 (Strem, 0.073 g, 0.071 mmol), and DMF (5.0 mL). This solution was added to the reaction flask, which was immediately heated to about 80° C. in order to solubilize the resulting mixture. The mixture was heated at about 80° C. for about 1 h. The cooled reaction mixture was concentrated to dryness under reduced pressure and the residue was dissolved in DCM and washed with 1 N HCl, 5 N HCl, water, and brine. The solution was dried over MgSO4, filtered, and concentrated to dryness under reduced pressure. The crude product was recrystallized from ACN to give a light yellow powder, followed by RP-HPLC (Table 1, Method l) purification to give the title compound as an off-white powder (0.025 g, 3.5%): LC/MS (Table 1, Method a) Rt=2.47 min; MS m/z 399.1 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ 8.28 (d, 1 H), 8.26 (d, 1 H), 8.22 (d, 1 H), 7.85-7.71 (m, 2 H), 7.07 (dd, 1 H), 3.73-3.66 (m, 1 H), 1.44 (d, 6 H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C1(C)C(C)=CC=CC=1.[C:15]([Si:19]([CH3:22])([CH3:21])Cl)([CH3:18])([CH3:17])[CH3:16].[OH-].[Na+]>C1(C)C=CC=CC=1>[Si:19]([N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:22])[CH3:21]
Reactant: C1CNCCN1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: Cc1ccccc1C
Product: CC(C)(C)[Si](C)(C)N1CCNCC1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A flask equipped with a stirrer, reflux condenser; dropping funnel and thermometer was charged with 1076.3 g (12.5 mol) of piperazine and 500 ml of xylene and heated at 110° C. Once the internal temperature became steady, 1507.0 g (5.0 mol) of a 50 wt % toluene solution of t-butyldimethylchlorosilane was added dropwise over 3 hours. Stirring was continued for 2 hours at the temperature. The reaction solution was cooled to room temperature, to which 2,500 g of a 10 wt % sodium hydroxide aqueous solution was added. The organic layer was separated. On distillation, 646.6 g of a fraction having a boiling point of 70-71° C./0.2 kPa was collected, which was 1-t-butyldimethylsilylpiperazine.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:13]([C:29]([F:32])([F:31])[F:30])=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C:22]([N+:26]([O-])=O)([CH3:25])[CH2:23][OH:24])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]>C(O)(=O)C.CO.[Zn]>[NH2:26][C:22]([C:17]1[CH:16]=[CH:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][C@H:8]3[CH2:7][CH2:6][C@H:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10][CH2:9]3)[C:13]=2[C:29]([F:31])([F:32])[F:30])[CH:18]=1)([CH3:25])[CH2:23][OH:24]
Reactant: CC(CO)(c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1)[N+](=O)[O-]
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: CC(N)(CO)c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2-[6-(trans-4-tert-Butyl-cyclohexyloxy)-5-trifluoromethyl-naphthalen-2-yl]-2-nitro-propan-1-ol (57 mg, 0.00012 mol) was dissolved in acetic acid (0.50 mL, Fisher), followed by addition of zinc (76 mg, 0.0012 mol, Aldrich) dust in small portions at room temperature. The reaction mixture was then allowed to stir at room temperature for 1.5 hours. The reaction was diluted with methanol, filtered and evaporated. The white solid was taken up in methylene chloride, washed with 1N NaOH, washed with water, dried with magnesium sulfate, filtered and evaporated. 45 mg of product isolated (85%). MS: m/z=424.57 [M+H]+. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm: 8.20 (dd, J=9.3, 1.5 Hz, 1H), 7.90-7.95 (m, 1H), 7.89 (d, J=1.8 Hz, 1H), 7.63 (dd, J=9.2, 2.1 Hz, 1H), 7.31 (d, J=9.0 Hz, 1H), 4.24-4.34 (m, 1H), 3.77 (d, J=10.5 Hz, 1H), 3.68 (d, J=10.5 Hz, 1H), 2.14-2.23 (m, 2H), 1.94-2.13 (m, 3H), 1.81-1.92 (m, 2H), 1.48-1.59 (m, 5H), 1.24-1.38 (m, 1H), 1.03-1.19 (m, 3H), 0.88 (s, 9H).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[C:10]([CH:18]=O)=[C:11]4[C:16](=[CH:17][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1)[CH:15]=[CH:14][CH:13]=[CH:12]4.[NH2:20][C:21]([CH3:26])([CH2:24][OH:25])[CH2:22][OH:23]>CCO.CCOCC>[CH:1]1[C:9]2[C:8]3[C:10]([CH2:18][NH:20][C:21]([CH3:26])([CH2:24][OH:25])[CH2:22][OH:23])=[C:11]4[C:16](=[CH:17][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1)[CH:15]=[CH:14][CH:13]=[CH:12]4
Reactant: O=Cc1c2ccccc2cc2oc3ccccc3c12
Reactant: CC(N)(CO)CO
Solvent: CCOCC
Solvent: CCO
Product: CC(CO)(CO)NCc1c2ccccc2cc2oc3ccccc3c12
Yield: 68.8 %

Procedure:
Using the procedure outlined in Example 1, benzo[b]naphtho[2,3-d]furan-11-carbaldehyde (2B) and 2-amino-2-methyl-1,3-propanediol (Aldrich) gave a 68.8% yield of 2-[[(benzo[b]naphtho[2,3-d]furan-11-yl)methyl]amino]-2-methyl-1,3-propanediol methanesuylfonate, mp 219°-220° (dec), (C,H,N,S), (EtOH/Et2O).
Reaction SMILES: Cl.[Cl:2][CH:3]([C:17]1[CH:18]=[CH:19][C:20]([O:27][CH3:28])=[C:21]([S:23]([NH2:26])(=[O:25])=[O:24])[CH:22]=1)[CH2:4][NH:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16]>CO.[C].[Pd]>[ClH:2].[CH3:28][O:27][C:20]1[CH:19]=[CH:18][C:17]([CH2:3][CH2:4][NH:5][CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[CH:22][C:21]=1[S:23]([NH2:26])(=[O:25])=[O:24]
Reactant: COc1ccccc1OCCNCC(Cl)c1ccc(OC)c(S(N)(=O)=O)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1ccccc1OCCNCCc1ccc(OC)c(S(N)(=O)=O)c1
Yield: 88.3 %

Procedure:
In 150 ml of methanol was dissolved 3.8 g of 5-{1-chloro-2-[2-(2-methoxyphenoxy)ethylamino]ethyl}-2-methoxybenzenesulfonamide hydrochloride and after adding thereto 0.5 g of 10% palladium carbon, it was dechlorinated under a hydrogen stream at normal temperature and pressure. Then, palladium carbon was filtered away and the filtrate was concentrated under reduced pressure to provide 3.1 g of 2-methoxy-5-{2-[2-(2-methoxyphenoxy)ethylamino]ethyl}benzenesulfonamide hydrochloride, which was recrystallized from 120 ml of a mixture of methanol and ethanol (1:4 by volume ratio) to provide 2.3 g of the colorless crystals thereof.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:16])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].C(O)(=O)C.OO>O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([CH:15]=1)=[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[O:8][N:16]=2
Reactant: Cc1ccc(N)c(C(=O)c2ccccc2)c1
Agent: OO
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc2noc(-c3ccccc3)c2c1

Procedure:
A solution of 31.6 g (0.15 mole) of 5-methyl-2-aminobenzophenone, 350 ml of glacial acetic acid and 17 ml of 30% hydrogen peroxide was let stand at ambient temperature for 72 hr. The solution was poured into 2.5 liters of water. The mixture was let stand at ambient temperature for several days until the residue became crystalline. The solid was collected by filtration, dried, and chromatographed on 250 g silica gel to give 12.5 g (40%) of pale yellow solid, m.p. 64°-66° C. (after recrystallization from 2-propanol).
Reaction SMILES: N#N.C1N2CN3CN(C2)CN1C3.C1CCN2C(=NCCC2)CC1.[CH3:24][O:25][C:26]([CH:28]1[CH2:32][O:31][C:30]([CH2:33][C:34]2[S:35][C:36]([C:39]3([CH3:44])[O:43][CH2:42][CH2:41][O:40]3)=[CH:37][CH:38]=2)=[N:29]1)=[O:27]>C(Cl)Cl.[Cu](Br)Br>[CH3:24][O:25][C:26]([C:28]1[N:29]=[C:30]([CH2:33][C:34]2[S:35][C:36]([C:39]3([CH3:44])[O:43][CH2:42][CH2:41][O:40]3)=[CH:37][CH:38]=2)[O:31][CH:32]=1)=[O:27]
Reactant: COC(=O)C1COC(Cc2ccc(C3(C)OCCO3)s2)=N1
Agent: Br[Cu]Br
Agent: C1N2CN3CN1CN(C2)C3
Agent: N#N
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1coc(Cc2ccc(C3(C)OCCO3)s2)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), hexamethylenetetramine (273 mg, 1.92 mmol) and DBU (0.29 mL, 1.92 mmol) were added to a stirred suspension of copper (II) bromide (429 mg, 1.92 mmol) in deoxygenated dry CH2Cl2 (2.0 mL). After 20 min, a deoxygenated solution of 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-4,5-dihydro-oxazole-4-carboxylic acid methyl ester (240 mg, 0.77 mmol) in CH2Cl2 (5.0 mL) was added and the reaction mixture was stirred at rt for 2 h. The solvent was removed under reduced pressure and the residue was partitioned between EA (60 mL), and 40 mL of a 1:1 mixture of sat. aq. NH4Cl and 25% aq. NH4OH. The aq. layer was extracted with EA (40 mL) and the combined organic layers were washed with 40 mL of a 1:1 mixture of sat. aq. NH4Cl and 25% aq. NH4OH followed by 10% citric acid (40 mL), sat. aq. NaHCO3 (40 mL) and brine (40 mL). The organic phase was dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (2:1→1:4 hept-EA) gave the title compound as a pale yellow oil. TLC: rf (1:3 hept-EA)=0.40. LC-MS-conditions 01: tR=0.88 min, [M+H]+=309.98.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:26])=[C:21]([CH:23]=[CH:24][CH:25]=2)[NH2:22])[CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.[F:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=1[S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:26])=[C:21]([NH:22][S:41]([C:35]3[CH:36]=[C:37]([F:40])[CH:38]=[CH:39][C:34]=3[F:33])(=[O:43])=[O:42])[CH:23]=[CH:24][CH:25]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccnc(Cl)n2)c1F
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.2 %

Procedure:
To a solution of 3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluoroaniline (1.24 g, 3.17 mmol) in DCM (31.7 mL) was added pyridine (0.269 mL, 3.33 mmol) and 2,5-difluorobenzenesulfonyl chloride (0.448 mL, 3.33 mmol). The reaction was stirred 18 h at rt. The reaction mixture was concentrated onto silica gel. Purification by chromatography (5 to 100% EtOAc:DCM) afforded the title compound (1.21 g, 2.13 mmol, 67.3% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.79 (s, 1H), 8.57 (d, J=5.5 Hz, 1H), 7.37-7.67 (m, 5H), 7.32 (t, J=7.9 Hz, 1H), 6.90 (d, J=5.3 Hz, 1H), 3.93 (dd, J=11.4, 2.0 Hz, 2H), 3.39-3.58 (m, 2H), 3.26-3.40 (m, 1H), 1.98-2.09 (m, 2H), 1.63-1.86 (m, 2H). MS (ESI): 567.06 [M+H]+.
Reaction SMILES: [C:1]([NH:4][C:5](=[N:8][N+:9]([O-:11])=[O:10])SC)(=[O:3])[CH3:2].[NH2:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([Cl:20])=[N:18][CH:19]=1>C(#N)C>[C:1]([NH:4][C:5]([NH:12][CH2:13][C:14]1[CH:19]=[N:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=[N:8][N+:9]([O-:11])=[O:10])(=[O:3])[CH3:2]
Reactant: CSC(=N[N+](=O)[O-])NC(C)=O
Reactant: NCc1ccc(Cl)nc1
Solvent: CC#N
Product: CC(=O)NC(=N[N+](=O)[O-])NCc1ccc(Cl)nc1
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a mixture of 0.5 g of N-acetyl-S-methyl-N'-nitroisothiourea and 5 ml of acetonitrile was dropwise added a solution of 0.44 g of 5-(aminomethyl)-2-chloropyridine in 3 ml of acetonitrile under ice-cooling, followed by stirring for 30 minutes under ice-cooling. The reaction mixture was concentrated and the residue was recrystallized from ethanol to afford 0.59 g of N-acetyl-N'-(6-chloro-3-pyridylmethyl)-N"-nitroguanidine (Compound No. 42) as white crystals.