Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4]O.Cl[Si](C)(C)C.[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.[K]>CS(C)=O.CN(C=O)C.C(OCC)(=O)C.O>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][N:20]1[C:16](=[O:26])[C:17]2=[CH:25][CH:24]=[CH:23][CH:22]=[C:18]2[C:19]1=[O:21]
Reactant: Cc1cccc(C)c1CO
Reactant: O=C1NC(=O)c2ccccc21
Agent: C[Si](C)(C)Cl
Agent: [K]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: Cc1cccc(C)c1CN1C(=O)c2ccccc2C1=O
Reaction time: 1 h

Procedure:
To a stirred solution of 2,6-Dimethylbenzyl Alcohol (Step A, 6.59 g, 48.4 mmol) in DMSO (20 ml) was added chlorotrimethylsilane (15.75 ml, 145 mmol) at room temperature, and the mixture was stirred for one hr. To this reaction mixture were added ethyl acetate and water, the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give an oil. The oily residue was redissolved in DMF (100 ml) and potassium phthalimide (10.76 g, 58.1 mmol) was added. The reaction mixture was stirred for 16 hours at room temperature, ethyl acetate was added, and the organic layer was washed with 3% Na2CO3, 1 N HCl, dried over Na2SO4, filtered and concentrated to give white solid. The purification was done by flash chromatography on silica gel column (chloroform:methanol 95:5) to provide the title compound as white solid.
Reaction SMILES: [C:1]([C:4]1([NH:10][CH3:11])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[NH2:2].Br[CH2:13][CH2:14][O:15][CH3:16]>>[CH3:16][O:15][CH2:14][CH2:13][N:7]1[CH2:8][CH2:9][C:4]([NH:10][CH3:11])([C:1]([NH2:2])=[O:3])[CH2:5][CH2:6]1
Reactant: COCCBr
Reactant: CNC1(C(N)=O)CCNCC1
Product: CNC1(C(N)=O)CCN(CCOC)CC1

Procedure:
4-Carbamoyl-4-methylaminopiperidine was coupled with 2-bromoethylmethyl ether using an analogous method to that described for the equivalent step in Example 22 to give 1-(2-methoxyethyl)-4-(methylamino)piperidine-4-carboxamide as a white crystalline solid; 1H NMR Spectrum: (DMSO-d6) 1.44 (m, 2H); 1.78 (m, 2H); 1.89 (s, 1H); 2.05 (s, 3H); 2.28-2.44 (m, 6H); 3.21 (s, 3H); 3.38 (t, 2H); 6.84 (s, 1H); 7.16 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:15]=[C:14]([O:16]C)[C:13]([O:18]C)=[C:12]([O:20]C)[CH:11]=2)=[CH:4][CH:3]=1.O>C(Cl)Cl>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH2:9][C:10]2[CH:15]=[C:14]([OH:16])[C:13]([OH:18])=[C:12]([OH:20])[CH:11]=2)=[CH:6][CH:7]=1
Reactant: COc1cc(CSc2ccc(O)cc2)cc(OC)c1OC
Solvent: O
Solvent: ClCCl
Product: Oc1ccc(SCc2cc(O)c(O)c(O)c2)cc1
Temperature: -78 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
3,4,5-Trimethoxybenzyl 4-hydroxyphenyl thioether (12 g, 39.2 mmol), prepared as described in Example 1, was dissolved in 240 ml of dry methylene chloride, and cooled to -78° C. A solution of borontribromide (18.6 ml, 195.6 mmol) in 60 ml of dry methylene chloride was added dropwise to the above solution. The mixture was warmed to room temperature, stirred overnight, cooled to 0° C., and added 300 ml of water. The aqueous layer was then extracted twice with 200 ml of ethyl acetate, dried over magnesium sulfate, concentrated and purified on silica gel column chromatography (ethyl acetate/n-hexane=2/1) to give 8.6 g (77% yield) of 3,4,5-trihydroxybenzyl 4-hydroxyphenyl thioether as a white powder.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([O:19][CH3:20])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:29][C:30]([O:32][CH3:33])=[O:31]>CC(C)=O>[CH3:33][O:32][C:30](=[O:31])[CH2:29][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][NH:10][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:21])=[CH:13][C:14]=1[O:19][CH3:20]
Reactant: COc1cc(CNC(=O)OCc2ccccc2)ccc1O
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(CNC(=O)OCc2ccccc2)cc1OC
Yield: 89.9 %

Procedure:
A solution of 14 (0.287 g, 1 mmol) in acetone (20 mL) was treated with K2CO3 (0.552 g, 4 mmol) and methyl bromoacetate (0.14 mL, 1.5 mmol) and refluxed for 3 h. After cooling, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography over silica gel using EtOAc:Hex (3:2) as eluant to give 15 as white solid (0.323 g, 90%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)([CH2:14][OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N+]1([O-])CCOCC1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)([CH:14]=[O:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(C2CCCCC2)CC1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C=O)(C2CCCCC2)CC1

Procedure:
To a mixture of 4-cyclohexyl-4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester, 3, (1.0 g, 3.36 mmol), 4-methylmorpholine N-oxide (0.54 g, 4.64 mmol), and molecular sieves (0.5 g) in methylene chloride (20 mL) under argon atmosphere is added tetrapropylammonium perruthenate (35.5 mg) at room temperature. The mixture is stirred for 30 min to 1 hour after which the solution is filtered through a pad of silica and the solvent removed in vacuo to afford the desired product as a colorless oil, which is used without further purification. MS (ESI) m/z 318, (M+Na+).
Reaction SMILES: N#N.[C:3]([SiH2:7][O:8][C:9]([CH3:22])([CH3:21])[C:10]1[O:11][CH:12]=[C:13]([CH2:15]OS(C)(=O)=O)[N:14]=1)([CH3:6])([CH3:5])[CH3:4].[N+:23]([C:26]1[CH:30]=[N:29][NH:28][N:27]=1)([O-:25])=[O:24].CCN(C(C)C)C(C)C>CN(C=O)C.CC(=O)OCC.O>[C:3]([SiH2:7][O:8][C:9]([CH3:22])([CH3:21])[C:10]1[O:11][CH:12]=[C:13]([CH2:15][N:28]2[N:27]=[C:26]([N+:23]([O-:25])=[O:24])[CH:30]=[N:29]2)[N:14]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1nc(COS(C)(=O)=O)co1
Reactant: O=[N+]([O-])c1cn[nH]n1
Agent: N#N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[SiH2]OC(C)(C)c1nc(Cn2ncc([N+](=O)[O-])n2)co1
Temperature: 50 °C
Reaction time: 20 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of methanesulfonic acid 2-(tert-butyl-dimethyl-silanyloxymethyl)-oxazol-4-ylmethyl ester (651 mg, 2.02 mmol) in DMF (3.0 mL) was added to a solution of 4-nitro-2H-[1,2,3]triazole (210 mg, 1.84 mmol) in DMF (3.0 mL) pre-treated for 30 min with DIPEA (0.63 mL, 3.68 mmol) and the reaction mixture was stirred for 20 h at 50° C. Water (10 mL), followed by EA (10 mL) were added. The aq. layer was extracted with EA (10 mL) and the combined org. extracts were dried over NaSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (5:1 to 2:1 hept-EA) gave the title compound as a yellow oil: TLC:rf (1:2 hept-EA)=0.30. LC-MS-conditions 02: tR=1.10 min; [M+H]+=340.47.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[O:4][CH2:5][C:6]#[N:7].[F:12][C:13]1[CH:18]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:16]=[CH:15][C:14]=1[C:28]1[CH:29]=[N:30][C:31]([NH2:34])=[N:32][CH:33]=1>>[NH2:34][C:31]1[N:32]=[CH:33][C:28]([C:14]2[CH:15]=[CH:16][C:17]([C:2]3[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=3[O:4][CH2:5][C:6]#[N:7])=[CH:18][C:13]=2[F:12])=[CH:29][N:30]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: N#CCOc1ccccc1Br
Product: N#CCOc1ccccc1-c1ccc(-c2cnc(N)nc2)c(F)c1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 2-(2-bromophenoxy)acetonitrile and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C18H13FN4O, 320.11; m/z found, 320.9 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.47 (d, J=1.5, 2H), 7.60-7.56 (m, 1H), 7.46-7.34 (m, 4H), 7.26 (d, J=8.0, 1H), 7.18-7.14 (m, 1H), 6.87 (s, 2H), 5.18 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:10](=[O:13])[N:11]([CH2:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[Cl:35])[CH:24]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccccc1-c1cc(CBr)ccn1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Product: O=c1n(Cc2ccnc(-c3ccccc3Cl)c2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F

Procedure:
Analogously to the preparation of the compound in Example 89, 261 mg (0.85 mmol) of the compound from Example 5A and 240 mg (0.85 mmol) of the compound from Example 65A were reacted with one another. This gave 249 mg (54% of theory) of the target compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7](=O)[CH2:8][C:9]3([O:13]2)[CH2:12][CH2:11][CH2:10]3)=[C:5]([CH3:17])[C:4]=1[OH:18])[CH3:2].Cl.[CH3:20][O:21][NH2:22].C([O-])(=O)C.[Na+].O>CO>[CH3:20][O:21][N:22]=[C:7]1[C:6]2[C:14](=[CH:15][C:3]([CH2:1][CH3:2])=[C:4]([OH:18])[C:5]=2[CH3:17])[O:13][C:9]2([CH2:12][CH2:11][CH2:10]2)[CH2:8]1
Reactant: CCc1cc2c(c(C)c1O)C(=O)CC1(CCC1)O2
Reactant: CON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCc1cc2c(c(C)c1O)C(=NOC)CC1(CCC1)O2
Temperature: 80 °C
Reaction time: 8 h
Yield: 59.3 %

Procedure:
A mixture of 7-ethyl-6-hydroxy-5-methylspiro[chroman-2,1′-cyclobutan]-4-one (0.8 g), methoxyamine HCl salt (500 mg) and sodium acetate (300 mg) in MeOH (20 mL) was stirred at 80° C. overnight. The mixture was poured into water and extracted with ethyl acetate. The ethyl acetate was dried and evaporated. The residue was purified by silica gel column eluting with 10% ethyl acetate in hexane, giving 7-ethyl-6-hydroxy-5-methylspiro[chroman-2,1′-cyclobutan]-4-one O-methyl oxime (530 mg).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.N[C@H](C(O)=[O:23])CCCNC(=N)N>>[NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:23])=[CH:6][CH:5]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Product: N[C@@H](Cc1ccc(O)cc1)C(=O)O

Procedure:
Phe 1.00(1); Arg 2.06(2);
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[C:6]([N+:9]([O-])=O)[C:5]([N+:12]([O-:14])=[O:13])=[C:4]([F:15])[CH:3]=1.Cl>CO.O>[NH2:9][C:6]1[C:5]([N+:12]([O-:14])=[O:13])=[C:4]([F:15])[CH:3]=[C:2]([Br:1])[C:7]=1[OH:8]
Reactant: O=[N+]([O-])c1c(F)cc(Br)c(O)c1[N+](=O)[O-]
Agent: Cl
Solvent: CO
Solvent: O
Product: Nc1c(O)c(Br)cc(F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
6-Bromo-4-fluoro-2,3-dinitrophenol (4.4 g, 16 mmol) was stirred in methanol (88 mL) and 12.0 M hydrogen chloride in water (40 mL), followed by addition of stannous chloride dihydrate (11 g, 47 mmol) and the mixture was stirred at room temperature for 15 min. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was separated and concentrated. Purification on silica gel eluting ethyl acetate in hexanes gave the amine product.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][N:9]([CH2:18][C:19]([O:21]CC)=O)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:24]([N:26]([CH2:29][CH2:30][NH2:31])[CH2:27][CH3:28])[CH3:25].C(N(C(C)C)CC)(C)C>CCOCC>[CH2:24]([N:26]([CH2:27][CH3:28])[CH2:29][CH2:30][NH:31][C:19](=[O:21])[CH2:18][N:9]1[CH:10]=[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:8]1)[CH3:25]
Reactant: CCN(CC)CCN
Reactant: CCOC(=O)Cn1cc(-c2ccccc2)c(-c2ccccc2)n1
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)CCNC(=O)Cn1cc(-c2ccccc2)c(-c2ccccc2)n1
Reaction time: 18 h
Yield: 55.2 %

Procedure:
A mixture of 10 g (0.033 mol) of ethyl 3,4-diphenyl-1H-pyrazole-1-acetate, 6.9 mL (0.049 mol) of diethylaminoethylamine and 39 mL of diisopropylethylamine was stirred on a steam bath under nitrogen for 18 hours. The reaction was stripped, the residue taken up in about 300 mL of ether and washed twice with water. The ether layer was extracted twice with a total of 150 mL of cold water containing 20 mL of 10% HCl. The combined water extracts were washed once with ether, cooled, made basic with solid sodium carbonate, extracted several times with methylene dichloride, dried over sodium sulphate, treated with decolorizing carbon, filtered and stripped. The oily red residue was crystallized from ether to yield 6.86 g of N-[2-(diethylamino)ethyl]-3,4-diphenyl-1H-pyrazole-1-acetamide, mp 80°-83° C.
Reaction SMILES: Cl[CH:2]1[CH2:6][O:5][C:4](=[O:7])[O:3]1.[C:8]([NH:11][C:12]1[C:13]([I:28])=[C:14]([N:23]([C:25](=[O:27])[CH3:26])[CH3:24])[C:15]([I:22])=[C:16]([C:19]([O-:21])=[O:20])[C:17]=1[I:18])(=[O:10])[CH3:9].[K+].[I-].[Na+]>CN(C=O)C>[C:8]([NH:11][C:12]1[C:13]([I:28])=[C:14]([N:23]([C:25](=[O:27])[CH3:26])[CH3:24])[C:15]([I:22])=[C:16]([C:19]([O:21][CH:2]2[CH2:6][O:5][C:4](=[O:7])[O:3]2)=[O:20])[C:17]=1[I:18])(=[O:10])[CH3:9]
Reactant: O=C1OCC(Cl)O1
Reactant: CC(=O)Nc1c(I)c(C(=O)[O-])c(I)c(N(C)C(C)=O)c1I
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1c(I)c(C(=O)OC2COC(=O)O2)c(I)c(N(C)C(C)=O)c1I
Temperature: 50 °C
Reaction time: 96 h

Procedure:
4-Chloro-1,3-dioxolan-2-one (1.35 g, 11 mmol) was added at room temperature to a solution of potassium 5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate (6.66 g, 10 retool) and sodium iodide (0.15 g, 1 retool) in dry DMF (50 ml). After stirring at 50° C. for 6 hours and at room temperature for 4 days the solvent was removed at reduced pressure. The residue was dissolved in chloroform (100 ml) and washed four times with a saturated sodium hydrogen carbonate solution and finally twice with water. After treatment with magnesium sulfate the solution was finally evaporated to dryness. Yield: 5.6 g. Purity by HPLC: 93%. 1H-NMR (DMSO-d6): delta=1.67 (N(CH3)COCH3); 2.05(NCOCH3); 2.96 (NCH3); 4.7; 4.9(CH2); 7.02(CH); 10.14 ppm (NH).
Reaction SMILES: [Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:12])(=[O:11])[N:7]([CH3:13])[C:6]([C:14]([O:16]C)=O)=[C:5]([OH:18])[C:4]=2[CH:3]=1.[NH2:19][C:20]1[S:21][CH:22]=[CH:23][N:24]=1>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:11])(=[O:12])[N:7]([CH3:13])[C:6]([C:14](=[O:16])[NH:19][C:20]3[S:21][CH:22]=[CH:23][N:24]=3)=[C:5]([OH:18])[C:4]=2[CH:3]=1
Reactant: COC(=O)C1=C(O)c2cc(Cl)sc2S(=O)(=O)N1C
Reactant: Nc1nccs1
Solvent: Cc1ccccc1C
Product: CN1C(C(=O)Nc2nccs2)=C(O)c2cc(Cl)sc2S1(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.4 g. of 6-chloro-4-hydroxy-2-methyl-3-methoxycarbonyl-2H-thieno[3,2-e]1,2-thiazine-1,1-dioxide is heated under reflux for 16 hours with 0.19 g. of 2-aminothiazole in 45 ml. of absolute xylene, while passing a stream of nitrogen through the mixture. The reaction mixture is cooled to room temperature, and the product is crystallized out by scratching and then kept overnight in the cold. The precipitate crystals are removed by filtration under suction, recrystallized from ethanol, and 6-chloro-4-hydroxy-2-methyl-3-(2-thiazolecarbamoyl)-2H-thieno[3,2-e]1,2-thiazine-1,1-dioxide having a melting point of 136°-138° (with decomposition) is obtained.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].S(Cl)([Cl:16])=O>>[CH2:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:16])=[O:10])=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: O=S(Cl)Cl
Reactant: C=CCOc1ccc(C(=O)O)cc1
Product: C=CCOc1ccc(C(=O)Cl)cc1

Procedure:
A mixture containing 29.9 g. of 4-allyloxybenzoic acid and 250 ml. of thionyl chloride was stirred and refluxed for 90 minutes and the excess thionyl distilled off, first at atmospheric pressure and then at reduced pressure. Ethylene dichloride was added and the solution evaporated in vacuo to remove the ethylene dichloride and remaining traces of thionyl chloride to give a quantitative yield of 4-allyloxybenzoyl chloride.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([CH2:8][NH:9][CH2:10][CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:6][CH:5]=1)([O-])=O.O.NN>CCO.[Ni]>[N:12]1([CH2:11][CH2:10][NH:9][CH2:8][C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:18][CH:17]=2)[CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: O=[N+]([O-])c1ccc(CNCCN2CCCC2)cc1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1ccc(CNCCN2CCCC2)cc1
Temperature: 65 °C
Reaction time: 0.75 h
Yield: 75.2 %

Procedure:
The (4-Nitro-benzyl)-(2-pyrrolidin-1-yl-ethyl)-amine (0.503 g, 2.02 mmol) was dissolved in EtOH (10 mL) under Ar(g), and hydrazine hydrate (0.439 mL, 14.14 mmol) was added. Subsequently, excess RaNi was added in dropwise until the solution stopped bubbling. The suspension was then allowed to stir for an additional 45 minutes at 65° C. The suspension was cooled to r.t. and then filtered over celite. The celite was washed with MeOH and the combined organic solutions were then concentrated in vacuo affording a pure 4-[(2-Pyrrolidin-1-yl-ethylamino)-methyl]-phenylamine as a light purple oil (0.331 g, 1.52 mmol, 75% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][C:12]#[N:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].C[Si]([N:18]=[N+:19]=[N-:20])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10][CH2:11][C:12]2[NH:20][N:19]=[N:18][N:13]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#CCSc1ccc([N+](=O)[O-])cc1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(SCc2nnn[nH]2)cc1
Temperature: 25 °C
Yield: 80.7 %

Procedure:
To 2-[(4-nitrophenyl)sulfanyl]acetonitrile (6.8 g) was added toluene (70 ml), and to this solution was added trimethylsilylazide (8.1 g) and then, dibutyl tin oxide (VI) (0.87 g), and the mixture was heated to reflux for 6 hours. After allowing the mixture to be cooled to room temperature, the solvent was removed under reduced pressure, and azeotropically distilled with methanol. To the obtained residue was added 10% aqueous solution (50 ml) of sodium carbonate, and the mixture was washed with ethyl acetate. The pH was adjusted to about pH 3 with 6N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the residue was washed with hexane/ethyl acetate to give 5-[[(4-nitrophenyl)sulfanyl]methyl]-1,2,3,4-tetrazole (6.7 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].C[Si](C)(C)N[Si](C)(C)C.[Li].CO[C:23]([C:25]1[CH:30]=[C:29]([CH3:31])[C:28]([N+:32]([O-:34])=[O:33])=[CH:27][N:26]=1)=O.Cl>O1CCCC1>[CH3:31][C:29]1[C:28]([N+:32]([O-:34])=[O:33])=[CH:27][N:26]=[C:25]([C:23]2[O:1][C:2]3[C:3]([C:8](=[O:10])[CH:9]=2)=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:30]=1
Reactant: COC(=O)c1cc(C)c([N+](=O)[O-])cn1
Reactant: CC(=O)c1ccccc1O
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [Li]
Solvent: C1CCOC1
Product: Cc1cc(-c2cc(=O)c3ccccc3o2)ncc1[N+](=O)[O-]
Temperature: -10 °C
Reaction time: 2 h
Yield: 66.6 %

Procedure:
A solution of 2′-hydroxyacetophenone (1.68 g, 12.39 mmol) in tetrahydrofuran (120 ml) under argon was cooled to −78° C. and treated dropwise with lithium hexamethyldisilazane (1M in tetrahydrofuran, 2.25 ml, 2.25 mmol). The solution was stirred at −78° C. for 1 hour and at −10° C. for 2 hours then cooled down to −78° C. and treated dropwise with a solution of 4-Methyl-5-nitro-pyridine-2-carboxylic acid methyl ester (WO2005/103003) (2.42 g, 12.39 mmol) in tetrahydrofuran (60 ml). The dark red solution was stirred at −78° C. for 1 hour then at room temperature for 18 hours. The mixture was poured into a ice-cold 1 N solution of hydrochloric acid (200 ml) and extracted several times with ethyl acetate. The combined extracts were dried over sodium sulfate and concentrated to dryness. The residue was dissolved in acetic acid (60 ml), treated with sulfuric acid (0.33 ml) and heated to 100° C. for 30 minutes. After cooling to room temperature, the solution was concentrated and the residue added with water and neutralized with a saturated solution of sodium hydrogenocarbonate. The precipitate was filtrated, washed with water and dried under vacuum to yield 2-(4-Methyl-5-nitro-pyridin-2-yl)-chromen-4-one (2.33 g, 66%) as a brown solid. The previous chromen-4-none (770 mg, 2.72 mmol) was treated with tert-butyl-hydroxylamine hydrochloride (685 mg, 5.45 mmol) in methanol (20 ml) at 130° C. for 30 minutes under microwave irradiation (method D, step 1) to yield the title compound (394 mg, 41%) after purification by silica gel flash chromatography (gradient cyclohexane/dichloromethane 0-80%) as a gold solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.[I:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22]>CN1CCCC1=O>[Cl:1][C:2]1[N:7]=[C:6]([NH:22][C:21]2[CH:23]=[CH:24][CH:25]=[C:19]([I:18])[CH:20]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Nc1cccc(I)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Clc1nccc(Nc2cccc(I)c2)n1
Temperature: 120 °C
Yield: 0 %

Procedure:
A solution of 2,4-dichloropyrimidine (3.0 g, 20 mmol) and N,N-diisopropylethylamine (4.2 mL, 24 mmol) in N-methylpyrrolidinone (20 mL) was treated with 3-iodoaniline (2.4 mL, 20 mmol) dropwise and heated at 120° C. for 2 h. The reaction mixture was concentrated, diluted with ethyl acetate (150 mL), and washed with water (150 mL). The aqueous layer was separated and extracted with ethyl acetate (150 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to a crude oil. This material was purified by flash column chromatography to give the desired product (3.2 mg, 48%) as a tan solid. LCMS for C10H8ClIN3 (M+H)+: m/z=331.9.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:24]([CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9](/[C:19](=[N:21]/O)/[NH2:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.C([O-])=O.[NH4+].CO.C(Cl)Cl>C(O)(=O)C.[Pd]>[CH:1]1([C:4]2[C:5]([N:24]([CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19](=[NH:20])[NH2:21])[C:8]=3[CH:23]=2)[CH2:2][CH2:3]1
Reactant: CC(C)CCN(c1cc2oc(-c3ccc(F)cc3)c(/C(N)=N/O)c2cc1C1CC1)S(C)(=O)=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: CC(C)CCN(c1cc2oc(-c3ccc(F)cc3)c(C(=N)N)c2cc1C1CC1)S(C)(=O)=O
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 90.6 %

Procedure:
In a 25-mL round bottom flask purged with nitrogen, (Z)-5-cyclopropyl-2-(4-fluorophenyl)-N′-hydroxy-6-(N-isopentylmethylsulfonamido)benzofuran-3-carboximidamide (200 mg, 0.422 mmol) was dissolved in glacial acetic acid (4 mL), and ammonium formate (133 mg, 2.112 mmol) and 10% Pd—C (100 mg, 0.094 mmol) were added. The mixture was heated in an oil bath at 120° C. for 2.5 hours. TLC (SiO2, 5% methanol/CH2Cl2) showed the reaction was complete. The reaction was cooled to room temperature, filtered through Celite® 545, washed with additional ethyl acetate, and concentrated the filtrate by rotary evaporation. The amidine acetic acid salt was dissolved in H2O (25 mL) and ethyl acetate (50 mL), the pH was adjusted with 1 N aqueous NaOH, and the mixture was stirred for 10 minutes, re-adjusting the aqueous pH˜12 as needed. The organic phase was washed with brine (25 mL), dried over anhydrous MgSO4, filtered, and concentrated by rotary evaporation co-evaporating with CH2Cl2/hexanes to afford the title compound as a yellow solid (175 mg). The material was 84% pure by analytical HPLC. MS (ESI+) m/z 458 (M+H)+, 915 (2M+H)+; MS (ESI−) m/z 456 (M−H)−.