Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:18][C@@H:19]1[CH2:24][NH:23][CH2:22][CH2:21][NH:20]1.O(C(C)(C)C)[Na]>C1(C)C=CC=CC=1>[CH3:18][C@H:19]1[NH:20][CH2:21][CH2:22][N:23]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]3[CH:17]=[CH:16][N:15]=[CH:14][N:13]=3)(=[O:10])=[O:9])=[CH:4][CH:3]=2)[CH2:24]1
Reactant: C[C@@H]1CNCCN1
Reactant: O=S(=O)(Nc1ccncn1)c1ccc(Br)cc1
Agent: CC(C)(C)O[Na]
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(c2ccc(S(=O)(=O)Nc3ccncn3)cc2)CCN1
Yield: 100 %

Procedure:
Synthesized according to general procedure 8. The reaction was set up with 4-bromo-N-(pyrimidin-4-yl)benzenesulfonamide (2.4 mmol), (R)-2-methylpiperazine (4.7 mmol), Pd(dba)3 (0.12 mmol) 2-(di-t-butylphosphino)biphenyl (0.50 mmol), NaO-tBu (10 mmol), and toluene (12 mL). For the purification, 10% MeOH in CH2Cl2 with the addition of 1% triethylamine was used as a solvent system to obtain the desired amine as a white solid. (900 mg, 100% yield). LC/MS (10%/99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=334.3; tR=0.4 min.
Reaction SMILES: S(=O)(=O)(O)O.O.[C:7]([C@:9]1([OH:31])[C:14](=[CH2:15])[CH2:13][C@H:12]2[C@H:16]3[C@H:26]([CH2:27][CH2:28][C@:10]12[CH3:11])[C@:24]1([CH3:25])[C:19](=[CH:20][C:21](=[O:29])[CH2:22][CH2:23]1)[C:18](=[CH2:30])[CH2:17]3)#[CH:8].C1C[O:35]CC1.C(=O)([O-])[O-].[Na+].[Na+]>O.CO>[C:7]([C@:9]1([OH:31])[C:14](=[CH2:15])[CH2:13][C@H:12]2[C@H:16]3[C@H:26]([CH2:27][CH2:28][C@:10]12[CH3:11])[C@:24]1([CH3:25])[C:19](=[CH:20][C:21](=[O:29])[CH2:22][CH2:23]1)[C:18](=[CH2:30])[CH2:17]3)(=[O:35])[CH3:8]
Reactant: C#C[C@]1(O)C(=C)C[C@H]2[C@@H]3CC(=C)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Reactant: C1CCOC1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C=C1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC(=C)[C@@]3(O)C(C)=O)[C@@]2(C)CCC(=O)C=C12
Reaction time: 8 h

Procedure:
Mercuric oxide red (0.32 g) was mixed with sulfuric acid/water (sulfuric acid, 0.4 ml; water, 6.0 ml) and let stand overnight. 17α-Ethynyl-17β-hydroxy-6,16-dimethyleneandrosta-4-en-3-one (Example 6, 5.0 g) is mixed with THF (15 ml). The mercuric sulfate solution is added the reaction heated to 41°-49° over a period of 6 hrs at which time TLC indicates the reaction is completed. Sodium carbonate (0.79 g) in water (10 ml) is added and the mixture stirred for 5 min. Celite (5 g) is added and the mixture stirred 1/2 hr at 20°-25°. The mixture is filtered through Celite (5 g), the solids washed with methanol/THF; 1/1 (2×10 ml) and once with THF (10 ml), followed by methylene chloride (10 ml). The filtrate and washings are concentrated under reduced pressure to about 35 ml, at which point crystals begin forming. Methanol (50 ml) is added and the mixture again concentrated under reduced pressure and permitted to sit overnight at 20°-25° under nitrogen atmosphere. Water (500 ml) is added, slowly at first, with stirring over a period of 15 min. The mixture is filtered, the solids washed with water (3×20 ml), and hexane (2×10 ml). The solids were dried under nitrogen to give the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([S:9][CH3:10])[N:6]=[C:5]([OH:11])[CH:4]=1.[Na+].[CH3:13][S:14]([O-:16])=[O:15].CN(C=O)C>C(#N)C>[CH3:10][S:9][C:7]1[N:6]=[C:5]([OH:11])[CH:4]=[C:3]([CH2:2][S:14]([CH3:13])(=[O:16])=[O:15])[N:8]=1
Reactant: CS(=O)[O-]
Reactant: CSc1nc(O)cc(CCl)n1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CSc1nc(O)cc(CS(C)(=O)=O)n1
Temperature: 100 °C

Procedure:
6-(Chloromethyl)-2-methylsulfanyl-pyrimidin-4-ol (19.07 g, 100 mmol) was suspended in acetonitrile (400 ml). To this stirring suspension was added methanesulphinic acid sodium salt (12.255 g, 120 mmol) and DMF (100 ml). The reaction was then heated to 100° C. to give a dark suspension and monitored by LCMS. Once complete, the solvents were removed and the resultant product added to 1:1 MeOH:DCM (200 ml) and acidified with acetic acid (10 ml). The resultant precipitate was collected, washed with water (200 ml) and MeOH (100 ml) and dried overnight in vacuo to afford the title compound as a white solid, 16.45 g.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[NH:7][C:6]=1[CH:16]1[CH2:18][CH2:17]1.[H-].[Na+].[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[N:7]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:6]=1[CH:16]1[CH2:17][CH2:18]1
Reactant: COC(=O)Cc1c(C2CC2)[nH]c2ccc(OC)cc12
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1c(C2CC2)n(Cc2ccccc2)c2ccc(OC)cc12
Reaction time: 0.5 h
Yield: 4 %

Procedure:
A solution of 3.8 g (146 mmol) of 2-cyclopropyl-5-methoxyl-1H-indole-3-acetic acid methyl ester in 50 mL of DMF was treated with 0.59 g (0146 mol) of 60% NaH/mineral oil, stirred 0.5 hour, and 1.69 mL (146 mmol) of benzyl chloride added. After 20 hours, the reaction mixture was diluted with water, extracted with EtOAc, the EtOAc solution was washed four times with water and dried over Na2SO4. After concentrating at reduced pressure, the product was purified by chromatography on silica, eluting with a gradient, 5% EtOAc/toluene→15% EtOAc/toluene, to give 2.05 g (40% yield) of 2-cyclopropyl-5-methoxy-1-(phenylmethyl)-1H-indole-3-acetic acid methyl ester as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[NH:15][C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1.Cl[CH2:24][C:25]1[CH:29]=[C:28]([CH3:30])[N:27]([CH3:31])[N:26]=1>>[CH3:31][N:27]1[C:28]([CH3:30])=[CH:29][C:25]([CH2:24][N:15]2[C:16]([CH3:19])([CH3:20])[C:17](=[O:18])[N:13]([C:11]3[CH:10]=[N:9][N:8]([CH2:7][C:6]4[C:2]([CH3:1])=[N:3][O:4][C:5]=4[CH3:22])[CH:12]=3)[C:14]2=[O:21])=[N:26]1
Reactant: Cc1cc(CCl)nn1C
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)NC(C)(C)C2=O)cn1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)N(Cc3cc(C)n(C)n3)C(C)(C)C2=O)cn1

Procedure:
Prepared as in Example 12-16 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-5,5-dimethylimidazolidine-2,4-dione (Example 12-16a) and 3-(chloromethyl)-1,5-dimethyl-1H-pyrazole. MS 412 (MH+). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.16 μM.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:26])[CH2:9][N:10]([CH3:25])[S:11]([C:14]2[C:15]3[CH2:22][CH2:21][CH2:20]/[C:19](=[N:23]/[OH:24])/[C:16]=3[S:17][CH:18]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:34](Cl)(=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36]>ClCCl>[CH3:36][C:35]([CH3:38])([CH3:37])[C:34]([O:24]/[N:23]=[C:19]1/[CH2:20][CH2:21][CH2:22][C:15]2[C:14]([S:11]([N:10]([CH2:9][CH:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[OH:26])[CH3:25])(=[O:13])=[O:12])=[CH:18][S:17][C:16]/1=2)=[O:39]
Reactant: CN(CC(O)c1ccc(F)cc1)S(=O)(=O)c1csc2c1CCC/C2=N/O
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CC(O)c1ccc(F)cc1)S(=O)(=O)c1csc2c1CCC/C2=N/OC(=O)C(C)(C)C
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
To a solution of the compound (30 mg) of Example 1 and triethylamine (18 μL) in dichloromethane (10 mL) was added dropwise pivaloyl chloride (13 mg) in dichloromethane (1 mL) on an ice bath. After stirring for 30 minutes, the solvent was removed at reduced pressure, the residue was purified by silica gel column chromatography (hexane/ethyl acetate), and the title compound (35 mg) was obtained as a colorless amorphous substance.
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH2:11])[CH2:2]1)[CH2:8]2.[F:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](O)=[O:17].N>>[N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH:11][C:16](=[O:17])[C:15]3[CH:19]=[CH:20][CH:21]=[C:13]([F:12])[CH:14]=3)[CH2:2]1)[CH2:8]2
Reactant: NC1C2CC3CC1CN(C3)C2
Reactant: O=C(O)c1cccc(F)c1
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1cccc(F)c1

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine and 3-fluorobenzoic acid (Aldrich) according to method B; 1H NMR (500 MHz, methanol-d4) δ 1.88-1.98 (m, 3H), 2.03 (s, 1H), 2.26-2.33 (m, 4H), 3.42 (s, 2H), 3.48-3.56 (m, 4H), 4.37 (s, 1H), 7.27-7.32 (m, 1H), 7.44-7.53 (m, 1H), 7.55-7.62 (m, 1H), 7.66 (d, J=8 Hz, 1H); MS (APCI/NH3) m/z 275 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:16])=[CH:4][C:5]2[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[OH:11])[S:7][C:6]=2[C:14]=1[Cl:15].Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CC(=O)CC>[Cl:1][C:2]1[C:3]([O:16][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:4][C:5]2[CH:9]=[C:8]([C:10]([OH:11])([CH3:13])[CH3:12])[S:7][C:6]=2[C:14]=1[Cl:15]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(O)c1cc2cc(O)c(Cl)c(Cl)c2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)COc1cc2cc(C(C)(C)O)sc2c(Cl)c1Cl

Procedure:
To a mixture of 6,7-dichloro-5-hydroxy-α,α-dimethylbenzo[b]thiophene-2-methanol in 250 ml of 2-butanone is added a solution of 7.7 g of t-butyl bromoacetate in 50 ml 2-butanone and the resultant mixture is placed in a preheated oil-bath at 95°. To the mixture is added 6.7 g of potassium carbonate and 3 ml of dimethylformamide and the reaction mixture is refluxed at 95° for 21/2 hrs. The cooled mixture is filtered and 100 ml of water is added. The layers are separated and the aqueous phase is extracted two times with ethyl ether. The organic extracts are washed, dried over anhydrous magnesium sulfate, filtered and concentrated to give a solid. Recrystallization from ethyl ether and pentane gives 11.5 g of t-butyl [[6,7-dichloro-2-(1-hydroxy-1-methylethyl)benzo[b]thien-5-yl]oxy]acetate, mp 137°-138°.
Reaction SMILES: [C:1](Cl)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:21]([OH:44])(=O)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]/[CH:33]=[CH:34]\[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>C(OCC)(=O)C.CCCCCC>[CH2:21]([O:44][C:1](=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH:33]=[CH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CCCCCCCC/C=C\CCCCCCCCCCCC(=O)O
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCCCCCC=CCCCCCCCCCCCCOC(=O)CCCCCCCC=CCCCCCCCC
Yield: 94.5 %

Procedure:
Compound D was prepared from Oleoyl chloride and Erucic acid following the general procedure discussed before and as shown in FIG. 9. Pure compound D was a colorless oil obtained by column chromatography with Ethyl acetate/Hexane=1:40. Reaction conditions for branched derivative compounds D2, D3, and D4 are also shown below.
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:10][CH:9]([N:11]([CH2:13][C@@H:14]2[C@@H:21]3[C@@H:17]([O:18][C:19]([CH3:23])([CH3:22])[O:20]3)[C@H:16]([N:24]3[CH:32]=[N:31][C:30]4[C:25]3=[N:26][CH:27]=[N:28][C:29]=4[NH2:33])[O:15]2)[CH3:12])[CH2:8]1)(=O)=O.[N-:34]=[N+:35]=[N-:36].[Na+].O>CN(C=O)C>[N:34]([CH2:6][CH:7]1[CH2:8][CH:9]([N:11]([CH2:13][C@@H:14]2[C@H:21]3[O:20][C:19]([CH3:22])([CH3:23])[O:18][C@H:17]3[C@H:16]([N:24]3[CH:32]=[N:31][C:30]4[C:25]3=[N:26][CH:27]=[N:28][C:29]=4[NH2:33])[O:15]2)[CH3:12])[CH2:10]1)=[N+:35]=[N-:36]
Reactant: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(COS(C)(=O)=O)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CN=[N+]=[N-])C1
Temperature: 70 °C
Yield: 67.6 %

Procedure:
To a solution of (3-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(methyl)amino)cyclobutyl)methyl methane sulfonate (150 mg, 0.31 mmol) in DMF (3 ml) was added NaN3 (81 mg, 1.24 mmol). The mixture was heated at 70° C. for 3 h. Water (30 ml) was added and the mixture was extracted with ethyl acetate (20 ml×3). The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by Prep-TLC (DCM:MeOH=30:1) to obtain the title compound (90 mg, Yield 67%). ESI-MS (m/z): 430.2[M+1]+.
Reaction SMILES: C([C@]1(CO)O[C@@](C(=O)C)([N:9]2[C:19]3[N:18]=[C:16]([NH2:17])[NH:15][C:13](=[O:14])[C:12]=3[N:11]=[CH:10]2)[C@](C(=O)C)(O)[C@]1(C(=O)C)O)(=O)C.[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[ClH:41]>C(#N)C>[ClH:41].[ClH:41].[CH2:33]([N:11]1[C:12]2[C:13](=[O:14])[NH:15][C:16]([NH2:17])=[N:18][C:19]=2[N:9]=[CH:10]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)[C@@]1(O)[C@@](O)(C(C)=O)[C@](CO)(C(C)=O)O[C@@]1(C(C)=O)n1cnc2c(=O)[nH]c(N)nc21
Agent: Cl
Solvent: CC#N
Product: Nc1nc2ncn(Cc3ccccc3)c2c(=O)[nH]1
Temperature: 50 °C
Reaction time: 17 h
Yield: 57.4 %

Procedure:
Tetraacetylguanosine (0.904 g, 2.00 mmols) was dissolved in 2 ml of acetonitrile, and 0.59 ml (2.48 equivalents) of benzyl bromide were added thereto. The reaction was conducted at 50° C. for 17 hours. After it was identified through HPLC that the starting material disappeared, 5 ml (29.6 equivalents) of conc. hydrochloric acid were added to the reaction solution, and the mixture was stirred at 50° C. for 3 hours. Then, the reaction solution turned black, and the gray solid was precipitated. The temperature was returned to room temperature, and 5 ml of methanol were added to the solid. The slurry was stirred for 20 minutes, and then filtered. The crystals were washed with 10 ml of methanol, and dried at 50° C. under reduced pressure to give 0.690 g of gray crystals in a yield of 57.4%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[C:5]2[CH:12]([CH3:24])[N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:15][O:16][C:4]=12.[H-].[Na+].[CH3:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34](Cl)(=[O:36])=[O:35]>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[S:34]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH3:27])(=[O:36])=[O:35])=[C:5]2[CH:12]([CH3:24])[N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:15][O:16][C:4]=12
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: COc1cc2[nH]ccc2c2c1OCCN(C(=O)OC(C)(C)C)C2C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(ccn2S(=O)(=O)c2ccccc2C)c2c1OCCN(C(=O)OC(C)(C)C)C2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.5 %

Procedure:
tert-Butyl 6-methoxy-1-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 36, 25 mg, 0.059 mmol) was dissolved in DMF (1 mL) and sodium hydride (60% in mineral oil, 4.0 mg, 0.15 mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes before 2-methylbenzenesulfonyl chloride (22 mg, 0.113 mmol) was added. The reaction mixture was allowed to stir at room temperature overnight and a few drops of water were added. The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give tert-butyl 6-methoxy-1-methyl-8-[(2-methylphenyl)sulfonyl]-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (3.3 mg) which was dissolved in DCM (1 mL) and TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 3 hours and evaporated to give the title compound (3.4 mg). MS m/z 387 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][OH:9])[CH3:2].Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH:21][C:22]2[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=2)[N:12]=1>>[CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH:21][C:22]2[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=2)[N:12]=1)[CH3:2]
Reactant: CCOCCOCCO
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Product: CCOCCOCCOc1nc(Nc2cc(C)[nH]n2)cc2ccccc12

Procedure:
Similar procedure as described in example 10 was used, starting from 2-(2-ethoxy-ethoxy)-ethanol and (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give {-[2-(2-ethoxy-ethoxy)-ethoxy]-isoquinolin-3-yl}-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 357(MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9][CH2:10][C:11]([OH:28])([CH3:27])[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)=[O:13])[CH:6]=[CH:7][CH:8]=1.OO.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[OH2:44].[Cl-].[Na+].[OH2:47]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9]([CH2:10][C:11]([OH:28])([CH3:27])[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[C:17]([C:23]([F:24])([F:25])[F:26])[CH:16]=2)=[O:13])(=[O:47])=[O:44])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(SCC(C)(O)C(=O)Nc2ccc(C#N)c(C(F)(F)F)c2)c1
Reactant: O
Agent: OO
Agent: [Cl-]
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc(S(=O)(=O)CC(C)(O)C(=O)Nc2ccc(C#N)c(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-(3-methoxyphenylthio)-N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide (29 mg, 0.07 mmol) in dichloromethane (0.18 mL) at −78° C. was added 30% hydrogen peroxide (16 μL, 0.57 mmol) followed by the slow addition of trifluoroacetic anhydride (60 μL, 0.45 mmol). The reaction was stirred at room temperature for 16 h. The reaction was diluted with dichloromethane. Cold water and brine were added, and the reaction was stirred for 20 minutes. The organic layer was separated, dried over magnesium sulfate, filtered and evaporated. Purification by column chromatography (hexane:EtOAc 50:50) yielded 19 mg of desired product. Production of PLM5 was confirmed by 1-H NMR, 13-C NMR, and mass spectral analysis.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([C:4](=[O:14])[CH2:5][C:6](=[N:8][CH2:9][CH2:10]N(C)C)[CH3:7])[CH3:3].[O-]S([O-])(=O)=O.[Na+].[Na+].[CH3:23][N:24]([CH3:29])[CH2:25]CCN>>[CH3:15][C:2]([CH3:1])([C:4](=[O:14])[CH2:5][C:6](=[N:8][CH2:9][CH2:10][CH2:23][N:24]([CH3:29])[CH3:25])[CH3:7])[CH3:3]
Reactant: CN(C)CCCN
Reactant: CC(CC(=O)C(C)(C)C)=NCCN(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: CC(CC(=O)C(C)(C)C)=NCCCN(C)C
Yield: 89 %

Procedure:
In a procedure analogously to 2,2-dimethyl-5-(dimethylaminoethyl-imino)-3-hexanone, starting with 2,2-dimethylhexa-3,5-dione (19.27 g, 136 mmol), Na2SO4 (13 g, 92 mmol), and 3-(dimethylamino)propylamine (15.72 g, 154 mmol). A yellow liquid was obtained via a short-path vacuum distillation apparatus after removal of all volatiles. The yield is 89%.
Reaction SMILES: [CH2:1]([Si:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6](=[O:11])[CH2:7][CH:8]([CH3:10])[CH3:9])[CH2:2][CH:3]=[CH2:4].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[CH2:1]([Si:5]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:6]([OH:11])[CH2:7][CH:8]([CH3:10])[CH3:9])[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCC[Si](C(=O)CC(C)C)(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: C=CCC[Si](c1ccccc1)(c1ccccc1)C(O)CC(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 69.6 %

Procedure:
To a solution of 33 (3.0 g, 9.3 mmol) in ethyl ether (100 mL) at 0° C. was added lithium aluminum hydride (1.0 M in ethyl ether, 47 mmol). After stirring for 15 min at 0° C. under argon, the reaction mixture was diluted with ethyl ether (300 mL) and quenched with saturated aqueous Na2SO4 until evolution of hydrogen had ceased. The mixture was dried with solid Na2SO4 and filtered, and the residue was extracted with ether (50 mL). The organic extracts were combined and concentrated in vacuo. Flash chromatography over silica gel (1/9 EtOAc:hexane) gave pure 34 as a colorless oil (2.1 g, 69%): Rf=0.60 (1/9 EtOAc:hexane); 1H NMR (300 MHz, CDCl3) δ 7.57 (m, 4H), 7.37 (m, 6H), 5.87 (m, 1H), 4.97 (dd, J=17.1, 1.7 Hz, 1H), 4.88 (dd, J=102, 1.7 Hz, 1H), 4.08 (d, J=12.1 Hz, 1H), 2.12 (m, 2H), 1.85 (m, 1H), 1.58 (m, 1H), 1.26 (m, 4H), 0.88 (d, J=6.2 Hz, 6H); 13C NMR (75 MHz CDCl3) δ 141.4, 135.7, 133.8, 129.8, 128.2, 113.3, 61.5, 42.4, 27.5, 24.2, 23.7, 20.7, 9.8; IR (neat) 3565 (m), 3452 (m, br), 3069 (m), 3050 (m), 2955 (s), 2910 (s), 2869 (m), 1965 (w), 1894 (w), 1832 (w), 1642 (m), 1469 (m), 1434 (s), 1369 (w), 1116 (s), 1001 m), 916 (m), 743 (s), 705 (s) cm−1; MS (FAB) m/e (rel. intensity) 323 (MH+−2, 5), 269 (21), 238 (11), 198 (57), 1.83 (100), 181 (10), 177 (23), 161 (14), 159 (56), 123 (15), 99 (12); HRMS (FAB) calcd for C21H27OSi: 323.1831 (MH+−2). found: 323.1824. Anal. Calcd for C21H28SiO: C, 77.72; H, 8.70. Found: C, 77.60; H, 8.67.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])[CH:11]=[C:10]([NH:23]C(OC(C)(C)C)=O)[N:9]=1)(C)(C)C.[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]>ClCCl>[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].[Cl:20][C:18]1[CH:17]=[CH:16][C:15]([O:21][CH3:22])=[C:14]([C:12]2[CH:13]=[C:8]([NH2:7])[N:9]=[C:10]([NH2:23])[CH:11]=2)[CH:19]=1
Reactant: COc1ccc(Cl)cc1-c1cc(NC(=O)OC(C)(C)C)nc(NC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Cl)cc1-c1cc(N)nc(N)c1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of [6-tert-butoxycarbonylamino-4-(5-chloro-2-methoxy-phenyl)-pyridin-2-yl]-carbamic acid tert-butyl ester (220 mg, 0.49 mmol) in dichloromethane (8 ml) was added trifluoroacetic acid (6 ml). After stirring for 1 hour, volatiles were evaporated under reduced pressure. Treatment with toluene (15 ml) and evaporation of volatiles under reduced pressure provided 4-(5-chloro-2-methoxy-phenyl)-pyridine-2,6-diamine trifluoroacetic acid salt (180 mg, 100% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([CH2:19][CH2:20][NH:21][NH2:22])#[N:18]>>[C:17]([CH2:19][CH2:20][NH:21][N:22]=[CH:13][C:12]1[CH:15]=[CH:16][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:11]=1)#[N:18]
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: N#CCCNN
Product: N#CCCNN=Cc1ccc(OCc2ccccc2)cc1
Yield: 86 %

Procedure:
4-(benzyloxy)benzaldehyde (2-cyanoethyl)hydrazone is prepared by condensation of 4-(benzyloxy)benzaldehyde with (2-cyanoethyl)hydrazine according to the following procedure:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[N:22]=[C:21]([Cl:23])[C:20]([F:24])=[CH:19][C:15]=1[C:16]([OH:18])=[O:17].CN([CH:28]=[O:29])C.Cl>C1COCC1>[Cl:13][C:14]1[C:15]2[C:16](=[O:18])[O:17][CH:28]([OH:29])[C:19]=2[C:20]([F:24])=[C:21]([Cl:23])[N:22]=1
Reactant: O=C(O)c1cc(F)c(Cl)nc1Cl
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C1OC(O)c2c(F)c(Cl)nc(Cl)c21
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
To a solution of diisopropylamine (96 g, 0.94 mol) in THF (800 mL) was slowly added n-butyllithium (379 mL, 0.95 mol, 2.5 M) at −78° C. The mixture was stirred at the same temperature for 30 minutes. To the mixture was added 2,6-dichloro-5-fluoronicotinic acid (90 g, 0.43 mol) in THF (500 mL). The solution was stirred for an additional 2 h. To the mixture was added DMF (154 mL, 1.94 mol) dropwise, The mixture was stirred for 1 h, after which 2N HCl (1.54 L) (pH<1) was introduced. The mixture was subsequently extracted with EtOAc and the organic layers were basified with aqueous NaHCO3 (pH>8). The aqueous layer was separated, acidified with 2N HCl (1.2 L) (pH<1), and extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was washed with DCM to give the title compound as a reddish solid (81.6 g, 80%). 1H NMR (DMSO-d6, 400 MHz) δ ppm 6.85 (s, 1H), 8.83 (s, 1H). [M+H] calc'd for C7H2C12FNO3, 238. found, 238.