Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=[C:5]2[C:4]([NH2:15])=[N:3]1.O=[CH:17][C:18]([OH:20])=[O:19].[BH3-]C#N.[Na+]>CO>[CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11]([F:14])([F:12])[F:13])[CH:10]=[C:5]2[C:4]([NH:15][CH2:17][C:18]([OH:20])=[O:19])=[N:3]1
Reactant: Cn1nc(N)c2cc(C(F)(F)F)cnc21
Reactant: O=CC(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cn1nc(NCC(=O)O)c2cc(C(F)(F)F)cnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 1-methyl-5-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-3-amine (as prepared in the previous step, 284 mg, 1.31 mmol) in MeOH (20 mL), 2-oxoacetic acid (184 mg, 1.577 mmol) and NaBH3CN (86 mg, 1.37 mmol). The reaction mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. After flash chromatography (silica gel, ethyl acetate) the title compound was isolated as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][C:8]([OH:10])=[O:9])[N:3]=1.[N+](=[CH2:13])=[N-]>>[CH3:13][O:9][C:8](=[O:10])[CH2:7][C:4]1[N:3]=[C:2]([CH3:1])[O:6][N:5]=1
Reactant: Cc1nc(CC(=O)O)no1
Reactant: C=[N+]=[N-]
Product: COC(=O)Cc1noc(C)n1

Procedure:
Using the procedure of Example 10, 10 g of crude 5-methyl-1,2,4-oxadiazol-3-yl acetic acid were reacted with diazomethane to obtain 5.9 of methyl-5-methyl-1,2,4-oxadiazol-3-yl-acetate with a b.p. of 70°-72° C. at 0.6-0.7 mm and a refractive index nD =1.4495.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:15]=[C:16]([NH:25][C:26]2[N:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=2)[CH:17]=[C:18]([C:20]2[S:24][CH:23]=[N:22][CH:21]=2)[CH:19]=1.[CH3:36][C:37]([CH3:39])=[O:38]>C1COCC1>[Br:13][C:14]1[CH:19]=[C:18]([C:20]2[S:24][C:23]([C:37]([OH:38])([CH3:39])[CH3:36])=[N:22][CH:21]=2)[CH:17]=[C:16]([NH:25][C:26]2[N:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:29]=[CH:28][N:27]=2)[CH:15]=1
Reactant: CC(C)=O
Reactant: FC(F)(F)c1ccnc(Nc2cc(Br)cc(-c3cncs3)c2)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(O)c1ncc(-c2cc(Br)cc(Nc3nccc(C(F)(F)F)n3)c2)s1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 61.6 %

Procedure:
A solution of diisopropylamine (0.220 mL, 1.545 mmol) in 4 mL THF was cooled to 0° C., then n-BuLi (2.5 M in hexanes, 0.598 mL, 1.495 mmol) was added dropwise. The mixture was stirred at this temperature for 15 minutes, then cooled to −78° C. Intermediate 11 (200 mg, 0.498 mmol) was then added dropwise as a solution in 1.0 mL THF, and the mixture stirred for 30 minutes. Acetone (0.110 mL, 1.495 mmol) was then added, and the mixture was stirred at −78° C. for 30 minutes, then allowed to warm to room temperature. The reaction was quenched by the addition of ˜1 mL brine, then the mixture was diluted with ethyl acetate (100 mL) and washed with brine (100 mL). The organic extracts were dried (sodium sulfate) filtered, and concentrated in vacuo. Purification by chromatography on silica gel (80:20 to 40:60, hexanes:ethyl acetate) provided 141 mg (0.307 mmol, 61.6%) of 2-[5-(3-bromo-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]propan-2-ol as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[CH2:10].[C:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])C=C>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: C=Cc1ccc(C)cc1C
Reactant: C=CC(=O)OC(C)(C)C
Product: Cc1ccc(/C=C/C(=O)OC(C)(C)C)c(C)c1
Yield: 74 %

Procedure:
The representative procedure was followed using 2,4-dimethyl-1-vinylbenzene (66 mg, 0.50 mmol), tert-butyl acrylate (128 mg, 1.00 mmol) and Grubbs-2 catalyst (8.5 mg, 0.01 mmol). Column chromatography on silica gel (eluting with 2% EtOAc/hexanes) afforded the product as a colorless oil (86 mg, 74%).
Reaction SMILES: [CH:1]1(O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].CC1C=CC(S([O:20][CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][C:31]3[CH:36]=[C:35]([Br:37])[CH:34]=[CH:33][C:32]=3[Cl:38])=[CH:26][CH:25]=2)(=O)=O)=CC=1>C1COCC1>[Br:37][C:35]1[CH:34]=[CH:33][C:32]([Cl:38])=[C:31]([CH2:30][C:27]2[CH:26]=[CH:25][C:24]([O:23][CH2:22][CH2:21][O:20][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:29][CH:28]=2)[CH:36]=1
Reactant: OC1CCCCC1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc(Cc3cc(Br)ccc3Cl)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1ccc(Br)cc1Cc1ccc(OCCOC2CCCCC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
To a solution of cyclohexanol (0.76 g, 7.56 mmol) in anhydrous THF (10 mL), NaH (60%, 0.18 g, 7.56 mmol) was added in portions at 0° C. The mixture was stirred at 0° C. for 0.5 h, and then 2-(4-(5-bromo-2-chlorobenzyl)phenoxy)ethyl 4-methylbenzenesulfonate (intermediate AB) (0.66 g, 1.26 mmol) was added in portions. Then the mixture was stirred at room temperature overnight, whereupon TLC showed the reaction was complete. Then the reaction mixture was quenched with saturated NH4Cl, extracted with EtOAc, washed with water and brine, dried with anhydrous Na2SO4, and concentrated to a crude oil. The crude oil was purified by column chromatography (PE:EA=100:1) to obtain oil AE (0.3 g, yield 56.6%). 1H NMR (400 MHz, CD3OD): δ 7.28-7.21 (m, 3H), 7.07 (d, 2H, J=8.8 Hz), 6.86 (d, 2H, J=8.4 Hz), 4.08 (t, 2H, J=4.8 Hz), 3.98 (s, 2H), 3.80 (t, 2H, J=4.8 Hz), 3.40-3.20 (m, 1H), 1.95-1.93 (m, 2H), 1.76-1.73 (m, 2H), 1.32-1.22 (m, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH2:17][CH:18]([CH3:21])[CH2:19][CH3:20])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][OH:35].[I-].[K+]>CC(C)=O>[OH:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH2:17][CH:18]([CH3:21])[CH2:19][CH3:20])=[O:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCC(C)COC(=O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: OCCCCCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(C)COC(=O)c1ccc(-c2ccc(OCCCCCCO)cc2)cc1
Yield: 34.1 %

Procedure:
2.84 g of 2-methylbutyl 4'-hydroxybiphenyl-4-carboxylate, 4.14 g of potassium carbonate, 4.10 g of 6-chloro-1-hexanol and 4.28 g of potassium iodide were heat-refluxed for 48 hours in acetone. The mixture was subjected to filtration, condensation and purification by column chromatography to obtain 1.31 g of the objective product (yield: 34%).
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.Br[CH2:19][CH2:20][CH2:21][CH2:22][N:23]1[C:27](=[O:28])[C:26]2[CH:29]=[C:30]([N+:33]([O-:35])=[O:34])[CH:31]=[CH:32][C:25]=2[S:24]1(=[O:37])=[O:36].Cl>>[O:37]=[S:24]1(=[O:36])[C:25]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][C:26]=2[C:27](=[O:28])[N:23]1[CH2:22][CH2:21][CH2:20][CH2:19][N:13]1[CH2:12][CH2:11][CH:10]([N:6]2[C:5]3[CH:16]=[CH:17][C:2]([CH3:1])=[CH:3][C:4]=3[O:8][C:7]2=[O:9])[CH2:15][CH2:14]1
Reactant: O=C1c2cc([N+](=O)[O-])ccc2S(=O)(=O)N1CCCCBr
Reactant: Cc1ccc2c(c1)oc(=O)n2C1CCNCC1
Agent: Cl
Product: Cc1ccc2c(c1)oc(=O)n2C1CCN(CCCCN2C(=O)c3cc([N+](=O)[O-])ccc3S2(=O)=O)CC1

Procedure:
From 4-(6-methyl-2-oxo-3-benzoxazolinyl)-piperidine and 2-(4-bromobutyl)-1,1-dioxido-5-nitro-1,2-benzisothiazol-3(2H)-one using the procedure described for Example 15, Step 5 there was obtained a white solid:1H NMR, HCl salt, (400 MHz, CDCl3): 8.87 (d, J=2.0 Hz, 1H), 8.74 (d, J=2.18 Hz, 1H), 8.72 (d, J=1.8 Hz, 1H), 8.14 (d, J=8.4 Hz, 1H), 7.11 (d, J=6.54 Hz, 1H), 7.03 (s, 1H), 6.94 (d, J=8.06 Hz, 1H), 4.18 (m, 1H), 3.89 (t, J=7.39 Hz, 2H), 3.06 (d, J=10.07 Hz, 2H), 2.46 (m, 2H), 2.38 (s, 3H), 2.34 (m, 2H), 2.14 (t, J=11.5 Hz, 2H), 1.94 (m, 2H), 1.85 (d, J=11.4 Hz, 2H), 1.65 (m, 2H).
Reaction SMILES: C(Cl)Cl.[CH3:4][O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][N:10]([CH3:16])[CH2:11]2.[CH3:17][O:18]C(Cl)Cl.[OH-].[Na+]>[Ti](Cl)(Cl)(Cl)Cl.O>[CH3:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([CH:17]=[O:18])=[C:12]2[C:7]=1[CH2:8][CH2:9][N:10]([CH3:16])[CH2:11]2
Reactant: COc1cccc2c1CCN(C)C2
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C=O)c2c1CCN(C)C2
Temperature: 0 °C
Yield: 74.5 %

Procedure:
Into a flask equipped with a mechanical stirrer, an equilibrium addition funnel, and a condenser fitted with a calcium chloride drying tube, were placed methylene chloride (150 ml) and 5-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline (15.0 g, 0.085 mole). The solution was cooled to 0° C and stirred. Titanium tetrachloride (51.6 g, 0.272 mole) was added gradually, followed by the rapid dropwise addition of α,α-dichloromethyl methyl ether (9.8 g, 0.085 mole). After the reaction mixture was allowed to warm to room temperature, it was refluxed for 7 hours. The titanium chloride complex of the product was decomposed with water and ice, and the resulting solution kept cool as it was made basic with excess sodium hydroxide (20%). The resulting suspension was extracted with chloroform. The extract was dried over sodium sulfate and the solvent removed, affording the crude product which was vacuum distilled (b.p. 122° C/0.1 mm) to yield 13.0 g (74%) of 5-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-8-carboxaldehyde. The hydrochloride salt melted at 244°-245° C after recrystallization from absolute ethanol. Anal. Calcd. for C12H13NO2Cl; C, 59.6; H, 6.7; N, 5.8; Cl, 14.7. Found: C, 59.8; H, 6.8; N, 5.8; Cl, 14.4.
Reaction SMILES: C(O)C.C(=O)([O-])[O-].[Na+].[Na+].[N+:10]([C:13]1[CH:14]=[C:15]([CH:24]=[CH:25][CH:26]=1)[CH:16]=[CH:17][CH:18]=[N:19][NH:20][C:21]([NH2:23])=[S:22])([O-])=O>[H][H].[S]>[NH2:10][C:13]1[CH:14]=[C:15]([CH:24]=[CH:25][CH:26]=1)[CH:16]=[CH:17][CH:18]=[N:19][NH:20][C:21]([NH2:23])=[S:22]
Reactant: [H][H]
Reactant: NC(=S)NN=CC=Cc1cccc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [S]
Solvent: CCO
Product: NC(=S)NN=CC=Cc1cccc(N)c1
Temperature: 50 °C
Yield: 67.9 %

Procedure:
A solution of 10 mL ethanol and 2 mL sodium carbonate 2N is saturated in hydrogen sulfur. 500 mg (2 mmoles) 3-nitrocinnamaldehyde thiosemicarbazone prepared in step 2A are added. The solution is heated 10 minutes at 50° C., then 3 minutes at 75° C. The solution is cooled in a ice bath. The crystals formed are filtered, washed with ethanol. 299 mg of 3-aminocinnamaldehyde thiosemicarbazone is obtained. Yield 68%.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[CH2:4][CH2:3]1.O.NN>C(O)C.[Ni].O>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(CCCNc2ccc([N+](=O)[O-])cc2)CC1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: CN1CCN(CCCNc2ccc(N)cc2)CC1
Temperature: 50 °C

Procedure:
A suspension of 0.1385 gms. of [3-(4-methyl-piperazin-1-yl)-propyl]-(4-nitro-phenyl)-amine in 3 mL of ethanol is heated to 50° C. Once dissolution is achieved 0.144 mL hydrazine monohydrate is added to the solution. A Raney nickel slurry in water is added to the 50° C. solution dropwise, waiting after each addition for the gas evolution to cease. Sufficient quantities of Raney nickel have been added when continued addition of Raney nickel causes no further gas evolution. The reaction is then maintained at 50° C. for an additional hour, and subsequently is cooled to room temperature. The reaction mixture is filtered through a pad of celite (rinsing the pad with methanol). N-[3-(4-Methyl-piperazin-1-yl)-propyl]-benzene-1,4-diamine (0.116 gms.) is isolated upon evaporation of the filtrate, and is subsequently used without purification in the reaction of Example 302.
Reaction SMILES: Br[C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[C@@H:21]1([N:29]2[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]2=[O:31])[O:28][C@H:25]([CH2:26][OH:27])[C@@H:23]([OH:24])[CH2:22]1>N1C=CC=CC=1>[C:15]1([C:2]2([O:27][CH2:26][C@H:25]3[O:28][C@@H:21]([N:29]4[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]4=[O:31])[CH2:22][C@@H:23]3[OH:24])[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:8]3[C:3]2=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: BrC1(c2ccccc2)c2ccccc2-c2ccccc21
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Solvent: c1ccncc1
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](COC3(c4ccccc4)c4ccccc4-c4ccccc43)O2)c(=O)[nH]c1=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 40.2 %

Procedure:
770 mg (2.4 mmol) of 9-bromo-9-phenylfluorene were added to a solution of 242 mg (1 mmol) of thymidine in 10 ml of pyridine, and the resulting mixture was stirred at 100° C. for 8 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the concentrate was dissolved in 100 ml of methylene chloride. The solution was washed with 100 ml of a 5% w/v aqueous solution of sodium hydrogencarbonate and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 30 g of silica gel (230-400 mesh), using methylene chloride containing from 1 to 3% by volume of methanol as the eluent, to give 194.2 mg (yield 37%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8]Br.[C:11]1([SH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>>[CH3:1][O:2][C:3](=[O:10])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][S:17][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)C=CC=CCBr
Reactant: Sc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)C=CC=CCSc1ccccc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 141.8 %

Procedure:
To a solution of 6-bromohexa-2,4-dienoic acid methyl ester (0.57 g, 2.8 mmol) and thiophenol (0.28 mL, 2.8 mmol) was added triethylamine (0.43 mL, 3.1 mmol), dropwise, under an atmosphere of nitrogen. The mixture was stirred at 20° C. for one hour. The slurry was then filtered and the filtrate was washed with aqueous sodium hydroxide (1 M) then with brine. The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was subjected to column chromatography (9:1 60-80° C. petroleum ether:diethyl ether) to give the title compound (0.93 g, 88%) as a clear oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C:3]2[CH:7]=[N:8][CH:9]=[CH:10][C:2]1=2.[Br:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:15](O)=[O:16].P(Cl)(Cl)(Cl)=O.C(=O)([O-])O.[Na+]>>[Br:11][C:12]1[CH:13]=[C:14]([C:15]([N:4]2[CH2:5][CH2:6][O:1][C:2]3[CH:10]=[CH:9][N:8]=[CH:7][C:3]2=3)=[O:16])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: c1cc2c(cn1)NCCO2
Reactant: COc1ccc(C(=O)O)cc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(C(=O)N2CCOc3ccncc32)cc1Br
Temperature: 100 °C
Reaction time: 12 h

Procedure:
To a mixture of 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine (50 mg, 0.37 mmol) and 3-bromo-4-methoxy-benzoic acid (102 mg, 0.44 mmol), phosphorus oxychloride (2 ml) was added and stirred at 100° C. for 12 hours. The reaction mixture was cooled to 0° C., neutralized with saturated solution of sodium hydrogen carbonate to pH of 8-9 and extracted with ethyl acetate.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([C@:10]23[CH2:18][O:17][CH2:16][C@H:15]2[CH2:14][S:13][C:12]([NH:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:11]3)[CH:7]=[CH:8][CH:9]=1)=[N+]=[N-]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C@:10]23[CH2:18][O:17][CH2:16][C@H:15]2[CH2:14][S:13][C:12]([NH:19][C:20](=[O:27])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[N:11]3)[CH:7]=[CH:8][CH:9]=1
Reactant: [N-]=[N+]=Nc1cccc([C@]23COC[C@H]2CSC(NC(=O)c2ccccc2)=N3)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc([C@]23COC[C@H]2CSC(NC(=O)c2ccccc2)=N3)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.4 %

Procedure:
N-((4aS,7aS)-7a-(3-azidophenyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)benzamide (0.62 g, 1.63 mmol) is diluted with ethanol (10 mL) and Pd on carbon (10%, wet, 0.062 g). The mixture is degassed and stirred at room temperature under hydrogen (30 psi) overnight. The mixture is filtered through diatomaceous earth using ethanol as a rinse. The solvent is removed under reduced pressure to give the title compound, (0.106 g, 18%). ES/MS m/e: 354 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[C:26]([C:28]([NH:30][CH2:31][CH:32]([OH:35])[CH2:33][OH:34])=[O:29])[CH:25]=[C:24]([N+:36]([O-])=O)[CH:23]=2)=[O:20])[CH:7]=[C:8]([C:10]([NH:12][CH2:13][CH:14]([OH:17])[CH2:15][OH:16])=[O:11])[CH:9]=1)([O-])=O.Cl>CO.O.[Pd]>[NH2:36][C:24]1[CH:23]=[C:22]([NH:21][C:19]([NH:18][C:6]2[CH:7]=[C:8]([C:10]([NH:12][CH2:13][CH:14]([OH:17])[CH2:15][OH:16])=[O:11])[CH:9]=[C:4]([NH2:1])[CH:5]=2)=[O:20])[CH:27]=[C:26]([C:28]([NH:30][CH2:31][CH:32]([OH:35])[CH2:33][OH:34])=[O:29])[CH:25]=1
Reactant: O=C(Nc1cc(C(=O)NCC(O)CO)cc([N+](=O)[O-])c1)Nc1cc(C(=O)NCC(O)CO)cc([N+](=O)[O-])c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: Nc1cc(NC(=O)Nc2cc(N)cc(C(=O)NCC(O)CO)c2)cc(C(=O)NCC(O)CO)c1
Yield: 112.7 %

Procedure:
N,N'-bis[3-nitro-5-(2,3-dihydroxypropylaminocarbonyl)phenyl]urea (0.103 g, 0.19 mmol) was dissolved in a mixture of methanol (14 ml) and water (6 ml) containing 2M aqueous HCl (0.2 ml) and a Pd/C catalyst (10%, 0.1 g). Hydrogenation was carried out at 60 psi. The catalyst was filtered off and the solvents were evaporated. The residue was redissolved in water and lyophilized giving 0.102 g (97%) of the product.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:26]C)=[C:13]([C:15]2[C:23]3[CH2:22][NH:21][C:20]([NH2:24])=[N:19][C:18]=3[N:17]([CH3:25])[N:16]=2)[CH:14]=1.[BrH:28]>O>[NH2:24][C:20]1[N:19]=[C:18]2[N:17]([CH3:25])[N:16]=[C:15]([C:13]3[CH:14]=[C:9]([Cl:8])[CH:10]=[C:11]([Br:28])[C:12]=3[OH:26])[C:23]2=[CH:22][N:21]=1
Reactant: COc1ccc(Cl)cc1-c1nn(C)c2c1CNC(N)=N2
Reactant: Br
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(-c2cc(Cl)cc(Br)c2O)c2cnc(N)nc21

Procedure:
3-(5-Chloro-2-methoxy-phenyl)-1-methyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine trifluoroacetate is dissolved in 48% HBr in water (10 ml) and heated using microwave radiation at 120° C. for 2 hours. Purification of the reaction mixture by preparative HPLC (water/acetonitrile, 0.1% TFA) affords the title compound as the minor product of the reaction as the trifluoroacetate salt.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH3:11][NH:12][C:13]1[N:18]=[C:17]([CH:19]=O)[CH:16]=[CH:15][N:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+]>C1(C)C=CC=CC=1>[CH3:11][NH:12][C:13]1[N:18]=[C:17]([CH2:19][NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([OH:10])=[O:9])[CH:16]=[CH:15][N:14]=1
Reactant: Nc1ccccc1C(=O)O
Reactant: CNc1nccc(C=O)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CNc1nccc(CNc2ccccc2C(=O)O)n1
Temperature: 25 °C

Procedure:
A mixture of anthranilic acid (0.55 g, 4.0 mmol), 2-methylamino-pyrimidine-4-carbaldehyde (Step B, 0.72 g, 5.2 mmol), and p-toluenesulfonic acid mohohydrate (0.025 g, 0.13 mmol) in 20 mL of anhydrous toluene was stirred at reflux for 1 h, and cooled to RT. NaBH4 (0.41 g, 10.8 mmol) was added, and the mixture was stirred at RT for 30 min. The mixture was quenched with MeOH, the volatiles were removed under reduced pressure, and the residue was taken up in water. AcOH was added to bring the pH to 4 and the mixture was extracted with EtOAc. The combined organic portions were washed with brine, dried over MgSO4, filtered, condensed, and the residue was purified by flash column chromatography to give the titled compound. MS (ES+): 259.0 (M+H)+. Calc'd for C13H14N4O2-258.28
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:13]([N:15]([CH2:32][CH3:33])[CH2:16][CH2:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[C:25]([C:29](O)=[O:30])=[CH:24][CH:23]=[CH:22]2)[CH3:14].[NH2:34][C:35]([NH2:37])=[NH:36]>C1COCC1>[CH2:13]([N:15]([CH2:32][CH3:33])[CH2:16][CH2:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[C:25]([C:29]([NH:36][C:35]([NH2:37])=[NH:34])=[O:30])=[CH:24][CH:23]=[CH:22]2)[CH3:14]
Reactant: N=C(N)N
Reactant: CCN(CC)CCOc1ccc2c(C(=O)O)cccc2c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCN(CC)CCOc1ccc2c(C(=O)NC(=N)N)cccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.5 g of CDI are added to a suspension of 2.0 g of 6-(2-diethylaminoethoxy)-1-naphthoic acid in 50 ml of THF, and the reaction mixture is stirred at RT overnight. It is then treated with 2.0 g of guanidine, again stirred overnight and concentrated, and the residue is stirred with 100 ml of water. The precipitate formed is filtered off with suction and purified by FC using methylene chloride/methanol 1:1.0.66 g of 6-(2-diethylaminoethoxy)-1-naphthoylguanidine is obtained; m.p.: 168-169° C. 1H-NMR (DMSO-d6): δ [ppm]=1.0 (6H), 2.6 (4H), 2.85 (2H), 4.15 (2H), 7.15 (1H), 7.3 (1H), 7.4 (1H), 7.75 (2H), 8.7 (1H).
Reaction SMILES: Cl.[N:2]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[N:15]([O-])=[O:16].[Na+].[OH-].[Na+]>O.ClCCl>[N:15]([N:5]1[CH2:6][CH2:7][N:2]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3][CH2:4]1)=[O:16]
Reactant: O=N[O-]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(N=O)CC1

Procedure:
In a 500 mL round-bottomed flask, 6N aqueous HCl (30 mL) was cooled to −10° C., and tert-butyl piperazine-1-carboxylate (10 g) was added. Sodium nitrite (4.5 g) dissolved in 35 ml water was added slowly. NaOH (10 g in 20 mL water) was used to neutralize the solution. Dichloromethane (3×50 mL) was used to extract the product. After drying over Na2SO4 and filtration, the solution was concentrated. The crude product was added to a silica gel column (Analogix, SF65-400 g,) and purified by eluting with 0-30% ethyl acetate in hexane.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[N:3]=1.[CH3:17][CH:18]1[CH2:22][CH2:21][C:20](=O)[C:19]1=[O:24].C(O)(=O)C>C(O)C>[CH3:17][CH:18]1[C:19](=[O:24])[C:20]([N:14]2[CH2:13][CH2:12][C:11](=[CH:10][C:9]#[C:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[N:3]=3)[CH2:16][CH2:15]2)=[CH:21][CH2:22]1
Reactant: CC1CCC(=O)C1=O
Reactant: Cc1cccc(C#CC=C2CCNCC2)n1
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cccc(C#CC=C2CCN(C3=CCC(C)C3=O)CC2)n1

Procedure:
A mixture of the Compound of Example 3 (500 mg, 2.36 mmol), 3-methyl-1,2-cyclopentanedione (350 mg, 3.11 mmol), acetic acid (0.18 mL, 3.11 mmol) in ethanol (10 mL) was refluxed for 8 h. The reaction mixture was evaporated, poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried on Na2SO4 and evaporated to dryness in vacuo to afford a residue, which was purified by automated flash liquid chromatography (Horizon™-Biotage) eluting with Petroleum Ether-EtOAc 85:15, affording the title product as a brown solid.
Reaction SMILES: Br[CH:2]=[CH:3][CH:4]=[C:5]([CH3:14])[CH2:6][CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10].[CH3:15][C:16]([CH3:18])=[O:17]>>[CH2:9]([O:8][CH:7]([O:11][CH2:12][CH3:13])[CH2:6][C:5]([CH3:14])=[CH:4][CH:3]=[CH:2][C:16]([CH3:18])([OH:17])[CH3:15])[CH3:10]
Reactant: CCOC(CC(C)=CC=CBr)OCC
Reactant: CC(C)=O
Product: CCOC(CC(C)=CC=CC(C)(C)O)OCC

Procedure:
By proceeding as in Example 1, but starting with 6-bromo-3-methyl-1,1-diethoxy-3,5-hexadiene (0.43 g; 1.63 mmol) and an excess of acetone (0.4 g i.e. 4 equivalents), 1,1-diethoxy-3,7-dimethyl-7-hydroxy-3,5-octadiene, or C10 diethyl hydroxyacetal, (0.4 g) is obtained. After hydrolysis and purification by flash chromatography, eluting with a mixture of petroleum ether and diethyl ether (96/4 by volume), this compound yields dehydrocitral (0.121 g). The yield is 49.6%, based on the 6-bromo-3-methyl-1,1-diethoxy-3,5-hexadiene employed. The structure of the product obtained is confirmed by the infrared spectrum and the proton nuclear magnetic resonance spectrum.