Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C=O)C.Br[C:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[CH:13][CH:14]=2)[N:9]([C:24]2[N:29]=[CH:28][N:27]=[C:26]([NH:30][CH3:31])[CH:25]=2)[CH:8]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH2:40]([O:42][C:43]([C:45]1[CH:50]=[CH:49][C:48](B(O)O)=[CH:47][CH:46]=1)=[O:44])[CH3:41]>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.O.C(OCC)(=O)C>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([C:12]2[CH:11]=[C:10]3[C:15]([C:7]([C:48]4[CH:49]=[CH:50][C:45]([C:43]([O:42][CH2:40][CH3:41])=[O:44])=[CH:46][CH:47]=4)=[CH:8][N:9]3[C:24]3[CH:25]=[C:26]([NH:30][CH3:31])[N:27]=[CH:28][N:29]=3)=[CH:14][CH:13]=2)=[CH:21][CH:20]=1
Reactant: CNc1cc(-n2cc(Br)c3ccc(-c4ccc(OC)cc4)cc32)ncn1
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(-c2cn(-c3cc(NC)ncn3)c3cc(-c4ccc(OC)cc4)ccc23)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 29.9 %

Procedure:
DMF (5 mL) was added to a mixture of 6-(3-bromo-6-(4-methoxyphenyl)-1H-indol-1-yl)-N-methylpyrimidin-4-amine (200 mg, 0.49 mmol), K3PO4 (312 mg, 0.885 mmol) and 4-(ethoxycarbonyl)phenylboronic acid (143 mg, 0.74 mmol) and then the dissolved gas was removed. After adding Pd(PPh3)4 (85 mg, 0.075 mmol), the mixture was stirred at 100° C. for 4 hours. After adding ethyl acetate and water and filtering using a diatomite pad, the organic layer was separated and the aqueous layer was extracted with ethyl acetate. The collected organic layer was washed with brine and concentrated under reduced pressure by drying with anhydrous magnesium sulfate. The residue was purified by chromatography (silica gel, EA:Hx=1:4-1:1). The target compound (70 mg) was obtained as white solid.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[N:10]([O-])=O.[Na+].[CH3:14][C:15]1([CH3:24])[O:20][C:19](=[O:21])[CH:18]([CH3:22])[C:17](=[O:23])[O:16]1.C([O-])(=O)C.[Na+]>Cl.O.C(O)C>[Br:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[N:4]=[N:10][C:18]1([CH3:22])[C:17](=[O:23])[O:16][C:15]([CH3:14])([CH3:24])[O:20][C:19]1=[O:21]
Reactant: O=N[O-]
Reactant: Nc1ccc(F)cc1Br
Reactant: CC1C(=O)OC(C)(C)OC1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1(C)OC(=O)C(C)(N=Nc2ccc(F)cc2Br)C(=O)O1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
130 g 2-Bromo-4-fluoro-aniline was dissolved in 700 ml ice and 600 ml 3M hydrochloric acid. The resulting suspension was maintained at ca. 5° C. during the addition of a solution of 47.3 g sodium nitrite in 45 ml water. When the addition was complete, the mixture was stirred 45 min at ca 5° C. The resulting brown suspension was added slowly to a cooled mixture of 108.3 g 2,2,5-trimethyl-1,3-dioxan-4,6-dione and 932 g sodium acetate in 400 ml water and 700 ml ethanol, maintaining the temperature between 3 and 8° C. A yellow precipitate formed. The mixture was stirred a further 2 h at 3-8° C., filtered and the precipitate washed with water and dried under vacuum to afford the title compound as a yellow solid. ISP-MS: m/e 359 ([M+H]+). Yield 231 g, mp 92-93° C.
Reaction SMILES: Cl[C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:10]([Cu])#[N:11].N.O=O>CN1CCCC1=O.Cl[Cu].O>[NH2:5][C:4]1[C:3]([CH3:9])=[C:2]([CH:8]=[CH:7][CH:6]=1)[C:10]#[N:11]
Reactant: N#C[Cu]
Reactant: Cc1c(N)cccc1Cl
Agent: Cl[Cu]
Agent: N
Agent: O=O
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1c(N)cccc1C#N
Temperature: 225 °C
Reaction time: 6 h
Yield: 89 %

Procedure:
283 g (2.0 mol) of 3-chloro-2-methylaniline are dissolved in 250 ml of N-methylpyrrolidone and admixed with 200 g (2.23 mol) of CuCN. The reaction mixture is subsequently stirred under N2 and at 225° C. for six hours. After cooling to 100° C., the reaction mixture is poured into 2.5 l of 25 percent ammonia solution and stirred at 25° C. for one hour. During this time, the atmospheric oxygen oxidizes the Cu(I) nitrile complex of the product to a water-soluble Cu(II) salt, which is evident by the formation of the intensively blue tetramine complex. Some of the CuCl remains undissolved as a white solid and can be easily removed by filtration with suction. The filtrate is extracted with approximately 2 l of methyl tert-butyl ether and then washed with ammonia water and finally three times with water. The organic phase is dried over sodium sulfate and concentrated, affording 255 g (89% yield of crude product) of a dark oil which can be purified by recrystallization from cyclohexane/toluene (5:1).
Reaction SMILES: [Sn:1]([Cl:3])[Cl:2].[C:4]([CH2:7][C:8](=[O:10])[CH3:9])(=O)[CH3:5].C([Cl:21])(=O)C=CC1C=CC=CC=1>C(OCC)C>[CH3:5][C:4]([Sn:1]([Cl:21])([Cl:3])[Cl:2])=[CH:7][C:8](=[O:10])[CH3:9]
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: CC(=O)CC(C)=O
Reactant: Cl[Sn]Cl
Solvent: CCOCC
Product: CC(=O)C=C(C)[Sn](Cl)(Cl)Cl
Yield: 101.6 %

Procedure:
The procedure was analogous to Example 6. 50 g (0.26 mol) of tin(II) chloride and 25.6 g (0.26 mol) of acetylacetone was reacted with 44 g (0.26 mol) of cinnamoyl chloride in 150 ml of diethyl ether to give a quantitative yield of 81.4 g of 1-methylbut-1-en-3-onyltin trichloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Cl[CH2:23][CH2:24][CH2:25][C:26]([C:28]1[S:37][C:36]2[S:35][CH2:34][CH2:33][NH:32][C:31](=[O:38])[C:30]=2[CH:29]=1)=[O:27].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.C1(C)C=CC=CC=1.O>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:9]2[CH2:10][CH2:11][N:12]([CH2:23][CH2:24][CH2:25][C:26]([C:28]3[S:37][C:36]4[S:35][CH2:34][CH2:33][NH:32][C:31](=[O:38])[C:30]=4[CH:29]=3)=[O:27])[CH2:13][CH2:14]2)=[CH:16][CH:17]=1
Reactant: Clc1ccc(C(c2ccc(Cl)cc2)N2CCNCC2)cc1
Reactant: O=C(CCCCl)c1cc2c(s1)SCCNC2=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(CCCN1CCN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)CC1)c1cc2c(s1)SCCNC2=O
Temperature: 60 °C
Reaction time: 5 h
Yield: 4.5 %

Procedure:
The mixture of 2.4 g of 4-(bis(4-chlorophenyl)methyl)piperazine, 2.0 g of 7-(4-chlorobutyryl)-2,3-dihydrothieno[3,2-f][1,4]thiazepin-5(4H)-one, 1.9 g of potassium carbonate and 1.2g of potassium iodide in 15 ml of N,N-dimethylformamide and 15 ml of toluene was stirred at 60° C. for 5 hours. After the mixture was cooled in a water bath, water was added thereto. The precipitated crystals were filtered off and the filtrate was extracted with toluene. The organic layer was washed with saline solution, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography on a silica gel and the resulting crystals were recrystallized from isopropyl alcohol-isopropyl ether to give 0.18 g of 7-(4-(4-(bis(4-chlorophenyl)-methyl)piperazin-1-yl)butyryl)-2,3-dihydrothieno[3,2-f][1,4]thiazepin-5(4H)-one as white crystals, m.p. 185°-187° C. (decomposition).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[OH-:15].[K+].[CH3:17]O>>[CH3:17][O:15][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: [OH-]
Reactant: O=C(O)CCCCCCCCCCBr
Reactant: CO
Agent: [K+]
Product: COCCCCCCCCCCC(=O)O
Yield: 2.5 %

Procedure:
11-bromoundecanoic acid (10.0 g, 37.7 mmol) was added to a solution of potassium hydroxide (24.3 g, 433 mmol) in methanol (280 mL) and refluxed for 5 hrs. After cooling and acidification with HCl, solvent was removed under reduced pressure. The sample was dissolved in ethyl acetate and extracted with water. The organic phase was dried over sodium sulfate, and the solvent removed under reduced pressure. The product was purified by silica column chromatography using increasing concentrations of ethyl acetate in hexanes for elution. The product eluted in 25% ethyl acetate in hexanes. Solvent was removed under reduced pressure to give 11-(methoxy)undecanoic acid (200 mg, 2.5%): mp 31-32° C.; 1H NMR (300 MHz, CDC13) δ 1.1-1.3 (bm, 12H, methylene envelope). 1.45-1.63 (bm. 4H, O-CH2 --CH2, CH2 --CH2 --COOH), 2.34 (t, 2H, J=7.3, CH2 --COOH), 3.45 (s, 3H, CH3), 3.50 (t, 2H, J=6.8, 0--CH2), 10.70 (br, COOH); 13C NMR (75.4 MHz, CDC13) δ 24.64, 26.00, 29.00, 29.16, 29.29, 29.40, 34.00, 58.23, 72.81, 179.17; m/z 216 (M+).
Reaction SMILES: [SH:1][CH:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4].Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(=O)(O)[O-].[Na+].Cl>CCOCC.N1C=CC=CC=1>[CH2:25]([O:24][C:22]([S:1][CH:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4])=[O:23])[CH3:26]
Reactant: O=C(O)C(S)CCc1ccc(-c2ccccc2Cl)cc1
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCOC(=O)SC(CCc1ccc(-c2ccccc2Cl)cc1)C(=O)O

Procedure:
A solution of α-mercapto-γ-(2'-chloro-4-biphenylyl)butyric acid 0.02 moles in 25 ml. of pyridine is cooled in an ice bath. To this is added dropwise 2.1 ml. (0.022 moles) of ethyl chloroformate. The mixture is basified with 10% sodium bicarbonate solution. The alkaline mixture is worked with ether, then acidified with 10% hydrochloric acid, washed with ether, dried and filtered, the solvent is removed and the residue is triturated with hexane to obtain α-ethoxycarbonylthio-γ-(2'-chloro-4-biphenylyl)butyric acid.
Reaction SMILES: Cl.[N+](C1C=CC(C([NH:11][CH2:12][CH:13]([OH:26])[CH2:14][N:15]([CH:23]([CH3:25])[CH3:24])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=O)=CC=1)([O-])=O.[N+](C1C=CC(C(Cl)=O)=CC=1)([O-])=O>>[NH2:11][CH2:12][CH:13]([OH:26])[CH2:14][N:15]([CH:23]([CH3:24])[CH3:25])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)N(Cc1ccccc1)CC(O)CNC(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Product: CC(C)N(Cc1ccccc1)CC(O)CN
Yield: 71 %

Procedure:
1-(4-nitro benzamido)-3-(N-benzyl isopropylamino)-2-propanol hydrochloride, M. Pt. 163°-164° C, starting from 7.2 g (0.039 mole) of 4-nitro benzoyl chloride and 8.65 g (0.039 mole) of 1-amino-3-(N-benzyl isopropylamino)-2-propanol (yield 71%).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[C:11]([F:13])[C:5]2[N:6]([CH3:10])[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[CH3:14][O:15][C:16]([C@@H:18]1[O:20][CH2:19]1)=[O:17].FC(F)(F)S([O-])(=O)=O.[Li+]>C(#N)C.C(OCC)(=O)C>[F:13][C:11]1[C:5]2[N:6]([CH3:10])[C:7](=[O:9])[O:8][C:4]=2[CH:3]=[C:2]([NH:1][CH2:19][C@@H:18]([OH:20])[C:16]([O:15][CH3:14])=[O:17])[CH:12]=1
Reactant: Cn1c(=O)oc2cc(N)cc(F)c21
Reactant: COC(=O)[C@H]1CO1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Li+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](O)CNc1cc(F)c2c(c1)oc(=O)n2C
Temperature: 90 °C
Yield: 99.6 %

Procedure:
A mixture of 6-amino-4-fluoro-3-methyl-1,3-benzoxazol-2(3H)-one (Step 7, 0.630 g, 3.46 mmol), methyl (2R)-glycidate (0.353 g, 3.46 mmol) and lithium trifluoromethanesulfonate (0.540 g, 3.46 mmol) in acetonitrile (10 ml) is stirred and heated at 90° C. overnight. The reaction mixture is diluted with ethyl acetate, washed with water and saline, dried (MgSO4), and evaporated under reduced pressure. Final purification by flash column chromatography (50% ethyl acetate/hexane) gives pure product as a white solid (0.98 g, 60%); MS for C12H13FN2O5 m/z 285 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH:10](O)[CH2:11][C@H:12]2[CH2:17][CH2:16][Si@H:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9]/[CH:10]=[CH:11]/[C@H:12]2[CH2:13][CH2:14][Si@H:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:16][CH2:17]2)=[CH:6][CH:7]=1
Reactant: CCCCC[Si@H]1CC[C@H](CC(O)C#Cc2ccc(F)cc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCCCC[Si@H]1CC[C@H](/C=C/C#Cc2ccc(F)cc2)CC1

Procedure:
A mixture of 1-(4-fluorophenyl)-4-(trans-4-pentyl-4-silacyclohexyl)-1-butyne-3-ol 8.0 g (24 mmol), p-toluenesulfonic acid monohydrate 1.6 g, and benzene 200 ml was heated under reflux to remove the water and then subjected to a conventional post-treatment. The reaction mixture thus obtained was not only a mixture of trans- and cis-isomers, with respect to the silacyclohexane ring, but also a mixture of E- and Z-isomers, with respect to the double bond. Hence, the product was separated by chromatography to give 1.2 g of the desired product of the trans-E isomer (yield 15.9%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:12][CH:11]=2)[CH:3]=1.[Li][CH2:23]CCC.C[Si](C)(C)[O:29][C@@H:30]1[C@@H:35]([O:36][Si](C)(C)C)[C@H:34]([O:41][Si](C)(C)C)[C@@H:33]([CH2:46][O:47][Si](C)(C)C)[O:32][C:31]1=[O:52].CS(O)(=O)=O>CCCCCC.CO>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C@@:31]2([O:52][CH3:23])[C@H:30]([OH:29])[C@@H:35]([OH:36])[C@H:34]([OH:41])[C@@H:33]([CH2:46][OH:47])[O:32]2)=[CH:3][C:4]=1[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:12][CH:11]=1
Reactant: [Li]CCCC
Reactant: FC(F)(F)COc1ccc(Cc2cc(Br)ccc2Cl)cc1
Reactant: C[Si](C)(C)OC[C@H]1OC(=O)[C@H](O[Si](C)(C)C)[C@@H](O[Si](C)(C)C)[C@@H]1O[Si](C)(C)C
Agent: CS(=O)(=O)O
Solvent: CCCCCC
Solvent: CO
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCC(F)(F)F)cc3)c2)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: -78 °C
Reaction time: 16 h

Procedure:
4-bromo-1-chloro-2-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]benzene 7d (6.15 g, 16.2 mmol) was dissolved in 150 mL of mixed solution (THF and n-hexane, v:v=2:3) and cooled to −78° C., followed by dropwise addition of a solution of nBuLi in n-hexane (10 mL, 24.3 mmol). The reaction was stirred for 1 hour at −78° C. before a solution (35 mL) of (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-(trimethylsilyl-oxymethyl)tetrahydropyran-2-one 2f (8.32 g, 17.8 mmol) in n-hexane was dropwise added. Then, the reaction mixture was stirred for 2 hours at −78° C. before 50 mL methanol and 3.2 mL methylsulfonic acid were added. The reaction mixture was warmed and stirred for 16 hours at room temperature. Thereafter, the reaction mixture was concentrated under reduced pressure and was partitioned after 30 mL saturated sodium bicarbonate solution and 10 mL water were added. The aqueous phase was extracted with ethyl acetate (100 mL×3) and the organic extract was washed with saturated sodium chloride solution (20 mL) and combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system D to obtain the title compound (2S,3R,4S,5S,6R)-2-[4-chloro-3-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol 7e (3.93 g, white solid), yield: 49.2%. 1H NMR (400 MHz, CD3OD): δ 7.57 (d, 1H), 7.49 (dd, 1H), 7.38 (d, 1H), 7.18 (d, 2H), 6.99-6.88 (m, 2H), 4.49 (q, 2H), 4.19-4.01 (m, 3H), 3.99-3.91 (m, 1H), 3.89-3.71 (m, 2H), 3.66-3.55 (m, 1H), 3.49-3.39 (m, 1H), 3.14-3.04 (s, 3H).
Reaction SMILES: [Br-:1].[NH2:2][CH2:3][CH2:4][N+:5]([CH2:8][CH2:9][NH:10][C:11]([C:13]1[C:18]([NH2:19])=[N:17][C:16]([NH2:20])=[C:15]([Cl:21])[N:14]=1)=[O:12])([CH3:7])[CH3:6].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][S:30](Cl)(=[O:32])=[O:31])=[CH:25][CH:24]=1.CN1CCOCC1>CN(C=O)C>[Br-:1].[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29][S:30]([NH:2][CH2:3][CH2:4][N+:5]([CH2:8][CH2:9][NH:10][C:11]([C:13]2[C:18]([NH2:19])=[N:17][C:16]([NH2:20])=[C:15]([Cl:21])[N:14]=2)=[O:12])([CH3:6])[CH3:7])(=[O:32])=[O:31])=[CH:27][CH:28]=1
Reactant: O=S(=O)(Cl)Cc1ccc(Cl)cc1
Reactant: C[N+](C)(CCN)CCNC(=O)c1nc(Cl)c(N)nc1N
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C[N+](C)(CCNC(=O)c1nc(Cl)c(N)nc1N)CCNS(=O)(=O)Cc1ccc(Cl)cc1

Procedure:
A solution of (2-amino-ethyl)-{2-[(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-amino]-ethyl}-dimethyl-ammonium bromide (Intermediate K) (0.3 g, 0.78 mmol), (4-chloro-phenyl)-methanesulfonyl chloride (0.18 g, 0.78 mmol) and N-methylmorpholine (0.35 mL, 3.18 mmol) in DMF (5 mL) is shaken at RT for 16 h. After this time the solvent is removed in vacuo and the residue is subjected to chromatography (basic alumina, 0-15% methanol in DCM) to yield the title compound. M+ 490.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]2[CH:27]=[N:26][CH:25]=[CH:24][N:23]=2)=[O:21])=[CH:15][C:14]=1[F:28])(=[O:7])[CH3:6].C(=O)(O)[O-].[Na+]>O>[C:5]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[C:14]([F:28])=[CH:15][C:16]([NH:19][C:20]([C:22]2[CH:27]=[N:26][CH:25]=[CH:24][N:23]=2)=[O:21])=[C:17]([N+:1]([O-:4])=[O:2])[CH:18]=1)(=[O:7])[CH3:6]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)N1CCCC1c1ccc(NC(=O)c2cnccn2)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(=O)N1CCCC1c1cc([N+](=O)[O-])c(NC(=O)c2cnccn2)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
40 ml of fuming nitric acid was added to 3.9 g of N-(4-(1-acetylpyrrolidin-2-yl)-3-fluorophenyl)pyrazine-2-carboxamide with cooling with ice, and the reaction liquid was stirred at room temperature for 2 hours. The reaction liquid was diluted with water with ice, made basic with aqueous saturated sodium bicarbonate, and then extracted with chloroform. The organic layer was washed with saturated saline, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: chloroform/methanol=50/1) to obtain the entitled compound as a yellow oily substance.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[K+].[C:13](Cl)(=[O:22])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].Cl>O.C(O)(C)C>[C:13]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)(=[O:22])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCC(=O)Cl
Reactant: O=C(O)c1ccc(O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCCCCCCCC(=O)Oc1ccc(C(=O)O)cc1
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
138.1 g (1.0 mol) of para-hydroxybenzoic acid were first dissolved in 500 ml of water and 500 ml of isopropanol and this solution was admixed at 0 to 5° C. with 230.0 g of KOH solution (50% strength by weight aqueous solution, 2.05 mol). The resulting pH was 13.5. Metered into this solution over the course of one hour, then, at 0 to 5° C., were 176.6 g (1.0 mol) of nonanoyl chloride, and the batch was stirred for 30 minutes at 0 to 5° C. thereafter. At the end of the after-stirring, the pH of the reaction mixture was 9.0. The reaction mixture was subsequently adjusted to a pH of 8 at 0 to 5° C. using 25.0 g of HCl solution (32% strength by weight aqueous solution), and the complete solution was heated to 55 to 60° C. and then adjusted to a pH of 1.5 to 3 using 100 g of HCl solution (32% strength by weight aqueous solution). The reaction mixture was cooled to 20 to 25° C. and the solid was filtered off on a suction filter and washed ten times with 150 ml of water. The yield after drying under reduced pressure at 100° C. was 255.95 g (92.0% of theory). According to HPLC and NMR measurement, the product was free from nonanoic acid and from unreacted para-hydroxybenzoic acid. The purity of the product is >99.9% by weight.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:15][C:16](=[O:24])[CH:17]([CH:19]1CCO[CH2:20]1)[CH3:18])[CH3:14].C(Br)=C.Cl.[O:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH2:13]([O:15][C:16](=[O:24])[C:17]([CH3:18])([CH:31]1[CH2:32][CH2:33][O:29][CH2:30]1)[CH:19]=[CH2:20])[CH3:14]
Reactant: C1CCOC1
Reactant: CCOC(=O)C(C)C1CCOC1
Agent: C=CBr
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Product: C=CC(C)(C(=O)OCC)C1CCOC1
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 24 %

Procedure:
A solution of N,N-diisopropylamine (1.28 mL, 9.1 mmol) in anhydrous tetrahydrofuran (15 mL) was cooled to −30° C. before adding n-butyllithium (3.22 mL, 8.08 mmol, 2.5 M in hexanes). The reaction mixture was stirred at −30° C. for 15 minutes before adding a solution of 2-(tetrahydro-furan-3-yl)-propionic acid ethyl ester (0.87 g, 5.05 mmol) in tetrahydrofuran (6 mL) dropwise over 3 minutes. The reaction mixture was stirred for a further 15 minutes at −30° C. before adding dibromobis(tributylphosphine)palladium(II) (40 mg, 50 μmol) and then a solution of vinylbromide (9.0 mL, 9.0 mmol, 1 M in tetrahydrofuran). The reaction mixture was stirred at −30° C. for 30 minutes then warmed to room temperature for 18 h. The reaction mixture was treated with hydrochloric acid (2 M, 20 mL). The mixture was extracted with diethyl ether (3×20 mL). The organics extract was dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using iso-hexanes/diethyl ether 3:2 to yield the title product (237 mg, 24%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 1.14-1.30 (m, 6H), 1.61-1.75 (m, 1H), 1.84-1.99 (m, 1H), 2.68-2.82 (m, 1H), 3.52-3.95 (m, 4H), 4.10-4.21 (m, 2H), 5.09-5.23 (m, 2H), 5.95-6.07 (m, 1H). LCMS (m/z) 199.2 [M+H], Tr=2.17 min.
Reaction SMILES: C[O:2][C:3]1[CH:10]=[C:9]([C:11]([CH3:21])([CH3:20])[C:12](O)([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:8]=[C:5]([O:6]C)[CH:4]=1.[K].CI.COC1C=C(C(C)(C)C(C)=CCCCC)C=C(OC)C=1>CCOCC.C(=S)=S>[CH3:21][C:11]([C:9]1[CH:10]=[C:3]([OH:2])[CH:4]=[C:5]([CH:8]=1)[OH:6])([CH3:20])[CH:12]([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCC(C)(O)C(C)(C)c1cc(OC)cc(OC)c1
Agent: CCCCC=C(C)C(C)(C)c1cc(OC)cc(OC)c1
Agent: [K]
Solvent: CCOCC
Solvent: CI
Solvent: S=C=S
Product: CCCCCC(C)C(C)(C)c1cc(O)cc(O)c1
Reaction time: 0.5 h

Procedure:
To 0.2 mol. of methyl magnesium bromide (2N in tetrahydrofuran-benzene), under nitrogen, is added 55.6 g. of 2-(3,5-dimethoxyphenyl)-2-methyloct-3-one [J. Amer. Chem. Soc. 70:664 (1948); Helv. Chim. Acta 52:116 (1969)] in tetrahydrofuran. After refluxing for 12 hours the mixture is quenched with saturated aqueous ammonium chloride and extracted with ether. The extracts are washed with water, dried (MgSO4) and the solvent is removed to give 5-(2-hydroxy-1,1,2-trimethylheptyl)resorcinol dimethyl ether as an oil. A solution of 5.9 g. of the carbinol in ether is allowed to react over a six hour period with a suspension of 0.8 g. of metallic potassium in 60 ml. of ether. Carbon disulfide (1.5 g.) is added and the mixture is stirred for 30 minutes, then 2.8 g. of methyl iodide is added and the reaction mixture is refluxed for six hours and left at 25° for 12 hours. The mixture is filtered and the filtrate is concentrated and distilled in vacuo. The distillate is dissolved in ethanol, refluxed with Raney nickel and redistilled to give a mixture of 5-(1,1,2-trimethylhept-2-enyl)resorcinol dimethyl ether and 5-(1,1-dimethyl-2-methylenylheptyl)resorcinol dimethyl ether. Removal of the protective groups and hydrogenation is accomplished as described in Example 8 to give 5-(1,1,2-trimethylheptyl)resorcinol.