Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23]Cl)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[SH:26][C:27]1[S:28][CH:29]=[N:30][N:31]=1>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23][S:26][C:27]3[S:28][CH:29]=[N:30][N:31]=3)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Sc1nncs1
Reactant: O=C(CCCCl)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Product: O=C(CCCSc1nncs1)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Yield: 84 %

Procedure:
Following a procedure similar to that described in Example 34, but using N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-4-chlorobutyramide (prepared as described in Preparation 2) and 2-mercapto-1,3,4-thiadiazole as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in an 84% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C@H:9]([N:22]2[CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[C:27]([C:31]4[N:35]([CH3:36])[N:34]=[CH:33][CH:32]=4)[CH:28]=3)[C:23]2=[O:37])[CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[B-](F)(F)(F)[F:39].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>O1CCCC1.O>[F:39][C:32]1[CH:33]=[N:34][N:35]([CH3:36])[C:31]=1[C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:37])[N:22]([C@@H:9]([CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[CH2:10][N:11]1[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]1=[O:21])[CH2:30]2
Reactant: Cn1nccc1-c1ccc2c(c1)CN([C@@H](Cc1cccc(F)c1)CN1C(=O)c3ccccc3C1=O)C2=O
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: O
Solvent: C1CCOC1
Product: Cn1ncc(F)c1-c1ccc2c(c1)CN([C@@H](Cc1cccc(F)c1)CN1C(=O)c3ccccc3C1=O)C2=O
Temperature: 70 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a solution of 2-{(2S)-3-(3-fluorophenyl)-2-[5-(1-methyl-1H-pyrazol-5-yl)-1-oxo-1,3-dihydro-2H-isoindol-2-yl]propyl}-1H-isoindole-1,3(2H)-dione (200.0 mg, 0.4044 mmol) [prepared in Example 1] in tetrahydrofuran (7 mL) and water (0.5 mL) was added SELECTFLUOR® fluorinating reagent (1-chloromethyl-4-fluoro-1,4-diazoniabicyclo [2.2.2]-octane bis(tetrafluoroborate) (212.0 mg, 0.60 mmol). The reaction mixture was sealed and stirred at 70° C. for 1 h and then additional SELECTFLUOR® fluorinating reagent (212.0 mg, 0.60 mmol) was added. The reaction mixture was sealed again and stirred at 70° C. overnight. The reaction mixture was then filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep.—HPLC. The purification afforded 61 mg (30% yield) of the desired product as white solid. LC/MS found: 513.0 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:15]2[C:10]([C:11]([OH:24])=[N:12][CH:13]=[CH:14]2)=[N:9]1.FC(F)(F)S(O[CH2:31][C:32]([F:35])([F:34])[F:33])(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:15]2[C:10]([C:11](=[O:24])[N:12]([CH2:31][C:32]([F:35])([F:34])[F:33])[CH:13]=[CH:14]2)=[N:9]1
Reactant: Oc1nccc2c(-c3ccc(Cl)cc3)n(-c3ccccc3Cl)nc12
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=c1c2nn(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2ccn1CC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(2-chlorophenyl)-3-(4-chlorophenyl)-2H-pyrazolo[3,4-c]pyridin-7-ol (I-9A-1b: 150 mg, 0.421 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (107 mg, 0.463 mmol) and Cs2CO3 (151 mg, 0.463 mmol) in DMF (2.1 ml) were stirred overnight at room temperature. The reaction mixture was extracted from saturated aqueous NaHCO3 with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), concentrated in vacuo, and then purified on a Biotage™ Flash 12M column using 0-40% ethyl acetate in hexanes as eluant to give the title compound 9A-1 (145 mg, 79%) as a colorless solid: +ES MS (M+1) 438.3; 1H NMR (CD2Cl2) 67 7.70 (d, J=6.2 Hz, 1H), 7.59-7.56 (m, 1H), 7.52-7.43 (m, 3H), 7.38-7.34 (m, 2H), 7.29-7.25 (m, 3H), 5.03 (br s, 2H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([C@H:23]4[O:28][CH2:27][CH2:26][NH:25][CH2:24]4)=[CH:19][CH:18]=3)=[O:15])[NH:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:29]N1C(C(O)=O)=CC(C2C=CC=CC=2)=N1>>[ClH:2].[CH3:29][N:11]1[C:12]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C@H:23]3[O:28][CH2:27][CH2:26][NH:25][CH2:24]3)=[CH:19][CH:18]=2)=[O:15])=[CH:13][C:9]([C:6]2[CH:7]=[CH:8][CH:3]=[CH:4][CH:5]=2)=[N:10]1
Reactant: O=C(Nc1ccc([C@@H]2CNCCO2)cc1)c1cc(-c2ccc(Cl)cc2)n[nH]1
Reactant: Cn1nc(-c2ccccc2)cc1C(=O)O
Agent: Cl
Product: Cn1nc(-c2ccccc2)cc1C(=O)Nc1ccc([C@@H]2CNCCO2)cc1

Procedure:
The title compound was prepared in analogy to Example 1 using (R)-tert-butyl 2-(4-aminophenyl)morpholine-4-carboxylate (prepared in Example 12) instead of (S)-tert-butyl 2-(4-aminophenyl)morpholine-4-carboxylate and 1-Methyl-3-phenyl-1H-pyrazole-5-carboxylic acid (CAS-10250-64-3) instead of 3-phenyl-1H-pyrazole-5-carboxylic acid. White solid. MS (ISP): 363.3 ([M+H]+).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH3:19])[N:9]=[C:10]([C:11]3[O:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=3)[C:3]=12.[NH3:20]>C(O)C>[NH2:20][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH3:19])[N:9]=[C:10]([C:11]3[O:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=3)[C:3]=12
Reactant: N
Reactant: Cn1nc(-c2ccc([N+](=O)[O-])o2)c2c(Cl)ncnc21
Solvent: CCO
Product: Cn1nc(-c2ccc([N+](=O)[O-])o2)c2c(N)ncnc21

Procedure:
A mixture of 1.0 grams of 4-chloro-1-methyl-3-(5-nitro-2-furyl)-1H-pyrazolo[3,4-d]pyrimidine and a solution of 100 milliliters of dry ethanol saturated at room temperature with ammonia gas, was heated in a sealed stainless steel tube at a bath temperature of 130° C. and 7 atmospheres pressure for 3 hours, and cooled. The crystalline product was collected washed with water and dried. Recrystallisation from dimethylformamide gave 4-amino-1-methyl-3-(5-nitro-2-furyl)-1H-pyrazolo [3,4-d]pyrimidine having decomposition point 305° C. identical with the product obtained in Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH2:14]([CH:16]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]([CH3:26])[NH:17]1)[CH3:15]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:17]3[CH:16]([CH2:14][CH3:15])[CH2:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]3[CH3:26])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CCC1Cc2ccccc2C(C)N1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CCC1Cc2ccccc2C(C)N1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 3-Ethyl-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5](C(O)=O)=[CH:6][CH:7]=1.[C:11]([Cl:14])(Cl)=[O:12]>ClC1C=CC=CC=1>[C:2]1([CH3:1])[C:7]([C:11]([Cl:14])=[O:12])=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: O=C(Cl)Cl
Solvent: Clc1ccccc1
Product: Cc1ccccc1C(=O)Cl
Reaction time: 3 h

Procedure:
81.4 g (0.6 mol) of p-toluic acid and 892 g of monochlorobenzene are introduced into the reactor and 582 g (5.9 mol) of phosgene are then added. The set pressure is adjusted to 11.2 bar relative and the reaction medium is heated. The reaction is complete after 3 hours. Analysis of the final reaction medium is carried out by gas chromatography. The level of residual acid is 0.3 mol % and the level of toluoyl chloride obtained is 99.7 mol %.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]4[CH:24]=[CH:23][C:22]([N:25]5[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]5)=[CH:21][CH:20]=4)=[CH:16][CH:17]=3)[C:12]3[C:31]([Cl:35])=[CH:32][CH:33]=[N:34][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:36][N:37]1[CH2:42][CH2:41][C:40](=O)[CH2:39][CH2:38]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]4[CH:20]=[CH:21][C:22]([N:25]5[CH2:30][CH2:29][N:28]([CH:40]6[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]6)[CH2:27][CH2:26]5)=[CH:23][CH:24]=4)=[CH:16][CH:17]=3)[C:12]3[C:31]([Cl:35])=[CH:32][CH:33]=[N:34][C:11]2=3)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)n1c2ccc(-c3ccc(N4CCNCC4)cc3)cc2c2c(Cl)ccnc21
Reactant: CN1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN1CCC(N2CCN(c3ccc(-c4ccc5c(c4)c4c(Cl)ccnc4n5S(=O)(=O)c4ccccc4)cc3)CC2)CC1
Temperature: 25 °C
Yield: 93 %

Procedure:
Under an inert atmosphere 9-benzenesulfonyl-4-chloro-6-(4-(piperazin-1-yl)phenyl)-9H-pyrido[2,3-b]indole (30 mg, 0.0596 mmol) was dissolved in anhydrous DCM (1.2 mL, c=0.05M). N-methyl-4-piperidone (22 μL, 3 eq) was added, followed by the addition of two drops of glacial acetic acid. The mixture was stirred for 1 h15 at r.t. and then cooled to 0° C. Sodium triacetoxyborohydride (38 mg, 3eq) was added in portions and the resultant mixture was allowed to warm to room temperature, and then stirred 22 h. The reaction mixture was then quenched with water and saturated aq. NaHCO3. The aqueous layer was extracted with EtOAc (3×7 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to yield the desired compound (33 mg, 93%) as a white solid that was used without further purification.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].Cl[C:6]1[N:11]=[C:10]([NH2:12])[CH:9]=[CH:8][CH:7]=1>C(O)C>[CH2:2]([O:1][C:6]1[N:11]=[C:10]([NH2:12])[CH:9]=[CH:8][CH:7]=1)[CH3:3]
Reactant: CC[O-]
Reactant: Nc1cccc(Cl)n1
Agent: [Na+]
Solvent: CCO
Product: CCOc1cccc(N)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 36 %

Procedure:
In a vial in a water bath, a 21% wt solution of sodium ethoxide in ethanol (1.08 g, 1.25 mL, 15.9 mmol) was diluted in ethanol (4 mL) and stirred at 25° C. for 10 min then 6-chloropyridin-2-amine (2.0 g, 15.6 mmol) was added in a single portion. After 3 h the reaction mixture was transferred to a sealed flask and was stirred at 130° C. for 18 h. A second portion of 21% wt solution of sodium ethoxide in ethanol (1.08 g, 1.25 mL, 15.9 mmol) was added and the reaction was stirred at 130° C. for another 36 h. Finally, a third portion of a 21% wt solution of sodium ethoxide in ethanol (3.18 g, 3.66 mL, 46.7 mmol) was added and the mixture stirred at 140° C. for 6 h then at 130° C. for 18 h. The mixture was cooled, concentrated onto silica gel, and purified by chromatography (silica, Analogix 120 g, 0 to 100% ethyl acetate in hexanes, 60 min) to give 6-ethoxypyridin-2-amine (819 mg, 36%) that was used directly without further purification. MS (EI/CI) m/z: 139 [M+H].
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][N:8]=[N:7][CH:6]=1)[NH2:4].[C:11]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](Cl)=O)#[N:12].N>>[N:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:4]=[C:16]([C:15]3[CH:14]=[C:13]([CH:21]=[CH:20][CH:19]=3)[C:11]#[N:12])[O:1][N:2]=2)=[CH:6][N:7]=1
Reactant: N#Cc1cccc(C(=O)Cl)c1
Reactant: NC(=NO)c1ccnnc1
Agent: N
Product: N#Cc1cccc(-c2nc(-c3ccnnc3)no2)c1

Procedure:
The titled compound was prepared according to the procedure of Method D using the product of Example 83D and 3-cyanobenzoyl chloride (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.86 (t, J=7.9 Hz, 1 H), 8.09 (ddd, J=8.1, 1.4, 1.2 Hz, 1 H), 8.40 (dd, J=5.4, 2.2 Hz, 1 H), 8.55 (dt, J=7.9, 1.6 Hz, 1 H), 8.64 (t, J=2.0 Hz, 1 H), 9.46 (dd, J=5.4, 1.4 Hz, 1 H), 9.88 (dd, J=2.2, 1.4 Hz, 1 H) ppm; MS (DCI/NH3) m/z=250 (M+H)+.
Reaction SMILES: Cl[C:2]1[S:6][N:5]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4](=[O:15])[CH:3]=1.[Na+].[CH2:17]([N:24]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:25](=[S:27])[S-:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[I-].[Na+]>C(O)C>[CH2:28]([N:24]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:25]([S:27][C:2]1[S:6][N:5]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4](=[O:15])[CH:3]=1)=[S:26])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: S=C([S-])N(Cc1ccccc1)Cc1ccccc1
Reactant: O=c1cc(Cl)sn1CCc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Product: O=c1cc(SC(=S)N(Cc2ccccc2)Cc2ccccc2)sn1CCc1ccccc1

Procedure:
To a solution of 4.8 g. (0.02 mole) of 5-chloro-2-phenethyl-4-isothiazolin-3-one in 35 ml of ethanol was added 5.9 g. (0.02 mole) of N,N-dibenzyldithiocarbamic acid sodium salt followed by 0.15 g. sodium iodide. The mixture was concentrated in vacuo and the residue was treated with 300 ml of boiling hexane under reflux. The hexane solution decanted and cooled to give 0.63 g. of the named product, mp 98°-100°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH:13]=[C:14](Br)Br)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]#[CH:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC1C=C(Br)Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C#CC1CCCN1C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
To a stirred cold (minus 78° C.) solution of 1-(tert-butoxycarbonyl)-2-(2,2-dibromoethenyl)pyrrolidine (7.81 g, 22 mmol) in THF (200 mL) was added n-BuLi (1.59 M in hexane, 28 mL, 44 mmol) over 10 min. and the stirring was continued for 2 hr at the same temp. The reaction was quenched by the addition of sat. NH4Cl and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, and evaporated. The residue was chromatographed on silica-gel with n-hexane-AcOEt (10:1, v/v) as eluent to give 4.15 g (97%) 1-(tert-butoxycarbonyl)-2-ethynyl pyrrolidine as a light yellow oil. 1H-NMR (CDCl3) δ1.48 (9 H, s), 1.82-2.21 (4 H, m), 3.30-3.45 (2 H, m), 4.41-4.52 (1 H, m).
Reaction SMILES: O=[C:2]1[NH:7][C:6]2([CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8]2)[NH:5][C:4]2[N:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>O1CCOCC1>[S:31]=[C:2]1[NH:7][C:6]2([CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8]2)[NH:5][C:4]2[N:18]=[CH:19][CH:20]=[CH:21][C:3]1=2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)N1CCC2(CC1)NC(=O)c1cccnc1N2
Solvent: C1COCCO1
Product: CCOC(=O)N1CCC2(CC1)NC(=S)c1cccnc1N2
Yield: 152.3 %

Procedure:
A solution of ethyl 3′,4′-dihydro-4′-oxospiro[piperidine-4,2′-[1′H]-(pyrido[2,3-d]-pyrimidine)]-1-carboxylate (0.74 g, 2.55 mmol) and Lawesson's reagent (0.62 g, 1.5 mmol) in dioxane (15 ml) was heated at reflux for 2 h. The mixture was absorbed onto silica gel and purified by flash column chromatography on silica gel, eluting with dichloromethane/methanol (50:1) to afford the product as a white solid (0.7 g). MS (+CI) m/Z 307 [M+H]+; 1H NMR (d6-DMSO) 10.37 (1H, dd), 8.34 (1H, dd), 8.24 (1H, dd), 8.10 (H, s), 6.76 (1H, dd), 4.04 (2H, q), 3.6-3.78 (2H, m), 3.3-3.5 (2H, m), 1.75-1.90 (4H, m), 1.21 (3H, t).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].Br[CH2:10][CH2:11][CH2:12][CH2:13]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH2:7]([O:6][C:4]([C:3]1([C:1]#[N:2])[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:5])[CH3:8]
Reactant: BrCCCCBr
Reactant: CCOC(=O)CC#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1(C#N)CCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ethyl cyanoacetate (2.50 g, 22 mmol) and 1,4-dibromobutane (5.00 g, 23.0 mmol) were dissolved in anhydrous DMF (20 ml) under nitrogen and cesium carbonate (21.0 g, 64 mmoles) added with water bath cooling. After stirring at room temperature for 18 h the reaction was diluted with water and extracted with ethyl acetate (2×80 ml), the organic layers were combined and washed with water (40 ml) and saturated aqueous sodium chloride solution (25 ml). The organics were dried over magnesium sulphate, filtered and evaporated under reduced pressure to give 1-cyano-cyclopentanecarboxylic acid ethyl ester as an almost colourless oil (3.64 g, 98%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][OH:20])=[CH:13][CH:12]=2)=[N:8][CH:9]=1)([O-:3])=[O:2].N1C=CN=C1.[C:26]([Si:30](Cl)([CH3:32])[CH3:31])([CH3:29])([CH3:28])[CH3:27].O>CN(C=O)C>[Si:30]([O:20][CH2:19][CH2:18][CH2:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=2)=[CH:12][CH:13]=1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:32])[CH3:31]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(CCCO)cc2)nc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCCc1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
To a solution of 3-[4-(5-nitropyridin-2-yloxy)phenyl]-n-propanol (1.17 g, 4.3 mmol) in DMF (10 mL) were added imidazole (580 mg, 8.5 mmol) and t-butylchlorodimethylsilane (640 mg, 4.2 mmol), and the resulting solution was stirred for 13 hours at room temperature. Water was added to the reaction mixture, and extracted with diethyl ether, and the diethyl ether layer was washed with water and then brine. The diethyl ether layer was dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1), to thereby yield 1.14 g of the title compound.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH2:13])=[S:12])=[CH:6][CH:5]=1.Br[CH2:17][C:18](=O)[C:19]([OH:21])=[O:20]>C(O)C>[F:15][C:2]([F:14])([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]2[S:12][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[N:13]=2)=[CH:8][CH:9]=1
Reactant: NC(=S)Nc1ccc(OC(F)(F)F)cc1
Reactant: O=C(O)C(=O)CBr
Solvent: CCO
Product: O=C(O)c1csc(Nc2ccc(OC(F)(F)F)cc2)n1
Temperature: 60 °C

Procedure:
A mixture of 12.9 g (54.6 mmol) [4-(trifluoromethoxy)phenyl]-thiourea, and 9.3 g (55.7 mmol) bromopyruvic acid in 70 ml ethanol was heated to 60° C. for 1 h. The precipitate was filtered off and washed with small portions of cold ethanol to yield after drying 8.9 g (53%) of the title compound as crystalline solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6](/[CH:8]=C(\C#N)/C(NC(C2C=CC(OCCN(CC)CC)=CC=2)CCC)=O)[CH:5]=[CH:4][CH:3]=1.[C:33]([CH2:35][C:36]([NH:38][CH:39]([C:43]1[CH:72]=[CH:71][C:46]([O:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][O:53][CH2:54][CH2:55][N:56]([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])=[CH:45][CH:44]=1)[CH2:40][CH2:41][CH3:42])=[O:37])#[N:34]>>[Br:1][C:2]1[N:7]=[C:6](/[CH:8]=[C:35](\[C:33]#[N:34])/[C:36]([NH:38][CH:39]([C:43]2[CH:72]=[CH:71][C:46]([O:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][O:53][CH2:54][CH2:55][N:56]([C:57]([O:59][C:60]([CH3:62])([CH3:63])[CH3:61])=[O:58])[C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])=[CH:45][CH:44]=2)[CH2:40][CH2:41][CH3:42])=[O:37])[CH:5]=[CH:4][CH:3]=1
Reactant: CCCC(NC(=O)/C(C#N)=C/c1cccc(Br)n1)c1ccc(OCCN(CC)CC)cc1
Reactant: CCCC(NC(=O)CC#N)c1ccc(OCCOCCOCCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Product: CCCC(NC(=O)/C(C#N)=C/c1cccc(Br)n1)c1ccc(OCCOCCOCCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1

Procedure:
The title compound was prepared by using a similar procedure as described for the preparation of 33 except that (2-(2-(2-(4-(1-(2-cyanoacetamido)butyl)phenoxy)ethoxy)ethoxy)ethyl)imidodicarbonic acid, 1,3-bis-tert-butyl ester (46) was used instead of 2-cyano-N-(1-(4-(2-(diethylamino)ethoxy)phenyl)butyl)acetamide (29). This produced the crude product which was purified by flash silica gel column chromatography, eluting with 7:3 hexanes/ethyl acetate, to give 47 (105 mg, 85%) as a clear oil: MS (ES+) m/z 731.2 (M+H)+.
Reaction SMILES: [CH2:1](OC(OCC)OCC)C.[NH2:11][C:12]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[CH:30][C:13]=1[C:14]([NH:16][C:17]1[CH:22]=[C:21]([C:23]([NH:25][CH:26]2[CH2:28][CH2:27]2)=[O:24])[CH:20]=[CH:19][C:18]=1[CH3:29])=[O:15].C(O)(=O)C>C(O)C>[CH:26]1([NH:25][C:23](=[O:24])[C:21]2[CH:20]=[CH:19][C:18]([CH3:29])=[C:17]([N:16]3[C:14](=[O:15])[C:13]4[C:12](=[CH:33][CH:32]=[C:31]([N:34]5[CH2:35][CH2:36][O:37][CH2:38][CH2:39]5)[CH:30]=4)[N:11]=[CH:1]3)[CH:22]=2)[CH2:28][CH2:27]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(N2CCOCC2)ccc1N
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(N3CCOCC3)cc2c1=O
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Triethylorthoformate (0.969 ml) was added to a stirred mixture of 2-amino-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-morpholin-4-ylbenzamide (0.67 g) and glacial acetic acid (0.05 ml) in ethanol (5 ml). The mixture was heated to 80° C. and stirred for 16 hours. The reaction mixture was evaporated, dissolved in methylene chloride and washed with a saturated NaHCO3 solution. The organic phase was evaporated and the residue was purified by column chromatography on an ion exchange column (isolute SCX column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) using initially methanol and then a 99:1 mixture of methanol and aqueous ammonia solution to give the title compound (0.172 g); NMR Spectrum: (DMSOd6) 0.53 (m, 2H), 0.66 (m, 2H), 2.11 (s, 3H), 2.83 (m, 1H), 3.22 (m, 4H), 3.75 (m, 4H), 7.48 (m, 2H), 7.64 (m, 2H), 7.80 (s, 1H), 7.87 (m, 1H), 8.09 (s, 1H), 8.43 (m, 1H); Mass Spectrum: M+H+ 405.
Reaction SMILES: [C:1]1(=[O:16])[N:5](C2NC=CC=2)[C:4](=[O:11])[C:3]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:2]12.[Cl:17][C:18]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>ClC(Cl)C>[Cl:17][C:18]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:19]=1[C:20]([C:4]1[N:5]([N:5]2[C:1](=[O:16])[C:2]3=[CH:15][CH:14]=[CH:13][CH:12]=[C:3]3[C:4]2=[O:11])[CH:1]=[CH:2][CH:3]=1)=[O:21]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: O=C1c2ccccc2C(=O)N1c1ccc[nH]1
Solvent: CC(Cl)Cl
Product: O=C(c1ccc(Cl)cc1Cl)c1cccn1N1C(=O)c2ccccc2C1=O
Yield: 16.6 %

Procedure:
To a suspension of phthalimidopyrrole (748.6 g) and 2,4-dichlorobenzoyl chloride (1109.1 g) in 3.5 L of dichloroethane was added 707.3 g of K-10 Montmorillonite clay. The resulting mixture was stirred at reflux for 48 hrs, then filtered and concentrated to a semisolid. The semisolid was triturated with a large quantity of ether and collected to yield 112.5 g of powder. The ether wash was concentrated to give 162.0 of a residue. This was purified by high performance liquid chromatography (HPLC hereinafter, silica, dichloromethane) and recrystallized from absolute ethanol to yield 37.26 g of crystals, mp 152°-153° C.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH3:8][O:9][C:10]1[C:15]([CH3:16])=[C:14]([CH3:17])[C:13]([O:18][CH3:19])=[C:12]([CH3:20])[C:11]=1[CH2:21][CH2:22]/[C:23](/C)=[CH:24]\CO>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:5]([O:4][CH2:1]/[CH:2]=[C:23](/[CH3:24])\[CH2:22][CH2:21][C:11]1[C:12]([CH3:20])=[C:13]([O:18][CH3:19])[C:14]([CH3:17])=[C:15]([CH3:16])[C:10]=1[O:9][CH3:8])(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: COc1c(C)c(C)c(OC)c(CC/C(C)=C\CO)c1C
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COc1c(C)c(C)c(OC)c(CC/C(C)=C\COC(C)=O)c1C
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Acetic anhydride (0.2 ml) was dissolved at 0° C. in pyridine (10 ml) together with (Z)-5-(2,5-dimethoxy-3,4,6-trimethylphenyl)-3-methyl-2-penten-1-ol (0.39 g; 1.4 mmol). A spatula tip of 4-dimethylaminopyridine was added and the reaction mixture was left at 0° C. for 20 minutes. Thereafter, the mixture was poured into 150 ml of ice-cold 2N hydrochloric acid and extracted with ether. The extracts were washed with water, dried briefly and freed from solvent, yielding 0.39 g of (Z)-5-(2,5-dimethoxy-3,4,6-trimethylphenyl)-3-methyl-2-pentenyl acetate as an almost colourless oil.