Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21].[NH2:23][CH2:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=1.CCN(C(C)C)C(C)C.O>C(#N)C>[N+:20]([C:3]1[CH:4]=[C:5]([O:6][CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:18]=[CH:19][C:2]=1[NH:30][CH2:29][C:28]1[CH:31]=[CH:32][C:25]([C:24]#[N:23])=[CH:26][CH:27]=1)([O-:22])=[O:21]
Reactant: N#Cc1ccc(CN)cc1
Reactant: O=[N+]([O-])c1cc(OCc2ccc3ccccc3n2)ccc1F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: N#Cc1ccc(CNc2ccc(OCc3ccc4ccccc4n3)cc2[N+](=O)[O-])cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 2-((4-fluoro-3-nitrophenoxy)methyl)quinoline (298 mg, 1 mmol) and 4-(aminomethyl)benzonitrile (132 mg, 1 mmol) in acetonitrile (1 mL) was added DIPEA (2 mL, 12 mmol). The mixture was stirred at 80° C. overnight. The mixture was cooled to RT, water (20 mL) was added, and the mixture was extracted with DCM (3×20 mL). The organics were combined, washed with brine (20 mL), dried (Na2SO4), filtered and concentrated to dryness. The residue was recrystallized from ethanol to give 4-((2-nitro-4-(quinolin-2-ylmethoxy)phenylamino)methyl)benzonitrile. The recrystallized 4-((2-nitro-4-(quinolin-2-ylmethoxy)phenylamino)methyl)benzonitrile (307 mg, 0.75 mmol) was then dissolved in ethanol (20 mL) and SnCl2.2H2O (1 g, 4.5 mmol) was added. The resulting mixture was stirred at 90° C. overnight. The mixture was cooled to RT and the pH adjusted to ˜pH 8-9 by the addition of sat. aq. NaHCO3. The aqueous mixture was stirred at RT for 30 min. and then extracted with DCM (3×20 mL). The organics were combined, washed with brine (20 mL), dried (Na2SO4), filtered and concentrated to dryness to afford the title compound, which was used without further purification. MS (ESI): mass calcd. for C24H20N4O, 380.16; m/z found, 381.0 [M+H]+.
Reaction SMILES: [C:1]([CH2:3][C:4]([CH3:9])(O)[CH2:5][C:6]#[N:7])#[N:2].[BrH:10]>C(O)(=O)C>[NH2:2][C:1]1[N:7]=[C:6]([Br:10])[CH:5]=[C:4]([CH3:9])[CH:3]=1
Reactant: Br
Reactant: CC(O)(CC#N)CC#N
Solvent: CC(=O)O
Product: Cc1cc(N)nc(Br)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 66 %

Procedure:
56.4 g of 1,3-dicyano-2-methyl-2-hydroxypropane was added carefully to a 33% solution of hydrogen bromide in glacial acetic acid at ice-bath temperature. The reaction mixture was then stirred for 3 days at ambient temperature. The solvent was removed in vacuo and the residual oil was brought to pH 12 with a 10 molar aqueous solution of sodium hydroxide. This alkaline solution was extracted three times each with 100 ml ethyl acetate. The combined organic layers were dried with magnesium sulphate and the solvent removed in vacuo. 56 g (66%) of 6-amino-2-bromo-4-methylpyridine was obtained as a colourless solid of melting point 99° C.
Reaction SMILES: [CH2:1]1[C@H:6]([NH2:7])[C@@H:5]([O:8][C@H:9]2[O:14][C@H:13]([CH2:15][NH2:16])[C@@H:12]([OH:17])[C@H:11]([OH:18])[C@H:10]2[OH:19])[C@H:4]([OH:20])[C@@H:3]([O:21][C@H:22]2[O:27][C@H:26]([CH2:28][OH:29])[C@@H:25]([OH:30])[C@H:24]([NH2:31])[C@H:23]2[OH:32])[C@@H:2]1[NH2:33].OS(O)(=O)=O>O>[CH2:1]1[C@H:6]([NH2:7])[C@@H:5]([O:8][C@@H:9]2[O:14][C@@H:13]([CH2:15][NH2:16])[C@H:12]([OH:17])[C@@H:11]([OH:18])[C@@H:10]2[OH:19])[C@H:4]([OH:20])[C@@H:3]([O:21][C@H:22]2[O:27][C@H:26]([CH2:28][OH:29])[C@@H:25]([OH:30])[C@H:24]([NH2:31])[C@H:23]2[OH:32])[C@@H:2]1[NH2:33]
Reactant: NC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](N)[C@H]3O)[C@H](N)C[C@@H]2N)[C@H](O)[C@@H](O)[C@@H]1O
Agent: O=S(=O)(O)O
Solvent: O
Product: NC[C@@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](N)[C@H]3O)[C@H](N)C[C@@H]2N)[C@@H](O)[C@H](O)[C@H]1O
Yield: 113.6 %

Procedure:
Kanamycin sulfate (20.0 g) was dissolved in 200 mL of water. This was loaded on a column prepared with 400 g of AMBERLITE IRA-410 resin (6.4 cm×17.5 cm). The column was eluted with water, and the appropriate fractions were collected and lyophilized to give 18.9 g of kanamycin A (free base) (18).
Reaction SMILES: S1C=CC(C=O)=C1.[OH-].[K+].[N+:10]([CH2:12][C:13]([N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:14])#[C-:11].[S:20]1[CH:24]=[CH:23][C:22]([C@@H:25]2[O:29][CH:28]=[N:27][C@H:26]2[C:30]([N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[O:31])=[CH:21]1>CO>[S:20]1[CH:24]=[CH:23][C:22]([C@@H:25]2[O:29][CH:28]=[N:27][C@H:26]2[C:30]([N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[O:31])=[CH:21]1.[N:27]1[CH:24]=[CH:23][CH:22]=[CH:25][C:26]=1[C@@H:30]1[O:31][CH:11]=[N:10][C@H:12]1[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:14]
Reactant: [C-]#[N+]CC(=O)N1CCCC1
Agent: O=C([C@@H]1N=CO[C@H]1c1ccsc1)N1CCCC1
Agent: O=Cc1ccsc1
Agent: [K+]
Solvent: CO
Product: O=C([C@@H]1N=CO[C@H]1c1ccccn1)N1CCCC1
Yield: 40 %

Procedure:
BLE 04124A was prepared in accordance with method D using thiophen-3-carboxaldehyde (0.475 mL, 5.42 mmol), KOH (0.276 mg, 4.92 mmol) in methanol (5 mL) and 2-isocyano-1-(pyrrolidin-1-yl)ethanone BLE 04098 (0.75 g, 5.43 mmol). After work-up the residue obtained was recrystallized from ethyl acetate to obtain after filtration trans-(4,5-dihydro-5-(thiophen-3-yl)oxazol-4-yl)(pyrrolidin-1-yl)methanone BLE 04110A as a yellow pale solid (0.498 g, 40% yield).
Reaction SMILES: [CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:21][CH3:22])=[C:11]4[O:12][C@H:13]5[C@@H:14]([OH:20])[CH:15]=[CH:16][C@@H:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1.CN1[C@@H]2CC3C=CC(OC)=C4O[C@H]5[C@@H](O)C=C[C@@H]2[C@]5(C=34)CC1.O.OP(O)(O)=O.Cl>>[CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:21][CH3:22])=[C:11]4[O:12][C@H:13]5[C:14]([CH:15]=[CH:16][C@@H:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:20]
Reactant: COc1ccc2c3c1O[C@H]1[C@@H](O)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Agent: Cl
Agent: O=P(O)(O)O
Solvent: O
Product: COc1ccc2c3c1O[C@H]1C(=O)C=C[C@H]4[C@@H](C2)N(C)CC[C@]314
Temperature: 25 °C
Reaction time: 2.75 h

Procedure:
A solution of codeine or codeine phosphate was dissolved in the appropriate solvent system and a specified volume of hydrochloric acid of varying concentration was added. Manganese dioxide (either freshly prepared γ-manganese dioxide or activated manganese dioxide from Aldrich) was added and the reaction mixture was stirred at ambient temperature for 1.5 to 4 hours. The progress of the reaction was monitored by HPLC. The reaction mixture was filtered through a celite pad, washed with additional solvent or water, and neutralised with ammonium hydroxide. The product was extracted with methylene chloride (3×150 ml) and the combined extracts washed with water and dried over anhydrous sodium sulphate. The organic layer was then evaporated to yield codeinone.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]CC2C=CC=CC=2)=[CH:9][CH:8]=1)[CH3:2].CCOC(C)=O>[Pd].CCO>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)COc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)COc1ccc(O)cc1
Reaction time: 4 h
Yield: 98.2 %

Procedure:
Ethyl-4-benzyloxyphenoxyacetate compound (3.50 g, 12.2 mmol) was placed in a PARR bottle along with EtOAc (75 mL), EtOH (75 mL), and 5% Pd/C (1.20 g) and the mixture placed under 40 psi of H2. The reaction was shaken under pressure for 4 hours after which no starting material remained by TLC. The catalyst was removed by filtration through Celite and the filtrate concentrated in vacuo to give 2.35 g (97%) of the desired phenol. MP
Reaction SMILES: [CH2:1]([Sn:5](=O)[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].OC1C=CC(CCC(O)=O)=CC=1>>[CH2:1]([Sn:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[Sn](=O)CCCC
Agent: O=C(O)CCc1ccc(O)cc1
Product: CCCC[Sn]CCCC

Procedure:
Following the procedure of Example 1, dibutyltin oxide was reacted with 33.2 g (0.2 mole) 3-(4-hydroxyphenyl)propionic acid to yield 56 g of dibutyltin bis-(3-(4-hydroxyphenyl)propionatel, a white crystalline material melting at 48°-50° C.
Reaction SMILES: [Li+].[OH-].[I:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[N:13](S(C)(=O)=O)[S:14]([CH3:17])(=[O:16])=[O:15].[NH4+].[Cl-].Cl>C(O)C.O.C(O)C.O>[I:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[NH:13][S:14]([CH3:17])(=[O:16])=[O:15]
Reactant: CS(=O)(=O)N(c1ccc([N+](=O)[O-])cc1I)S(C)(=O)=O
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)Nc1ccc([N+](=O)[O-])cc1I
Temperature: 25 °C

Procedure:
LiOH (0.21 mg, 8.9 mmol) in a mixture ethanol/water 2/1 (18 ml) was added to a solution of N-(2-iodo-4-nitrophenyl)-N-(methylsulfonyl)methanesulfonamide (0.75 g, 1.78 mmol). The reaction mixture was refluxed for two hours. After cooling at room temperature, the reaction mixture was neutralized with H2O, NH4Cl and HCl 2N, then ethanol was eliminated, and the aqueous phase was extracted with ethyl acetate (3×20 ml). The organic solvent was removed by evaporating under reduced pressure to give N-(2-iodo-4-nitrophenyl)methanesulfonamide without further purification.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=[O:12].[ClH:14]>O=[Pt]=O.C(O)(=O)C>[ClH:14].[NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:11]([OH:13])=[O:12]
Reactant: O=C(O)c1ccc2ccccc2n1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)C1CCc2ccccc2N1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
2-Quinolinecarboxylic acid (30 g), glacial acetic acid (500 ml), and PtO2 (0.9 g) were combined and hydrogenated at 50°-58° for 45 minutes. After cooling to room temperature, concentrated hydrochloric acid (35 ml) was added, the catalyst was filtered, and the filtrate evaporated in vacuo. The residue was dissolved in acetonitrile (200 ml) and the solution cooled overnight. The resulting product was filtered; yield 25 g, m.p. 122°-125°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:39])([F:38])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[C:40]([OH:49])(=[O:48])[C@@H:41]([C@H:43]([C:45]([OH:47])=[O:46])[OH:44])[OH:42]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:38])([F:39])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[C:45]([C@@H:43]([C@H:41]([C:40]([O-:49])=[O:48])[OH:42])[OH:44])([O-:47])=[O:46]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc(C(F)(F)F)c2)cn1
Product: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Temperature: 40 °C
Reaction time: 4 h

Procedure:
Nilotinib base (0.300 g, 0.57 mmol) was dissolved in TFE (2 mL) at 40° C. The stirred mixture was added to a solution of L-tartaric acid (0.083 g, 0.57 mmol) in TFE (1 mL) at 40° C. The resulting clear solution was stirred for about 4 h at 40° C. and subsequently cooled to 5° C. and kept at this temperature overnight leading to precipitation. The precipitate was filtered and the filter cake was dried at 40° C. in a vacuum oven overnight to give to give Nilotinib L-tartrate form II.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]([OH:14])=[O:13])[C:6](=[CH:10][CH:11]=1)[C:7]([OH:9])=O.C(OC(=O)C)(=O)C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:12](=[O:13])[O:14][C:7](=[O:9])[C:6]2=[CH:10][CH:11]=1
Reactant: COc1ccc(C(=O)O)c(C(=O)O)c1
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2c(c1)C(=O)OC2=O
Temperature: 25 °C

Procedure:
4-Methoxyphthalic acid (959 gm., 5.06 m) and acetic anhydride (2 l.) were mixed together and warmed to reflux. After 2 hours at reflux the solution was filtered while hot. The filtrate was cooled to room temperature and then it was cooled at -70° C. overnight. The solid precipitate was recovered by suction filtration, washed with petroleum ether (40°-60°) and air dried. wt.=649 gm., m.p. 89°-94° C.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11](=[O:13])[CH3:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14](Cl)/[CH:15]=[CH:16]/[CH2:17]Cl>>[C:1]1([S:7]([C:10]2([C:11](=[O:13])[CH3:12])[CH2:17][CH:16]2[CH:15]=[CH2:14])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)CS(=O)(=O)c1ccccc1
Reactant: ClC/C=C/CCl
Product: C=CC1CC1(C(C)=O)S(=O)(=O)c1ccccc1

Procedure:
Utilizing a phase-transfer procedure similar to that described in Example I, phenylsulfonylacetone was reacted with 1,4-dichlorobutene-2 to obtain 1-phenylsulfonyl-1-acetyl-2-vinylcyclopropane. For the reaction, 9.91 grams phenylsulfonylacetone (Parish Chemical Co.) and 6.25 grams 1,4-dichlorobutene-2 were combined in 20 mls sulfolane containing 6.6 grams potassium hydroxide (85%) and 5 mole percent tricaprylylmethylammonium chloride. The reaction mixture was stirred at 35°-40° C. for 31/2 hours. One-hundred mls water was then added to dissolve the white granular precipitate which had formed and the mixture extracted several times with ether. A crude red oil (10.8 grams) was obtained after removal of the ether and further work-up utilizing a Waters Preparatory Liquid Chromatograph 500A equipped with a gel permeation column and operated at a flow rate of 0.1 l/min yielded the cis and trans isomers of 1-phenylsulfonyl-1-acetyl-2-vinylcyclopropane. ##STR18## trans 1-phenylsulfonyl-1-acetyl-2-vinylcyclopropane
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.S(Cl)(Cl)=O.[CH2:10]([S:13][CH2:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23])=O)[CH2:11][CH3:12]>C(Cl)Cl.C(N(CC)CC)C>[OH:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:15]([C:2]1[NH:1][CH:5]=[CH:4][N:3]=1)=[CH:14][S:13][CH2:10][CH2:11][CH3:12]
Reactant: CCCSCC(=O)c1ccccc1O
Reactant: c1c[nH]cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCCSC=C(c1ncc[nH]1)c1ccccc1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 1.02 g of imidazole, 1.52 g of triethylamine and 30 ml of dry methylene chloride, 1.78 g of thionyl chloride was added with ice-cooling. The resulting mixture was stirred for 30 minutes, followed by addition of 2.42 g of 2-n-propylthio-2'-hydroxyacetophenone and a solution consisting of 1.16 g of triethylamine and 5 ml of dry methylene chloride. The reaction mixture was stirred at room temperature for further 2 hours. Ice water was then added to the reaction mixture, followed by its extraction with methylene chloride. The organic, i.e., methylene chloride layer was washed with water, dried over magnesium sulfate, and then concentrated. The residue was dissolved in chloroform. The chloroform solution was subjected to chromatography on a silica gel column. Upon concentration of the resulting eluate, 0.2 g of Isomer A (Compound 19; m.p. 191°-192° C.) and 1.1 g of Isomer B (Compund 18; m.p. 127°-128° C.) of 1-(2-hydroxyphenyl)-1 -imidazolyl-2-n-propylthioethylene were obtained respectively as colorless crystals.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH:16]=O)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[C:18]1([NH:24][NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CO>[C:18]1([NH:24][N:25]=[CH:16][C:12]2[CH:13]=[CH:14][C:15]3[N:3]([CH2:1][CH3:2])[C:4]4[C:9]([C:10]=3[CH:11]=2)=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NNc1ccccc1
Reactant: CCn1c2ccccc2c2cc(C=O)ccc21
Solvent: CO
Product: CCn1c2ccccc2c2cc(C=NNc3ccccc3)ccc21

Procedure:
9-Ethylcarbazole-3-carbaldehyde (10 g, 0.045 mol, available from Aldrich Chemical, Milwaukee, Wis.) was dissolved in 300 ml of methanol under mild heating. Then, a solution of 7.25 g (0.067 mol) of N-phenylhydrazine (from Aldrich) in methanol was added. The reaction mixture was refluxed for 2 hours to form yellowish crystals. The yellowish crystals were filtered off and washed with a large amount of methanol and dried. The yield of the product, 9-ethyl-3-carbazolecarbaldehyde N-phenylhydrazone, was 13.12 g (92%). The melting point was found to be 136–137° C. The 1H-NMR spectrum (100 MHz) of the product in CDCl3 was characterized by the following chemical shifts (δ, ppm): 1.34 (t, J=7.0 Hz, 3H, CH3); 4.23 (q, J=7.0 Hz, 2H, CH2); 6.90–7.64 (m, 8H, Ar), 7.60 (s, 1H, Ar) 7.81 (dd, 1H, Ar), 8.08 (d, 2H, Ar), 8.15 (d, 1H, ═CH). The IR spectrum of the product was characterized by the following absorption frequencies (KBr, cm−1): ν(N—H) 3306, ν(C—H) 2972, ν(arene C—H) 3051, ν(C═C, C—N in Ar) 1602; 1494; 1475; 1237, ν(C—N) 1256, γ(Ar) 815; 747; 731. The mass spectrum of the product was characterized by the following mass peaks (m/z): 314 (90%, M+1); 222 (100%, H5C12–C12H7N—CH═NH).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=1[OH:12])[CH:2]=[CH2:3].[H][H]>[C].[Pd].CO>[CH2:1]([C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=1[OH:12])[CH2:2][CH3:3]
Reactant: C=CCc1cc(C#N)ccc1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCc1cc(C#N)ccc1O

Procedure:
A mixture of 8.15 g of 2-allyl-4-cyanophenol prepared in Reference Example 1-(ii), 1.5 g of 5% palladium-carbon and 100 ml of methanol, was stirred in a hydrogen stream for 2.5 hours. The catalyst was removed by filtration, and the solvent was distilled off from the filtrate to obtain 7.30 g of the above identified compound as a colorless oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].S(Cl)(Cl)=O.C([O-])(O)=O.[Na+].[CH2:23](O)[CH3:24]>>[CH2:23]([O:12][C:11](=[O:13])[CH2:10][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Br:1])[CH:3]=1)[CH3:24]
Reactant: CCO
Reactant: COc1ccc(CC(=O)O)cc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: CCOC(=O)Cc1ccc(OC)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 3-bromo-4-methoxyphenylacetic acid (24 g, 97.9 mmol) in ethanol (240 mL) was added thionyl chloride (7.8 mL, 107.7 mmol), and the reaction was stirred at room temperature for 1 hour. Once no starting material was seen by analytical LCMS, the mixture was basified with saturated aqueous NaHCO3 and extracted with dichloromethane. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].S(Cl)(Cl)=O.[CH3:18][CH2:19]O>>[CH2:18]([O:12][C:11](=[O:13])[CH2:10][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Br:1])[CH:3]=1)[CH3:19]
Reactant: CCO
Reactant: COc1ccc(CC(=O)O)cc1Br
Solvent: O=S(Cl)Cl
Product: CCOC(=O)Cc1ccc(OC)c(Br)c1
Reaction time: 0.58 h

Procedure:
To 3-bromo-4-methoxyphenylacetic acid (24 g, 97.9 mmol) in EtOH (240 mL) was added thionyl chloride (7.8 mL, 107.7 mmol), and the reaction was stirred for 35 minutes. Once no starting material was seen by analytical LCMS, the mixture was quenched with NaHCO3 until the solution was basic, and then extracted twice with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].[C:6](Cl)(=[O:10])[C:7]([Cl:9])=[O:8]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:10])[C:7]([Cl:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(=O)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
t-Butanol (765 μL, 8.0 mmol) was added dropwise to a solution of oxalyl dichloride (1.0 mL, 12.0 mmol) in DCM (5 mL) at 0° C. The mixture was stirred at room temperature for 1 hour then concentrated in vacuo to yield chloro-oxo-acetic acid t-butyl ester as a clear colorless liquid (1.1 g). A 1 M solution in DCM was prepared by dissolving the liquid (1.1 g, 6.7 mmol) in DCM (6.7 mL).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[N:17]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.O>CS(C)=O>[N+:8]([C:5]1[N:6]=[CH:7][C:2]([N:20]2[CH2:19][CH2:18][N:17]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Temperature: 65 °C
Reaction time: 8 h
Yield: 37.3 %

Procedure:
Into a solution of 5-bromo-2-nitropyridine (30 g, 148 mmol) in DMSO (1 L) were added K2CO3 (40 g, 296 mmol) and tert-butyl piperazine-1-carboxylate (28 g, 148 mmol). The mixture was stirred at 65° C. overnight. After cooling down, it was poured into water (2 L). The solid precipitated was collected and dried under vacuum. It was then further purified by flash column eluting with 20:1 petroleum ether/ethyl acetate and then with methylene chloride to give 101g as a yellow solid (17 g, 37%). MS: [M+H]+ 309.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[O-:13][C:14]#[N:15].[Na+]>C(O)(=O)C.O>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:14]([NH2:15])=[O:13])=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Reactant: N#C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)Nc1ccc(F)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Water (2.5 mL) is added slowly to a mixture of 4-fluoro-3-(trifluoromethyl)aniline (500 mg, 2.79 mmol) in glacial acetic acid (1.5 mL). A solution of sodium cyanate (200 mg, 3.07 mmol) in water (2.5 mL) is added slowly, and the mixture is stirred at room temperature for 4 h. The mixture is extracted twice with dichloromethane, and the combined organic layers are concentrated under reduced pressure. Yield: 588 mg; ESI mass spectrum [M+H]+=223; Retention time HPLC: 0.87 min (Z018_S04).
Reaction SMILES: O=[C:2]1[N:21]([CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2=[N:6][C:7]([C:10]3[CH:11]=[N:12][N:13]4[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][C:14]=34)=[CH:8][CH:9]=[C:4]2[NH:3]1.[C:28](OCC)(OCC)(OCC)C>CCO>[CH3:28][C:2]1[N:21]([CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2=[N:6][C:7]([C:10]3[CH:11]=[N:12][N:13]4[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][C:14]=34)=[CH:8][CH:9]=[C:4]2[N:3]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: N#Cc1ccn2ncc(-c3ccc4[nH]c(=O)n(C5CCOCC5)c4n3)c2c1
Solvent: CCO
Product: Cc1nc2ccc(-c3cnn4ccc(C#N)cc34)nc2n1C1CCOCC1
Temperature: 145 °C
Reaction time: 2.5 h
Yield: 15 %

Procedure:
To a solution of the compound obtained in example 2 section d (56.4 mg, 0,169 mmol) in EtOH (1.5 mL), PTSA monohydrate (3.21 mg, 0.017 mmol) and triethyl orthoacetate (547 mg, 3.37 mmol) were added. The reaction mixture was heated in a OEM Explorer microwave oven at 145° C. and 270 W for 2.5 hours. The crude residue was chromatographed on a silica gel flash system (ISCO Rf) using CH2Cl2/MeOH mixtures of increasing polarity a eluent to afford the desired product (15% yield).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH:12]1[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]1.[OH-].[Na+].Cl>O.O1CCOCC1>[CH2:5]([O:4][C:2]([N:12]1[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OC1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(OCc1ccccc1)N1CCC(O)CC1

Procedure:
Benzyl chloroformate (8.55 mL; 60 mmol) was added drop wise over a period of 30 min to a well stirred chilled mixture of piperidin-4-ol (5 g; 49.44 mmol), 1N aqueous NaOH (60 mL; 60 mmol) and dioxane (60 mL). The mixture was stirred for 30 min. at room temperature, treated with water, acidified with conc. HCl to pH 2 and extracted with EtOAc. The EtOAc layer was washed with water, brine, dried (Na2SO4), concentrated and purified using flash chromatography (silica gel, 50% CH2Cl2 in PE 60-80° C., 10% CH3CN+2% MeOH in chloroform). Yield, 12.5 g (99%), oil; MS (CI): 236 (M++1). 218, 192, 174, 91.