Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[N:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[N:16]([CH3:17])[C:15]4[CH:18]=[CH:19][C:20]([C:22]([NH:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[O:23])=[CH:21][C:14]=4[N:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[H][H].Cl>[Pd].CO>[NH2:2][CH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[N:16]([CH3:17])[C:15]4[CH:18]=[CH:19][C:20]([C:22]([NH:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[O:23])=[CH:21][C:14]=4[N:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1
Reactant: COC(=O)CCNC(=O)c1ccc2c(c1)nc(-c1ccc3c(c1)CCC3=NO)n2C
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)CCNC(=O)c1ccc2c(c1)nc(-c1ccc3c(c1)CCC3N)n2C

Procedure:
Prepared from 2-(1-hydroxyimino-5-indanyl)-5-[(2-methoxycarbonyl-ethyl)-aminocarbonyl]-1-methyl-benzimidazole by reduction with 5 bars of hydrogen in a 50:1 mixture of methanol and methanolic hydrochloric acid at ambient temperature in the presence of 10% palladium/charcoal.
Reaction SMILES: [F:1][CH:2]([F:11])[C:3](=O)[CH2:4][C:5]([O:7]CC)=O.Cl.[C:13](=[NH:18])([NH2:17])[CH2:14][CH2:15][CH3:16].C[O-].[Na+]>CO.C(OCC)(=O)C>[F:11][CH:2]([F:1])[C:3]1[N:17]=[C:13]([CH2:14][CH2:15][CH3:16])[NH:18][C:5](=[O:7])[CH:4]=1
Reactant: CCOC(=O)CC(=O)C(F)F
Reactant: CCCC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCc1nc(C(F)F)cc(=O)[nH]1
Reaction time: 8 h
Yield: 98.9 %

Procedure:
A mixture of ethyl 4,4-difluoro-3-oxobutanoate (5.0 g), butanimidamide hydrochloride (4.1 g) and sodium methoxide (28% methanol solution, 15 mL) in methanol (50 mL) was stirred overnight. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale yellow oil (5.6 g, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)=O)=O)=[CH:4][CH:3]=1.[C:19]1([NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH2:25].C(Cl)(Cl)Cl>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=3)=[N:26][C:19]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:25]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccccc1N
Reactant: O=C(C(=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: Brc1ccc(-c2nc3ccccc3nc2-c2ccc(Br)cc2)cc1
Temperature: 80 °C

Procedure:
In a 500 mL three-necked flask were placed 30 g (82 mmol) of 4,4′-dibromobenzil, 9.3 g (86 mmol) of 1,2-phenylenediamine, and 300 mL of chloroform. This solution was refluxed at 80° C. for 5 hours under a stream of nitrogen. After a predetermined time, the solution was cooled to room temperature, and water was added thereto. This aqueous layer was extracted with chloroform, and the extracted solution was combined with the organic layer and then dried with magnesium sulfate. After drying, the mixture was subjected to suction filtration and the filtrate was concentrated. The obtained solid was dissolved in toluene, and this solution was subjected to suction filtration through Florisil (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 540-00135), Celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855) and alumina. The filtrate was concentrated, and 30 g of a white powder of 2,3-bis(4-bromophenyl)quinoxaline, which was a target substance, was obtained at a yield of 99%.
Reaction SMILES: [CH3:1][C:2](O)([CH2:4][CH:5](O)[CH3:6])[CH3:3].[CH2:9]([C:12]1[C:18]([OH:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:13]=1[OH:14])[CH2:10][CH3:11].C(OC(C)C)(C)C.S(=O)(=O)(O)O>>[OH:19][C:18]1[C:12]([CH2:9][CH2:10][CH3:11])=[C:13]2[C:15]([CH:5]([CH3:6])[CH2:4][C:2]([CH3:3])([CH3:1])[O:14]2)=[C:16]([CH3:20])[CH:17]=1
Reactant: CC(O)CC(C)(C)O
Reactant: CCCc1c(O)cc(C)cc1O
Agent: O=S(=O)(O)O
Solvent: CC(C)OC(C)C
Product: CCCc1c(O)cc(C)c2c1OC(C)(C)CC2C
Yield: 72.6 %

Procedure:
An amount of 1.77 g. of 2-methylpentane-2,4-diol were added dropwise at the temperature of approximately 60° C. to a mixed solution prepared from 2.49 g. of 2-propyl-5-methyl resorcinol, 15 ml of isopropyl ether and 1 ml of concentrated sulfuric acid. The solution was cooled, and successively washed with water, aqueous 1 N sodium hydroxide solution, and again with water, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by subjecting to column chromatography filled with silica gel. There were thus obtained 2.7 g. (yield: 72.6%) of the subject compound in oily form.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([O:9][CH2:10][C:11]([N:13]=[C:14]([NH:17][C:18]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)=[O:19])[S:15][CH3:16])=O)(=[O:8])[CH3:7]>C(Cl)(Cl)Cl>[C:6]([O:9][CH2:10][C:11]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[C:18](=[O:19])[N:17]=[C:14]([S:15][CH3:16])[N:13]=1)(=[O:8])[CH3:7]
Reactant: CSC(=NC(=O)COC(C)=O)NC(=O)NCc1ccc(Cl)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CSc1nc(COC(C)=O)n(Cc2ccc(Cl)cc2)c(=O)n1
Temperature: 80 °C
Reaction time: 3 h
Yield: 104.6 %

Procedure:
A phosphorus oxychloride solution (3.0 mL) of 2-({[3-(4-chlorobenzyl)ureido](methylthio)methylene}amino)-2-oxoethyl acetate (201 mg, 0.616 mmol) synthesized in Reference Synthesis Example 327 was stirred at 80° C. for 3 hours. After completion of the reaction, the reaction solution was added to chloroform-saturated sodium bicarbonate aqueous solution and extraction from the resultant mixture with chloroform was performed. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1→0/1) to obtain the title compound (219 mg, quantitative).
Reaction SMILES: Br[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:9][S:10]([C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1)(=[O:12])=[O:11].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>CC#N.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:6]2[N:7]=[CH:2][C:3]([NH2:8])=[N:4][CH:5]=2)=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Nc1nccnc1Br
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(-c2cnc(N)cn2)cc1
Temperature: 60 °C
Yield: 88 %

Procedure:
Bromopyrazin-2-amine (2.0 g, 11.49 mmol), (4-methylsulfonylphenyl)boronic acid (2.758 g, 13.79 mmol) and K3PO4 (4.878 g, 22.98 mmol) were combined in MeCN (40 mL)/Water (10 mL) and Pd[P(tBu)3]2 (216 mg, 0.4227 mmol) was added. The reaction was heated at 60° C. for 1 hour. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was triturated with water, then Et2O then dried in vacuo to give the sub-title compound as a beige solid which was used without further purification (2.53 g, 88% Yield). 1H NMR (400.0 MHz, DMSO) δ 3.20 (s, 3H), 6.80 (br s, 2H), 7.94 (d, 2H), 8.00 (d, 1H), 8.17 (d, 2H) and 8.64 (d, 1H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:23](=[O:33])[NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)=[CH:20][C:21]=1[Br:22])=[O:16])[CH2:5][NH:6]C(OC(C)(C)C)=O.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>C(Cl)Cl>[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[CH3:1][O:2][C:3](=[O:34])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:23](=[O:33])[NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)=[CH:20][C:21]=1[Br:22])=[O:16])[CH2:5][NH2:6]
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1Br
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](CN)NC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-2-{[3-Bromo-5-(3-hydroxy-benzylcarbamoyl)-thiophene-2-carbonyl]-amino}-3-tert-butoxycarbonylamino-propionic acid methyl ester (0.142 g, 0.26 mmol) in DCM (5 mL) was added TFA (0.5 mL). The mixture was stirred at room temperature 1 h and evaporated to give crude product which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([O:10]C)=[O:9])=[C:6]([C:12]([F:15])([F:14])[F:13])[CH:5]=[C:4]([CH3:16])[N:3]=1.[OH-].[K+].[ClH:19]>C(O)C>[ClH:19].[CH3:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([C:12]([F:14])([F:13])[F:15])[CH:5]=[C:4]([CH3:16])[N:3]=1
Reactant: COC(=O)c1c(C(F)(F)F)cc(C)nc1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C(F)(F)F)c(C(=O)O)c(C)n1

Procedure:
Methyl 2,6-dimethyl-4-trifluoromethylpyridine-3-carboxylate (23.30 g, 99.9 mmol) was dissolved in ethanol (50 mL). A 5-mol/L aqueous potassium hydroxide solution (50 mL, 250 mmol) was added to the solution, followed by refluxing for 2 days. The reaction mixture was allowed to stand for cooling, and concentrated hydrochloric acid (15 mL) was added to the resultant mixture, followed by concentration under reduced pressure. To the obtained residue, ethanol was added, and the mixture was heated for dissolution. Insoluble matter was removed through filtration, and the filtrate was concentrated under reduced pressure. Ether was added to the thus-obtained residue, and the solid was collected through filtration, to thereby yield 2,6-dimethyl-4-trifluoromethylpyridine-3-carboxylic acid hydrochloride as a colorless powder (25.24 g, 99%).
Reaction SMILES: O[CH2:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:5][CH:4]=1.P(Br)(Br)[Br:20]>C(Cl)Cl>[Br:20][CH2:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:5][CH:4]=1
Reactant: BrP(Br)Br
Reactant: O=C(COc1ccc(CO)cc1)c1ccccc1
Solvent: ClCCl
Product: O=C(COc1ccc(CBr)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
To a 50 mL RB flask charged with 2-[4-(hydroxymethyl)phenoxy]-1-phenylethanone (10 g, 41.2 mmol) in DCM was added phosphorus tribromide (16.76 g, 61.9 mmol) in drops over period of 5 min at 0° C. Reaction mixture was stirred at RT for 1 h and then quenched with ice-water. Diluted it with excess DCM, washed with water, sat.NaHCO3 solution and brine solution successively. Organic phase was dried over anhydrous Na2SO4 and concentrated to afford product (9 g, Yield: 71.4%); 1H NMR (300 MHz, DMSO-d6): δ 7.90-7.93 (t, 2H), 7.53-7.58 (t, 1H), 7.41-7.46 (t, 2H), 7.23-7.26 (d, 2H), 6.81-6.84 (t, 2H), 5.20 (s, 2H), 4.40 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[O:5]C1CCCOC1.[C:15]([C:17]1[CH:18]=[C:19]([CH:27]=[CH:28][CH:29]=1)[O:20]C1CCCOC1)#[CH:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:20][C:19]1[CH:18]=[C:17]([C:15]#[C:16][C:2]2[CH:14]=[CH:13][CH:12]=[C:4]([OH:5])[CH:3]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: C#Cc1cccc(OC2CCCOC2)c1
Reactant: Brc1cccc(OC2CCCOC2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: Oc1cccc(C#Cc2cccc(O)c2)c1

Procedure:
Following the above procedure, the reaction was performed with 3-(3-bromophenoxy)tetrahydropyran (2.57 g), 3-(3 -ethynylphenoxy)tetrahydropyran (2.02 g), triphenylphosphine (105 mg), copper(I) iodide (19 mg) and bis(triphenylphosphine)palladium(II) dichloride (70 mg) in triethylamine (40 ml). The crude dark residue obtained after filtration over silica-gel column is dissolved in a mixture of dichloromethane (10 ml) and methanol (40 ml), then treated with 150 mg pyridinium p-toluene sulphonate at 60° C. for 2 h. The transparent reaction solution was then diluted with 100 ml of ether and washed twice with 40 ml of water then with 50 ml of saturated NaCl solution, dried over MgSO4 and evaporated to dryness to afford 1,2-bis-(3-hydroxyphenyl)ethyne as yellowish solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[CH:8]=[C:9]([NH:24][C:25]([C:27]2[C:32]([CH3:33])=[N:31][CH:30]=[CH:29][N:28]=2)=[O:26])[CH:10]=[CH:11][C:12]=1[C:13]([O:22][CH3:23])([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15])[CH:4]([CH3:6])[CH3:5].[C:34](Cl)(=[O:36])[CH3:35].Cl>C1COCC1>[C:34]([N:24]([C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:22][CH3:23])([C:18]([F:20])([F:21])[F:19])[C:14]([F:17])([F:16])[F:15])=[C:7]([CH2:3][CH:4]([CH3:6])[CH3:5])[CH:8]=1)[C:25]([C:27]1[C:32]([CH3:33])=[N:31][CH:30]=[CH:29][N:28]=1)=[O:26])(=[O:36])[CH3:35]
Reactant: COC(c1ccc(NC(=O)c2nccnc2C)cc1CC(C)C)(C(F)(F)F)C(F)(F)F
Reactant: CC(=O)Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(c1ccc(N(C(C)=O)C(=O)c2nccnc2C)cc1CC(C)C)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.4 %

Procedure:
Sodium hydride (32 mg, 60% by weight, 0.8 mmol) was suspended in THF (10 ml) and a THF (5 ml) solution of N-{3-isobutyl-4-[1-methoxy-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]phenyl}-3-methylpyrazine-2-carboxamide (300 mg, 0.67 mmol) was added dropwise thereto. The reaction solution was stirred at room temperature for 30 minutes, and was added with a THF (2 ml) solution of acetyl chloride (63 mg, 0.8 mmol) and stirred overnight. The reaction solution was poured into a diluted HCl solution, followed by extracting with ethyl acetate, and washing with water. The solution was dried over magnesium sulfate, and concentrated under reduced pressure, and then the residue was purified by using silica gel chromatography (hexane:ethyl acetate=3:1) to obtain 0.10 g of the desired compound.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([N:6]=[CH:7][C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C[Si]([C:22]#[N:23])(C)C>>[F:1][C:2]1[CH:17]=[CH:16][C:5]([NH:6][CH:7]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=2)[C:22]#[N:23])=[CH:4][CH:3]=1
Reactant: CSc1ccc(C=Nc2ccc(F)cc2)cc1
Reactant: C[Si](C)(C)C#N
Product: CSc1ccc(C(C#N)Nc2ccc(F)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(i), but using 4-methylthiobenzaldehyde and 4-fluoroaniline as starting materials, 4-fluoro-N-(4-methylthiobenzylidene)aniline was obtained in a yield of 89%. This aniline compound and trimethylsilyl cyanide were then reacted together in a similar manner to that described in Example 1(ii), to give the title compound as a slightly yellow powder (yield 47%).
Reaction SMILES: C(=O)([O-])O[CH2:3][CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1>>[C:4]([CH:5]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([O:15][CH3:14])[CH:17]=1)#[CH:3]
Reactant: COc1cccc(N)c1
Reactant: O=C([O-])OCC=Cc1ccccc1
Product: C#CC(Nc1cccc(OC)c1)c1ccccc1
Reaction time: 12 h
Yield: 82.6 %

Procedure:
The general procedure was followed with cinnamyl carbonate (0.188 g, 0.979 mmol) and m-anisidine (0.150 g, 1.22 mmol). The reaction was conducted at room temperature for 12 h. 1H NMR analysis of the crude reaction mixture indicated the ratio of regioisomers to be 97/3. The mixture was purified by flash column chromatography on silica gel (4% ethyl acetate in hexanes) to give the title compound (0.192 g, 82%). [α]DRT=(c, CHCl3). 1H NMR (400.13 MHz, CDCl3) δ 7.50-7.40 (m, 4H), 7.36 (tt, J=6.8, 2.0 Hz, 1H), 7.14 (t, J=8.0 Hz, 1H), 6.37 (dd, J=8.0, 2.4 Hz, 1H), 6.32 (dd, J=8.4, 2.0 Hz, 1H), 6.12 (ddd, J=16.8, 10.0, 6.0 Hz, 1H), 5.37 (dt, J=16.8, 1.4 Hz, 1H), 5.32 (dt, J=10.4, 1.4 Hz, 1H), 5.03 (br s, 1H), 4.18 (br s, 1H), 3.79 (s, 3H). 13C NMR (100.59 MHz, CDCl3) δ 160.50, 148.47, 141.68, 138.84, 129.71, 128.63, 127.35, 127.02, 115.98, 106.53, 102.62, 99.46, 60.71, 54.85. Anal. Calcd for C16H17NO: C, 80.30; H, 7.16; N, 5.85. Found: C, 80.17; H, 7.24; N, 5.78.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[N:26]=[CH:25][NH:24][N:23]=2)=[N:10]1.Cl.[NH:28]1[CH2:33][CH2:32][O:31][C@@H:30]([CH2:34][OH:35])[CH2:29]1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][N:28]2[CH2:33][CH2:32][O:31][C@@H:30]([CH2:34][OH:35])[CH2:29]2)[NH:12][C:11]([C:22]2[N:26]=[CH:25][NH:24][N:23]=2)=[N:10]1
Reactant: OC[C@H]1CNCCO1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nc[nH]n2)=NC1c1ccc(F)cc1Br
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCO[C@@H](CO)C2)NC(c2nc[nH]n2)=NC1c1ccc(F)cc1Br
Yield: 51.2 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(1H-1,2,4-triazol-3-yl)-1,4-dihydropyrimidine-5-carboxylate (0.75 g, 1.53 mmol) was reacted with (R)-morpholin-2-ylmethanol hydrochloride (0.24 g, 1.53 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a yellow solid (0.41 g, 51%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.Cl[C:15]1[C:16]2[S:33][C:32]([NH2:34])=[N:31][C:17]=2[N:18]=[C:19]([S:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=2[F:30])[N:20]=1>>[NH2:34][C:32]1[S:33][C:16]2[C:15]([NH:1][C@@H:2]3[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]3)=[N:20][C:19]([S:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=3[F:30])=[N:18][C:17]=2[N:31]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: Nc1nc2nc(SCc3cccc(F)c3F)nc(Cl)c2s1
Product: CC(C)(C)OC(=O)N1CC[C@@H](Nc2nc(SCc3cccc(F)c3F)nc3nc(N)sc23)C1

Procedure:
Prepared by the method of example 18 step a) using (R)-3-amino-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester and the product of example 4 step b).
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5]([CH:7]1[CH2:20][C:11]2[S:12][C:13]([C:15](OCC)=[NH:16])=[CH:14][C:10]=2[CH2:9][CH2:8]1)=[O:6])[CH3:3].[NH3:21]>CCO>[ClH:1].[C:15]([C:13]1[S:12][C:11]2[CH2:20][CH:7]([C:5]([O:4][CH2:2][CH3:3])=[O:6])[CH2:8][CH2:9][C:10]=2[CH:14]=1)(=[NH:16])[NH2:21]
Reactant: N
Reactant: CCOC(=N)c1cc2c(s1)CC(C(=O)OCC)CC2
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1CCc2cc(C(=N)N)sc2C1

Procedure:
6-Ethoxycarbonyl-2-(1-ethoxy-1-iminomethyl)-4,5,6,7-tetrahydrobenzo[b]thiophene hydrochloride (1.51 g), 2.7 N ethanol solution of ammonia (1.41 ml) and EtOH (5 ml) was stirred at reflux for 4 hours. After evaporation, the resulting oil was purified by chromatography on silica gel (CHCl3 -MeOH as eluent), and subsequently washed with Et2O to give 2-amidino-6-ethoxycarbonyl-4,5,6,7-tetrahydrobenzo[b]thiophene hydrochloride (1.20 g).
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:5]=2[O:4][N:3]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>CO>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:6]2[C:2]([CH:20]3[CH2:21][NH:22][CH2:23][CH2:24][N:19]3[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=3)=[N:3][O:4][C:5]=2[CH:10]=1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: COc1ccc2c(Cl)noc2c1
Solvent: CO
Product: COc1ccc2c(C3CNCCN3c3ccccn3)noc2c1
Temperature: 140 °C
Yield: 34.5 %

Procedure:
A sealed tube was charged with 3-chloro-6-methoxy-1,2-benzisoxazole (0.25 g, 1.4mmol) and 1-(2-pyridyl)piperazine (0.67 g, 4 mmol) and heated to 140° C. overnight. The reaction was cooled to room temperature, diluted with methanol, and concentrated in vacuo. The material was flash chromatographed (silica gel) eluting with CH2Cl2. The material was further purified through recrystallization from 1,2-dichloroethane/pet. ether to afford 0.15 g of the product, m.p.=123°-124° C.
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=1)[O:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].ClC1C=C(C=CC=1)C(OO)=[O:31]>C(Cl)Cl>[OH:1][CH:2]([C:8]1[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=1)[O:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N+:14]=1[O-:31])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCC(O)c1cccc(OCc2ccc3ccccc3n2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCCCC(O)c1cccc(OCc2ccc3ccccc3[n+]2[O-])c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 37.9 %

Procedure:
A mixture of 5.0 g (0.015 mol) 2-[3-(1-hydroxyhexyl)phenoxymethyl]quinoline and 3.0 g (0.017 mol) m-chloroperoxybenzoic acid in 100 ml CH2Cl2 was stirred at room temperature for a period of 24 hours. The reaction mixture was extracted with dilute NaHCO3 solution, washed with water, dried over MgSO4 and concentrated to dryness under reduced pressure. The residue was triturated with large amounts of ether to obtain a solid. This solid was filtered, washed with ether and dried to give the desired compound (2 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:9][C:3]1[CH:4]=[C:5]([OH:8])[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(O)cc1N
Yield: 99.3 %

Procedure:
10 g of 4-amino-3-nitrophenol in 180 ml of ethanol were hydrogenated under 40 bars pressure at 23° C. temperature with catalytic amound of palladium on carbon. Reaction was performed in an Inox flask for high pressure. After hydrogen uptake was complete, the catalyst was filtered off with suction, washed with methanol and the filtrate was concentred under reduced pressure yielding 8 g of crude 3,4-diaminophenol.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C@@H:17]2[O:35][C@H:18]2C2C=CC(OC)=C(OCC3C=CC=CC=3)C=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl.[CH3:39][O:40][CH:41]([O:45][CH3:46])[CH2:42][NH:43][CH3:44]>CC(O)CC>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C@H:17]([OH:35])[C@@H:18]([C:11]2[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:10]=2)[N:43]([CH2:42][CH:41]([O:45][CH3:46])[O:40][CH3:39])[CH3:44])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc([C@@H]2O[C@H]2c2ccc(OC)c(OCc3ccccc3)c2)cc1OCc1ccccc1
Reactant: CNCC(OC)OC
Solvent: CCC(C)O
Solvent: ClCCl
Product: COc1ccc([C@H]([C@@H](O)c2ccc(OC)c(OCc3ccccc3)c2)N(C)CC(OC)OC)cc1OCc1ccccc1

Procedure:
Mixture: 51.7 g (0.11 mol) of rel-(S,S)-3,3'-dibenzyloxy-4,4'-dimethoxystilbene oxide, 1800 ml of dichloromethane, 100 ml of 2-butanol, 25 ml (0.19 mol) of methylaminoacetaldehyde dimethyl acetal, 5 g of silica gel
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[CH:8][C:9]([CH:12](O)[CH3:13])=[N:10][CH:11]=2)=[CH:2]1.P(Br)(Br)[Br:16]>C(Cl)(Cl)Cl.C(OCC)(=O)C.C(=O)(O)[O-]>[Br:16][CH:12]([C:9]1[CH:8]=[CH:7][C:6]([C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)=[CH:11][N:10]=1)[CH3:13]
Reactant: BrP(Br)Br
Reactant: CC(O)c1ccc(-c2ccoc2)cn1
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(Br)c1ccc(-c2ccoc2)cn1
Temperature: 2.5 °C
Yield: 73.8 %

Procedure:
To a solution of 1-(5-(furan-3-yl)pyridin-2-yl)ethanol (0.075 g, 0.403 mmol) in chloroform (5 ml) was added PBr3 (0.321 g, 1.209 mmol), at 0-5° C., the reaction maintained at the same temperature for 15 min, the reaction was slowly warmed to rt and was maintained at rt for another 2 h. The contents were diluted with ethyl acetate (100 mL), bicarbonate solution (10 mL) was added, the organic layer was separated, the organic layer dried over sodium sulphate and distilled to provide 2-(1-bromoethyl)-5-(furan-3-yl)pyridine (0.075 g, 75% yield). LC-MS m/z calcd for [M+H]+ 253.99. found 254.0.