Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[CH2:4][NH:5][C:6]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[S:7].C(#N)C.P(Cl)(Cl)(Cl)=O>C(OCC)(=O)C>[CH3:1][NH:2][C:3]1[S:7][C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][CH:4]=1
Reactant: CNC(=O)CNC(=S)c1cccnc1
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CNc1cnc(-c2cccnc2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.9 %

Procedure:
To a dry 2 L round bottom flask equipped with mechanical stirrer, addition funnel and reflux condenser was charged N-methyl-2-(pyridine-3-carbothioamido)acetamide (100 g, 478 mmol) and acetonitrile (1 L). To this mixture was added phosphorus oxychloride (256 g, 1672 mmol) portionwise over 10 minutes. The reaction mixture was stirred at ambient temperature for 10 minutes during which time a slight exotherm occurred from 22° C. to 34° C. The reaction mixture was heated to 85° C. (refluxing gently). After 3 hours, all of the solid had dissolved, forming a dark amber solution. Analysis of an aliquot by TLC (70% ethyl acetate : 30% hexanes) after 4 hours indicated that the reaction was essentially complete. The reaction mixture was allowed to cool to 25° C. and the solvent removed by rotary evaporation. The residue was dissolved in water and treated with solid sodium bicarbonate until slightly basic (pH˜8) with continuous stirring. A brown precipitate started to form after a few minutes. The mixture was continued to stir at 25° C. for 16 hours. The brown solid was collected by vacuum filtration and washed with water. This gave a tan solid wet cake (91 g) which was then dried in vacuo at 40° C. to a constant weight. This gave N-methyl-2-(pyridin-3-yl)thiazol-5-amine as a sand colored solid (68.5 g, 75% yield); mp 140-141° C.; 1H NMR (400 MHz, CDCl3) δ 8.98 (dd, J=2.3, 0.7 Hz, 1H), 8.53 (dd, J=4.8, 1.6 Hz, 1H), 8.07 (ddd, J=8.0, 2.2, 1.7 Hz, 1H), 7.40-7.21 (m, 1H), 6.96 (s, 1H), 4.18 (s, 1H), 2.96 (s, 3H); 13C NMR (101 MHz, CDCl3) δ153.23, 149.15, 146.54, 132.23, 130.47, 123.65, 121.20, 34.48; Anal. Calc'd. for C9H9N3S: C, 56.52; H, 4.74; N, 21.97; S, 16.77. Found: C, 56.31: H, 4.74; N, 21.81; S, 16.96.
Reaction SMILES: [Mg].[CH2:2]([N:4]([CH2:19][CH3:20])[CH2:5][CH2:6][CH2:7][NH:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2Cl)[NH:11][N:10]=1)[CH3:3].C(Br)(C)C.O=O.C(=O)=[O:28].S(=O)(=O)(O)O>O.C(OCC)C>[CH2:2]([N:4]([CH2:19][CH3:20])[CH2:5][CH2:6][CH2:7][NH:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[OH:28])[NH:11][N:10]=1)[CH3:3]
Reactant: CCN(CC)CCCNc1n[nH]c2cccc(Cl)c12
Reactant: O=C=O
Agent: O=O
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Solvent: O
Solvent: CC(C)Br
Product: CCN(CC)CCCNc1n[nH]c2cccc(O)c12
Reaction time: 12 h
Yield: 41 %

Procedure:
To 20 ml of diethyl ether solution containing 600 mg of magnesium powder was added dropwise a mixed solution consisting of 2.81 g of the 3-(3-diethylaminopropylamino)-4-chloroindazole, 2.06 g of isopropyl bromide and 20 ml of diethyl ether. Into the solution were introduced dried oxygen gas and dried carbon dioxide gas for 10 hours so as to reflux the solution, and the solution was left to stand for 12 hours. The pH of the solution was adjusted to 4.0 by adding dropwise sulfuric acid to the solution at 0° C. The solution was added with 50 ml of water and filtered. To the aqueous layer of the filtrate was added an aqueous potassium carbonate solution to separate crystals. The crystals were obtained by filtration and dried to give 1.08 g of 3-(3-diethylaminopropylamino)-4-hydroxyindazole having the following analytical values in a yield of 41%.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2([C:15](=[O:24])[CH2:16][S:17][CH2:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[CH2:14][CH2:13][CH2:12]2)[CH:7]=[CH:8][C:9]=1[Cl:10].C(O)C>CO.O>[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2([CH:15]([OH:24])[CH2:16][S:17][CH2:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[CH2:14][CH2:13][CH2:12]2)[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: CN(C)CCCSCC(=O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCO
Product: CN(C)CCCSCC(O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Temperature: 25 °C
Reaction time: 168 h

Procedure:
Sodium borohydride (3.2 g) was added in portions at 0° C. under nitrogen to a stirred solution of 1-[1-(3,4-dichlorophenyl)cyclobutyl]-2-[3-(dimethylamino)-propylthio]ethanone (16 g, prepared by basification of the hydrochloride salt obtained in a similar manner to that described in Example 7) in methanol (200 ml) then the mixture was stirred at ambient temperature for 7 days and diluted with water (350 ml). The product was extracted into dichloromethane (4×100 ml) and the extracts washed with water (100 ml) and saturated aqueous sodium chloride solution (100 ml), dried over sodium sulphate and the solvent removed in vacuo to leave a green oil. The oil was resolved via preparative scale chiral high performance liquid chromatography to give (-)-1-[1-(3,4-dichlorophenyl)cyclobutyl]-2-[3 -(dimethylamino)propylthio]ethanol as an oil (3.5 g), [α]rtD =-8.615° (C=1;ethanol) and (+)-1-[1-(3 4-dichlorophenyl)cyclobutyl]-2-[3-(dimethylamino) propylthio]ethanol as an oil (3.4 g), [α]rtD =+9.740° (C=1; ethanol).
Reaction SMILES: C([N:4]1[CH2:8][CH2:7][N:6]=[C:5]1[NH:9][C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:13]=[C:12]([CH3:21])[CH:11]=1)(=O)C.[ClH:22]>CO>[ClH:22].[CH3:21][C:12]1[CH:11]=[C:10]([NH:9][C:5]2[NH:6][CH2:7][CH2:8][N:4]=2)[N:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:13]=1
Reactant: CC(=O)N1CCN=C1Nc1cc(C)nn1-c1ccccc1
Agent: Cl
Solvent: CO
Product: Cc1cc(NC2=NCCN2)n(-c2ccccc2)n1

Procedure:
1-Acetyl-2-(3-methyl-1-phenyl-5-pyrazolyl) amino-2-imidazoline (35.0 g.) was treated with HCl in methanol as described in Example II to give 28.7 g. product as the hydrochloride. mp 182°-184°.
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH2:10][C:11]([OH:14])([CH3:13])[CH3:12])=[CH:8][C:7]([C:15]#[N:16])=[N:6]1)[CH2:2][CH2:3][CH3:4].C([O-])(=O)C.[K+].[Br:22]Br>>[CH2:1]([N:5]1[C:9]([CH2:10][C:11]([OH:14])([CH3:12])[CH3:13])=[C:8]([Br:22])[C:7]([C:15]#[N:16])=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: BrBr
Reactant: CCCCn1nc(C#N)cc1CC(C)(C)O
Agent: CC(=O)[O-]
Agent: [K+]
Product: CCCCn1nc(C#N)c(Br)c1CC(C)(C)O
Temperature: 0 °C
Yield: 53.5 %

Procedure:
The method described in Part F of Examples 1 through 4 was used to treat 1-butyl-5-(2-hydroxy-2-methylpropyl)-1H-pyrazole-3-carbonitrile (18 g, 81 mmol) with potassium acetate (16.7 g, 171 mmol) and bromine (4.6 mL, 89 mmol). After the acetic acid was removed under reduced pressure, the residue was diluted with dichloromethane (100 mL) and adjusted to pH 12 with the addition of 50% w/w aqueous sodium hydroxide and ice while maintaining the temperature at 0° C. The resulting mixture was extracted with dichloromethane, and the combined extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography on a HORIZON HPFC system (601 cartridge, eluting with 0 to 50% ethyl acetate in hexanes to provide 13 g of 1-butyl-4-bromo-5-(2-hydroxy-2-methylpropyl)-1H-pyrazole-3-carbonitrile as a yellow oil.
Reaction SMILES: [CH:1]1([C:4]2[C:12]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:11][C:10]3[C:6](=[C:7]([C:25]([NH:27][CH3:28])=[O:26])[N:8]([C:18]4[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=4)[N:9]=3)[CH:5]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][CH2:37][OH:38]>C(#N)C>[CH:1]1([C:4]2[C:12]([N:13]([CH2:36][CH2:37][OH:38])[S:14]([CH3:17])(=[O:15])=[O:16])=[CH:11][C:10]3[C:6](=[C:7]([C:25]([NH:27][CH3:28])=[O:26])[N:8]([C:18]4[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=4)[N:9]=3)[CH:5]=2)[CH2:2][CH2:3]1
Reactant: CNC(=O)c1c2cc(C3CC3)c(NS(C)(=O)=O)cc2nn1-c1ccc(C)cn1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CNC(=O)c1c2cc(C3CC3)c(N(CCO)S(C)(=O)=O)cc2nn1-c1ccc(C)cn1
Temperature: 85 °C
Reaction time: 0.17 h
Yield: 15 %

Procedure:
To a solution of Compound (1) (300 mg, 0.75 mmol) in ACN (6 mL) was added potassium carbonate (311 mg, 2.25 mmol) followed by 2-bromoethanol (91.8 μL, 1.30 mmol). The mixture was heated at 85° C. (a thick precipitate was observed after 10 min) and stirred overnight. More potassium carbonate (300 mg, 2.17 mmol) and 2-bromoethanol (90 μL, 1.27 mmol) were added and the mixture was stirred at 90° C. for another 24 hr. The mixture was cooled to RT and the volatiles were removed in vacuo. The residue was suspended in EtOAc (10 mL) and the organics washed with water (10 mL), brine (10 mL) and dried (MgSO4). The volatiles were removed in vacuo and approximately one sixth of the residue was subjected to column chromatography on silica gel eluting with MeOH:DCM (gradient elution, 0% to 10%) to give partially purified material (50 mg). This material was purified further by column chromatography using C18-reverse phase preparative LCMS eluting with ACN:0.1% formic acid in water (gradient elution, 5% to 100% v/v) to give Compound (2) (7.23 mg). ESI-MS m/z calculated for [M+H]+: 444.2. found: 444.2. 1H NMR (400 MHz, CDCl3) δ 8.51-8.43 (m, 1H), 8.36 (d, J=0.8 Hz, 1H), 7.82-7.71 (m, 3H), 7.51 (s, 1H), 4.11 (dt, J=11.9, 5.6 Hz, 1H), 3.82-3.76 (m, 2H), 3.76-3.67 (m, 1H), 3.18 (s, 3H), 3.05 (d, J=4.8 Hz, 3H), 2.47 (s, 3H), 2.30 (tt, J=8.3, 5.6 Hz, 1H), 1.06-0.96 (m, 2H), 0.96-0.87 (m, 1H), 0.54-0.41 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[N:10][C:9]2[C:8](=[O:12])[NH:7][CH:6]=[N:5][C:4]=2[CH:3]=1.Br[CH2:14][CH2:15][O:16][CH3:17].C([O-])([O-])=O.[K+].[K+]>CC(C)=O.CN(C=O)C.O>[Br:1][C:2]1[CH:11]=[N:10][C:9]2[C:8](=[O:12])[N:7]([CH2:14][CH2:15][O:16][CH3:17])[CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: O=c1[nH]cnc2cc(Br)cnc12
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Solvent: O
Product: COCCn1cnc2cc(Br)cnc2c1=O

Procedure:
A solution of 7-bromopyrido[3,2-d]pyrimidin-4(3H)-one (200 mg, 0.89 mmol), 1-bromo-2-methoxyethane (148 mg, 1.06 mmol) and K2CO3 (184 mg, 1.3 mmol) in acetone (10 mL) and DMF (3 mL) was stirred at room temperature for 4 h. Then the mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (3×50 mL), the combined organic layers were washed with brine, dried over Na2SO4. After filtration and concentration, the residue was purified by silica gel chromatography to give the desired product. MS (ESI): 284, 286 (MH+).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1.[CH2:14]([NH2:18])[CH2:15][CH2:16][NH2:17].[S:19]1(=[O:30])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:22]1[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[S:19](=[O:30])[CH2:20][CH2:21]1)[N:11]=[C:10]2[NH:17][CH2:16][CH2:15][CH2:14][NH2:18]
Reactant: O=S1CCNCc2ccccc21
Reactant: Cc1ccc2nc(Cl)nc(Cl)c2c1
Reactant: NCCCN
Product: Cc1ccc2nc(N3CCS(=O)c4ccccc4C3)nc(NCCCN)c2c1

Procedure:
The title compound was prepared in analogy to Example 56-1 in Scheme 23 by using 2,4-dichloro-6-methylquinazoline, propane-1,3-diamine and 2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide. MS obsd. (ESI+) [(M+H)+] 396, 1H NMR (400 MHz, CD3OD) δ ppm 7.92 (s, 1 H), 7.81-7.79 (d, J=7.6 Hz, 1 H), 7.74-7.72 (d, J=7.6 Hz, 1 H), 7.64-7.50 (m, 4 H), 5.43-5.39 (d, J=15.6 Hz, 1 H), 5.12-5.05 (m, 1 H), 4.81-4.72 (m, 1 H), 4.53-4.46 (m, 2 H), 3.84-3.82 (m, 2 H), 3.52-3.48 (m, 2 H), 3.31-3.29 (m, 2 H), 2.43 (s, 3 H), 2.17-2.11 (m, 2 H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:10]2=[O:23])=[CH:4][C:3]=1[CH2:24][CH2:25][CH3:26].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:34]([C:40]1[CH:45]=[CH:44][C:43]2[O:46][CH2:47][O:48][C:42]=2[CH:41]=1)[C:35]([O:37][CH2:38][CH3:39])=[O:36]>CN(C=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[C:35]([CH:34]([C:40]1[CH:45]=[CH:44][C:43]2[O:46][CH2:47][O:48][C:42]=2[CH:41]=1)[O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:10]2=[O:23])=[CH:4][C:3]=1[CH2:24][CH2:25][CH3:26])([O:37][CH2:38][CH3:39])=[O:36]
Reactant: CCCc1cc(Cn2c(=O)n(C(=O)OCC)c3ccccc32)ccc1O
Reactant: CCOC(=O)C(Br)c1ccc2c(c1)OCO2
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1cc(Cn2c(=O)n(C(=O)OCC)c3ccccc32)ccc1OC(C(=O)OCC)c1ccc2c(c1)OCO2
Reaction time: 0.25 h
Yield: 81.5 %

Procedure:
To a solution of 0.105 g (0.30 mmol) of the product of step C in 1.0 mL of DMF was added 0.115 g (0.33 mmol) of cesium carbonate and the resulting suspension was stirred under a nitrogen atmosphere for 15 minutes. A solution of 0.094 g (0.33 mmol) ethyl α-bromo-3,4-methylenedioxyphenylacetate in 0.5 mL of DMF was then added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then suspended in 10% aqueous citric acid and extracted into ethyl acetate. The organic layer was separated, washed with saturated sodium bicarbonate, brine, dried (MgSO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 30% EtOAc-hexane; combination of the product fractions and evaporation in vacuo afforded 0.137 g (83%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](CC#N)=[C:4]([F:11])[C:3]=1[F:12].OS(O)(=O)=O.[CH3:18][C:19](=[O:23])[O:20]CC>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:18][C:19]([OH:20])=[O:23])=[C:4]([F:11])[C:3]=1[F:12]
Reactant: CCOC(C)=O
Reactant: N#CCc1ccc(Br)c(F)c1F
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)Cc1ccc(Br)c(F)c1F
Temperature: 100 °C
Reaction time: 1 h
Yield: 41.6 %

Procedure:
Compound 2-(4-bromo-2,3-difluorophenyl)acetonitrile (200 mg, 0.690 mmol) was dissolved in H2O (1 mL) and H2SO4 (1 mL) at 20° C. in one charge. The reaction mixture was stirred at 100° C. for 1 h. Then the solution was distributed between EA and H2O. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The resulting 2-(4-bromo-2,3-difluorophenyl)acetic acid (180 mg, 0.287 mmol, 41.6% yield) was used in the next step without further purification. TLC (PE/EA=2:1, Rf 0.6): 1H NMR (400 MHz, CDCl3) δ 7.27-7.20 (m, 1H), 6.92-6.85 (m, 1H), 3.65 (s, 2H); ES-LCMS m/z 250.0 (M+H).
Reaction SMILES: [S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[C:3]([CH:10]=O)=[CH:2]1.[C:12]([O:18][CH:19]([CH3:21])[CH3:20])(=[O:17])[CH2:13][C:14]([CH3:16])=O.[NH2:22]/[C:23](/[CH3:30])=[CH:24]\[C:25]([O:27][CH2:28][CH3:29])=[O:26]>C(O)C>[CH3:30][C:23]1[NH:22][C:14]([CH3:16])=[C:13]([C:12]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[CH:10]([C:3]2[C:4]3[CH:5]=[N:6][CH:7]=[CH:8][C:9]=3[S:1][CH:2]=2)[C:24]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CC(=O)CC(=O)OC(C)C
Reactant: CCOC(=O)/C=C(/C)N
Reactant: O=Cc1csc2ccncc12
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1csc2ccncc12
Yield: 29.7 %

Procedure:
A solution of 1 g of thieno[3,2-c]pyridine-3-carboxaldehyde, 1.08 g of isopropyl acetoacetate, and 0.9 g of ethyl 3-aminocrotonate in 4 ml of ethanol was heated to reflux for approximately 18 hours. Upon cooling, a solid formed which was recovered by filtration providing 0.73 g of the desired title product, m.p. 212°-215° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(N(CC)CC)C.Cl[C:22](=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl>C1COCC1>[NH2:6][C:4]([C:3]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:2]=1[NH:1][C:22](=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:5]
Reactant: NC(=O)c1cc([N+](=O)[O-])ccc1N
Reactant: CCOC(=O)C(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)Nc1ccc([N+](=O)[O-])cc1C(N)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 28.8 %

Procedure:
To a solution of 2-amino-5-nitrobenzamide (18.1 g) and triethylamine (15 mL) in THF (100 mL) was added dropwise a solution of ethyl chloroglyoxylate (14.4 g) in THF (20 mL) under ice-cooling, and the mixture was stirred at 0° C. for 1 hr. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydrogencarbonate and saturated brine, dried, and concentrated. The obtained crude crystals were washed with diisopropyl ether to give ethyl {[2-(aminocarbonyl)-4-nitrophenyl]amino}(oxo)acetate (8.1 g).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].F[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:22]=1[F:30].O>CN(C=O)C>[F:30][C:22]1[CH:23]=[C:24]([N+:27]([O-:29])=[O:28])[CH:25]=[CH:26][C:21]=1[N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a solution of tert-butyl piperazine-1-carboxylate (1120 mg, 6 mmol) in DMF (25 mL) was added K2CO3 (828 mg, 6 mmol) and 1,2-difluoro-4-nitrobenzene (795 mg, 5 mmol) at room temperature. The reaction was stirred at 80° C. for 24 hours. After that, the reaction was poured into 50 mL of water and extracted with EA (3×25 mL), washed with H2O (25 mL) and brine (25 mL), dried over Na2SO4 and concentrated to give yellow solid. MS (m/z): 226 (M−99)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([CH3:12])([CH3:11])[SH:10])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:14]1C=C(C=CC=1Cl)C(O)(C)C.[P:25]([S-:31])(=[S:30])([O:28][CH3:29])[O:26][CH3:27].[K+]>>[P:25]([S:31][CH2:14][S:10][C:9]([CH3:12])([CH3:11])[C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)(=[S:30])([O:28][CH3:29])[O:26][CH3:27]
Reactant: CC(C)(S)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(O)c1ccc(Cl)c(Cl)c1
Reactant: COP(=S)([S-])OC
Agent: [K+]
Product: COP(=S)(OC)SCSC(C)(C)c1ccc(Cl)c(Cl)c1

Procedure:
Using 3,4-dichloro-α,α-dimethyl-α-toluenethiol prepared from 3,4-dichloro-α,α-dimethylbenzyl alcohol by the procedure of Example 1, and using potassium O,O-dimethyl phosphorodithioate in place of potassium O,O-diethyl phosphorodithioate, the procedure of Example 6 gives the desired product as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH:11][CH:12]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=2)[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl.CO>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH:11][CH:12]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[C:13]2[CH:14]=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=2)[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C[C@@H](NC(c1ccc(F)cc1)c1cccc([N+](=O)[O-])c1)c1ccc(F)c(F)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C[C@@H](NC(c1ccc(F)cc1)c1cccc(N)c1)c1ccc(F)c(F)c1

Procedure:
Following a similar reaction, separation and purification procedure to that described in Example (59b), 18.44 g of N-[(R)-1-(3,4-difluorophenyl)ethyl]-N-[(4-fluorophenyl)-(3-nitrophenyl)methyl]amine, 22.69 g of nickel chloride hexahydrate, 7.22 g of sodium borohydride and 150 ml of methanol were reacted, to obtain 1.27 g of isomer A and 2.79 g of isomer B of the title compound, respectively, each as a pale yellow oil.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Al:10](CC)CC)C>>[O-:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O-:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O-:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Al+3:10]
Reactant: Oc1ccccc1
Reactant: CC[Al](CC)CC
Product: [Al+3]
Product: [O-]c1ccccc1

Procedure:
In a reactor was placed 19364 parts (206 moles) of phenol. The reactor was flushed with nitrogen and while stirring 114 parts (1 moles) of triethyl aluminum were added. The reactor was sealed and the mixture was reacted for 30 minutes to form aluminum triphenoxide. Then heat was applied while pumping isobutylene into the reactor. As the reaction became exothermic cooling was applied to hold the temperature in the range of 115°-125° C. Total isobutylene feed was 24282 parts over a 45 minute period. The maximum pressure was about 300 psig. Stirring was continued at about 115° C. as isobutylene reaction continued causing the pressure to drop to 105 psig over a 11/2 hour period. Analysis by GC showed the phenol content at this time to be 0.7 wt percent.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[OH:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11]O)=[CH:9][CH:8]=1.[I:15][CH3:16].[K+].[Br-]>>[I-:15].[OH:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][N:1]2[CH:5]=[CH:4][N+:3]([CH3:16])=[CH:2]2)=[CH:9][CH:8]=1
Reactant: OCc1ccc(O)cc1
Reactant: CI
Reactant: c1c[nH]cn1
Agent: [Br-]
Agent: [K+]
Product: C[n+]1ccn(Cc2ccc(O)cc2)c1
Product: [I-]
Temperature: 155 °C

Procedure:
Imidazole (0.1 mol) and 4-hydroxybenzyl alcohol (0.1 mol) were combined and heated to 155° C. The crude product was washed with cold ethanol and recrystallized in an EtOH/DMF mixture. This powder (3-(4-hydroxybenzyl)imidazole, 2.20 mmol) was then was dissolved in DMF (3 mL). Iodomethane (3.21 mmol) was added to the reaction mixture and refluxed for 24 hours at 80° C. The solvent was evaporated and remaining oil was washed using ethyl ether to yield a brown precipitate. Yield: 0.573 g, 82.2%. Mp: 82.9-85.5° C. FTIR: (KBr, cm−1) u(Ar) 1327.37, 1378.80, 1459.39, 1506.20, 1587.78; u(OH) 2922.97. 1H NMR (300 MHz, DMSO-d6) 3.836 (3H, s, CH3N), 5.265 (2H, s, NCH2Ar), 6.796 (2H, d, NCHCHN), 7.275 (2H, d, NCAr), 7.729 (2H, d, HOAr), 9.122 (1H, s, OH), 9.627 (1H, s, NHN).
Reaction SMILES: [C:1]1([CH:7]2[NH:12][CH2:11][CH2:10][N:9]([C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]([F:30])([F:29])[F:28])=[CH:17][CH:16]=3)=[O:14])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:31](N(CC)C(C)C)(C)C.IC>C(#N)C.ClCCl>[CH3:31][N:12]1[CH2:11][CH2:10][N:9]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:29])([F:30])[F:28])=[CH:17][CH:16]=2)=[O:14])[CH2:8][CH:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(c1ccc(-c2ccccc2C(F)(F)F)cc1)N1CCNC(c2ccccc2)C1
Reactant: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CI
Solvent: ClCCl
Product: CN1CCN(C(=O)c2ccc(-c3ccccc3C(F)(F)F)cc2)CC1c1ccccc1
Temperature: 80 °C

Procedure:
This compound could be made in the following manner: 100 mg of (3-phenyl-piperazin-1-yl)-(2′-trifluoromethyl-biphenyl-4-yl)-methanone would be dissolved in 3 mL of acetonitrile, 2 equiv. of N,N-diisopropylethylamine would be added followed by 1.1 equiv. of iodomethane. The reaction would be heated to 80° C. overnight. After cooling to room temperature, the reaction would be diluted with dichloromethane and washed with 1M aqueous sodium hydroxide solution, dried over sodium sulfate and concentrated in vacuo. The crude residue would be purified by column chromatography to afford the title compound.
Reaction SMILES: O.[NH2:2][NH2:3].[O:4]=[C:5]1[N:11]2[CH2:12][CH2:13][C@H:10]2[C:9]2=[C:14]([C:17]([O:19]CC)=O)[N:15]=[CH:16][N:8]2[C:7]2[CH:22]=[CH:23][S:24][C:6]1=2>C(O)C>[O:4]=[C:5]1[N:11]2[CH2:12][CH2:13][CH:10]2[C:9]2=[C:14]([C:17]([NH:2][NH2:3])=[O:19])[N:15]=[CH:16][N:8]2[C:7]2[CH:22]=[CH:23][S:24][C:6]1=2
Reactant: NN
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1sccc1-2
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ncn2c1C1CCN1C(=O)c1sccc1-2

Procedure:
10 ml of hydrazine hydrate were added to a suspension of 6.0 g (19.8 mmol) of ethyl (S)-8-oxo-11,11a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepine-1-carboxylate in 50 ml of ethanol and the mixture was heated at reflux for 3 hours. After cooling to 0° the crystals obtained were filtered off and there were obtained 5.6 g (98%) of S)-8-oxo-11,11a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c]thieno-[3,2-e][1,4]diazepine-1-carboxylic acid hydrazide as colourless needles of m.p. 260°-263°.