Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([O-:5])=[O:4].Br[CH2:14][C:15]1[S:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1.O>CN(C)C=O>[S:16]1[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=[C:15]1[CH2:14][C:10]1[CH:11]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=[CH:8][C:9]=1[OH:12]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: BrCc1nc2ccccc2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(O)c(Cc2nc3ccccc3s2)c1
Reaction time: 0.08 h
Yield: 85.7 %

Procedure:
855.5 mg of sodium hydride (as a 60% w/w dispersion in mineral oil) were added to a solution of 2.83 g of 4-nitrophenol in 30 ml of dimethylformamide cooled in an ice-water bath. The resulting mixture was stirred at the same temperature for 5 minutes, after which a solution of 4.88 g of 2-bromomethylbenzothiazole in 25 ml of dimethylformamide was added thereto. The temperature of the resulting mixture was elevated to room temperature, and the mixture was then stirred at this temperature for 4 hours. At the end of this time the reaction mixture was cooled in an ice-water bath and 100 ml of water was added to said reaction mixture resulting in the precipitation of a crystalline solid which was filtered off, washed with water and then further washed with hexane. The resulting crude crystalline solid was purified by column chromatography through silica gel using a 10:1 by volume mixture of hexane and ethyl acetate, to give 4.99 g (yield 86%) of the title compound having a melting point of 189° to 191° C.
Reaction SMILES: [OH:1]O.[C:3]([O:11][CH3:12])(=[O:10])[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1>C(O)(=O)C>[C:3]([O:11][CH3:12])(=[O:10])[C:4]1[CH:9]=[CH:8][N+:7]([O-:1])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccncc1
Reactant: OO
Solvent: CC(=O)O
Product: COC(=O)c1cc[n+]([O-])cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
To a solution of hydrogen peroxide (43 mL) in 250 mL of acetic acid was added methyl isonicotinate. The reaction mixture was stirred at 80° C. overnight (about eighteen hours). The solution was concentrated to about 50 mL, water was added and the mixture was saturated with sodium carbonate. The aqueous phase was extracted with methylene chloride. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and trituated with hexane. The resulting precipitate was filtered and air-dried to give 24.5 g (65% yield) of product as a white solid: mp: 118-120° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=4)=[C:14]([C:24]([NH:26][CH3:27])=[O:25])[C:13]=3[CH:28]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].N[C@@H:30]([CH:33]([CH3:35])[CH3:34])[CH2:31][OH:32]>C1(Cl)C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]2[O:16][C:12]3[CH:11]=[CH:10][C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:1]5[O:32][CH2:31][C@H:30]([CH:33]([CH3:35])[CH3:34])[N:2]=5)[CH:4]=4)=[CH:28][C:13]=3[C:14]=2[C:24]([NH:26][CH3:27])=[O:25])=[CH:18][CH:19]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C#N)c3)cc12
Reactant: CC(C)[C@H](N)CO
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Clc1ccccc1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C4=N[C@@H](C(C)C)CO4)c3)cc12
Yield: 18.3 %

Procedure:
Zinc chloride (8 mg, 0.054 mmol) was added to a stirring solution of 5-(3-cyanophenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (40 mg, 0.108 mmol) and (S)-2-amino-3-methylbutan-1-ol (111 mg, 1.080 mmol) in PhCl (3 mL) at rt. It was subjected for two 1 hr iterations to microwave irradiation at 200° C. The reaction was concentrated and purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (9 mg, 17%). 1H NMR (500 MHz, CD3OD) δ ppm 8.24 (1H, s), 7.93-7.99 (2H, m), 7.89-7.93 (2H, m), 7.86 (1H, d, J=7.63 Hz), 7.63-7.69 (2H, m), 7.56 (1H, t, J=7.78 Hz), 7.26 (2H, t, J=8.70 Hz), 4.52 (1H, t, J=9.31 Hz), 4.30 (1H, t, J=8.09 Hz), 4.15-4.22 (1H, m), 2.98 (3H, s), 1.86-1.96 (1H, m), 1.04 (3H, d, J=6.71 Hz), 0.97 (3H, d, J=6.71 Hz). LC-MS retention time: 1.63 min; m/z (MH+): 457. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 μm, Rt=10.06 min, purity=95%; Column: Waters Xbridge Phenyl column 4.6×150 mm, 3.5 μm, Rt=10.53 min, purity=95%.
Reaction SMILES: C[C:2]1[N+:7]([O-])=[C:6]2[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:5]2=[CH:4][C:3]=1C(OCC)=O.C(=O)([O-])[O-:20].[K+].[K+].O.[C:26](OCC)(=[O:28])[CH3:27]>C(OC(=O)C)(=O)C.CO>[N:7]1[C:27]2[C:5]3([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH:6]3[O:28][CH:26]=2)[CH2:4][C:3](=[O:20])[CH:2]=1
Reactant: CCOC(C)=O
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cc2c([n+]([O-])c1C)CCCCC2
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CO
Product: O=C1C=NC2=COC3CCCCCC23C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 41.3 %

Procedure:
Ethyl 2-methyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carboxylate N-oxide (8.00 g, 32.1 mmol) was dissolved in acetic anhydride (56.0 ml) and heated under reflux for 1.5 hours. After cooling, excess acetic anhydride was evaporated under reduced pressure, the thus obtained residue was mixed with ice water and 40% sodium hydroxide aqueous solution and extracted with ethyl acetate, and the resulting organic layer was washed with water and saturated brine in that order and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the thus obtained reaction product (10.27 g, 32.1 mmol) was dissolved in methanol (40.0 ml), mixed with potassium carbonate (4.88 g) and stirred at 0° C. for 30 minutes. The reaction solution was mixed with water and ethyl acetate, and the thus precipitated crystals were collected by filtration to obtain pale yellow powder of 6,7,8,9-tetrahydro-5H-cyclohepta[b]pyrido[3,2-c]furan-3-one (2.69 g, 41.3%) as a low polar component The resulting filtrate was extracted with ethyl acetate, and the thus obtained organic layer was washed with water and saturated brine in that order and dried over anhydrous sodium sulfate. By evaporating the solvent under reduced pressure, methyl 9-hydroxy-2-methyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carboxylate (4.20 g, 55.7%) was obtained in the form of white amorphous as a high polar component.
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[N+:16]([C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([N+:28]([O-:30])=[O:29])[CH:27]=1)[C:22](Cl)=[O:23])([O-:18])=[O:17]>C1(C)C=CC=CC=1>[N+:16]([C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([N+:28]([O-:30])=[O:29])[CH:27]=1)[C:22]([N:7]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]1=[O:8])=[O:23])([O-:18])=[O:17]
Reactant: O=C1CCCCCN1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C1CCCCCN1C(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
All glassware is dried thoroughly, and the reaction is kept under an inert atmosphere (argon) at all times. With stirring, 2.33 g (20.6 mmol) of caprolactam (Aldrich) and 2.30 g (22.7 mmol) of triethylamine (Aldrich, d=0.726 g/mol) are added to 100 mL toluene (Aldrich) in a 3-neck round bottom flask equipped with a reflux condenser, addition funnel, and mechanical stirrer, to give a clear, pale yellow solution. Addition of a solution of 4.75 g (20.6 mmol) of 3,5-dinitrobenzoyl chloride (Aldrich) in 100 mL toluene proceeds dropwise over a period of 30 min. The resulting reaction mixture is heated to reflux and stirred for 16 h. Upon cooling to room temperature, the reaction is filtered to remove the triethylamine hydrochloride, and poured into a separatory funnel. After dilution with 300 mL of chloroform, the organic solution is extracted with 5% aq HCl, 5% aq NaOH, and finally D.I. water. The organic layer is dried over Na2 SO4, filtered, and the solvent removed by evaporation under reduced pressure. Recrystallization of the crude product from toluene followed by drying under vacuum yields N-(3,5-dinitrobenzoyl)caprolactam as a light yellow, crystalline solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]([O:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([NH2:18])[CH2:14][CH2:13]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[C:19]([O:24][CH3:25])(=[O:23])[C:20](C)=[CH2:21]>CO>[CH3:1][C:2]1[C:10]([O:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([NH:18][CH2:21][CH2:20][C:19]([O:24][CH3:25])=[O:23])[CH2:14][CH2:13]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2
Reactant: Cc1c(O[C@H]2CC[C@H](N)CC2)ccc2[nH]ncc12
Reactant: C=C(C)C(=O)OC
Solvent: CO
Product: COC(=O)CCN[C@H]1CC[C@H](Oc2ccc3[nH]ncc3c2C)CC1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
A mixture of the trans-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexylamine (98.1 mg, 0.40 mmol) obtained in Example 408, methyl methacrylate (43 mg, 0.50 mmol) and methanol (2.0 ml) was stirred at 50° C. for 6 hours. The solvent was distilled off and the residue oil was subjected to elution by a silica gel column chromatography (ethyl acetate→ethyl acetate/triethylamine=20:1) to obtain methyl 3-({trans-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}-amino}propanoate (121 mg, 91%).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([O:8][C@H:9]1[C@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@@H:13]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:12][CH:11]=[CH:10]1)(=[O:7])[CH3:6].[Br-:24].[Li+]>C(#N)C.C(OCC)C>[C:5]([O:8][C@H:9]1[C@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@@H:13]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:12][C@H:11]([Br:24])[C@@H:10]1[N:1]=[N+:2]=[N-:3])(=[O:7])[CH3:6]
Reactant: [Br-]
Reactant: CC(=O)OC[C@H]1OC=C[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Li+]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOCC
Product: CC(=O)OC[C@H]1O[C@H](Br)[C@H](N=[N+]=[N-])[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: -30 °C
Reaction time: 20 h

Procedure:
A 1 L flask containing 400 mL of acetonitrile was charged with sodium azide (7.75 g, 119.2 mmol) and ceric ammonium nitrate (120.7 g, 219.4 mmol). The resulting suspension was cooled to −30° C. and a solution of tri-O-acetyl-D-glucal (20.75 g, 76.22 mmol) in 100 mL acetonitrile was added to it dropwise. The reaction mixture was stirred at −30° C. for 20 hours and then warmed to room temperature, taken up in 800 mL of diethyl ether and washed with water (3×250 mL). The organics were dried over magnesium sulfate, filtered, and the solvent removed in vacuo to yield an oil. This oil was placed in a 1 L flask containing 400 mL of acetonitrile and lithium bromide (33.53 g, 386.1 mmol) and stirred at room temperature for at least 4 hours. The solvent was removed in vacuo and the resulting residue was taken up in 400 mL of dichloromethane. The organic layer was washed with water (2×250 mL), dried over magnesium sulfate and filtered. The solvent was removed in vacuo to yield the title compound as a gold oil which was used directly as in Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+].BrC[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1>CN1CCCC1=O.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:20][CH2:21][N:22]3[CH:26]=[CH:25][CH:24]=[CH:23]3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: BrCCc1ccccn1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: CN1CCc2c(c3cc(Cl)ccc3n2CCn2cccc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 7 %

Procedure:
8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0 g, 0.45 mmol) was dissolved in N-methyl 2-pyrolidone (3.0 mL), Powdered potassium hydroxide (0.224 g, 4 mmol) was added and heated at 100 deg C. for 3 h. 2-(2-Bromo-ethyl)pyridine (0.09 g, 0.51 mol) was added at the same temperature and stir for 3 h at RT Reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3×50 mL). Organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure using rotary evaporator. The crude was purified-through column chromatography (4% MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch) to provide the desired compound as light yellow oil, (00.0 g, 7% yield). 8-Chloro-2-methyl-5-(2-pyrrol-1-yl-ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.010 g, 0.0319 mmol) was dissolved in THF (0.5 mL), A solution of oxalic acid dihydrate (0.004 g, 0.0319 tool) in THF (0.5 mL) was added and stirred for 30 min at RT. The precipitate was filtered and dried to give oxalate salt as white solid (00.1 g, 78% yield).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].N1C2C(=CC=CC=2)C2(COC3C=[C:37]4[C:41](=[CH:42][C:32]2=3)[CH2:40][CH2:39][O:38]4)C1=O.BrCC1CCOCC1.BrCC1CCCCO1>>[O:38]1[CH2:39][CH2:40][CH:41]([CH2:37][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:21]4[C:12](=[CH:13][C:14]5[O:19][CH2:18][CH2:17][O:16][C:15]=5[CH:20]=4)[O:11][CH2:10]3)[C:2]2=[O:22])[CH2:42][CH2:32]1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Agent: BrCC1CCCCO1
Agent: BrCC1CCOCC1
Product: O=C1N(CC2CCOCC2)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and 4-(bromomethyl)tetrahydro-2H-pyran to replace 2-(bromomethyl)tetrahydro-2H-pyran, 1′-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (95%) as a colorless solid: mp 129-131° C. (hexanes); 1H NMR (300 MHz, CDCl3) δ7.29 (ddd, J=7.9, 7.9, 1.3 Hz, 1H), 7.16 (d, J=7.5 Hz, 1H), 7.04 (ddd, J=7.4, 7.4, 1.0 Hz, 1H), 6.89 (d, J=8.1 Hz, 1H), 6.50 (s, 1H), 6.18 (s, 1H), 4.87 (d, J=8.9 Hz, 1H), 4.62 (d, J=8.9 Hz, 1H), 4.22-4.16 (m, 2H), 4.15-4.09 (m, 2H), 4.03-3.94 (m, 2H), 3.74 (dd, J=13.8, 7.7 Hz, 1H), 3.55 (dd, J=13.8, 7.1 Hz, 1H), 3.42-3.30 (m, 2H), 2.20-2.03 (m, 1H), 1.66-1.56 (m, 2H), 1.53-1.40 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.8, 155.4, 144.7, 142.8, 138.4, 132.5, 128.9, 124.2, 123.4, 121.1, 111.5, 108.7, 99.5, 80.4, 67.6, 67.5, 64.6, 64.0, 58.1, 46.2, 34.0, 30.93, 30.86; MS (ES+) m/z 394.2 (M+1); Anal. Calcd for C23H23NO5: C, 70.21; H, 5.89; N, 3.56. Found: C, 70.15; H, 5.92; N, 3.20.
Reaction SMILES: [Cl:1][C@@:2]1([CH3:30])[C@H:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:6]2[C:16](=[O:29])[C@@H:17]([NH:18]C(=O)COC3C=CC=CC=3)[C@H:5]2[S:4][CH2:3]1.N1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl>C1C=CC=CC=1.O1CCCC1>[NH2:18][C@@H:17]1[C:16](=[O:29])[N:6]2[C@@H:7]([C:8]([O:10][CH2:11][C:12]([Cl:14])([Cl:13])[Cl:15])=[O:9])[C@@:2]([Cl:1])([CH3:30])[CH2:3][S:4][C@H:5]12
Reactant: C[C@@]1(Cl)CS[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2[C@H]1C(=O)OCC(Cl)(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C[C@@]1(Cl)CS[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)OCC(Cl)(Cl)Cl
Reaction time: 8 h
Yield: 90.3 %

Procedure:
To a solution of 2,2,2-trichloroethyl 3β-chloro-3α-methyl-7β-phenoxyacetamidocepham-4α-carboxylate (2.29 g) in benzene (130 ml) is added pyridine (10 ml) and the mixture is cooled at -60°C in the presence of phosphorous pentachloride (1.51 g) for 2 hours. The reaction mixture is evaporated in vacuo to remove benzene, methanol (250 ml) is added thereto, and the solution kept at room temperature overnight. The solution is concentrated to give a residue which is dissolved in 50% aqueous tetrahydrofuran (50 ml), and the tetrahydrofuran is evaporated after 15 minutes. The residual solution is neutralized with 1N sodium hydroxide, and evaporated to give 2,2,2-trichloroethyl 7β-amino-3β-chloro-3α-methylcepham-4α-carboxylate (1.53 g).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]([C:14]([OH:16])=[O:15])[C:11]2[C:6](=[CH:7][C:8]([Cl:18])=[CH:9][C:10]=2[Cl:17])[N:5]=1)([OH:3])=[O:2].[CH3:19]O>>[C:14]([C:12]1[C:11]2[C:6](=[CH:7][C:8]([Cl:18])=[CH:9][C:10]=2[Cl:17])[N:5]=[C:4]([C:1]([O:3][CH3:19])=[O:2])[CH:13]=1)([OH:16])=[O:15]
Reactant: O=C(O)c1cc(C(=O)O)c2c(Cl)cc(Cl)cc2n1
Reactant: CO
Product: COC(=O)c1cc(C(=O)O)c2c(Cl)cc(Cl)cc2n1
Reaction time: 1 h

Procedure:
2,4-Dicarboxy-5,7-dichloroquinoline was added to methanol (presaturated with dry hydrogen chloride) (500 ml) and the solution left at room temperature for 1 h. After this time the volume of solvent was reduced to approximately 100 ml and the white solid that precipitated was collected by filtration and dried in a vacuum oven at 100° C. (20 mm Hg) for 2 h to give the title compound (18.5 g, m.p. 260°-262° C.); δ (250 MHz, DMSO) 3.98 (3H, s, CH3), 8.11 (1H, s, 3-H), 8.15 (1H, d, J=2.1 Hz, 6-H or 8-H), 8.36 (1H, d, J=2.1 Hz, 6-H or 8-H); m/e 299 (M+) 241 (100%, M-CO2CH3 +H); Found: C, 47.58; H, 2.42; N, 4.62. C12H7Cl2NO4. 0.2 H2O requires C, 47.46; H, 2.46; N, 4.61%.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].CO.[CH3:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][CH:19]=1)=[O:17].Cl>CC(OC)(C)C>[F:9][C:2]([F:1])([F:8])[C:3](=[O:5])[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][CH:19]=1)=[O:17]
Reactant: CSc1ccc(C(C)=O)cc1
Reactant: CCOC(=O)C(F)(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CO
Product: CSc1ccc(C(=O)CC(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a solution of ethyl trifluoroacetate (7.95 ml, 1.1 eq) in MTBE (125 ml) was added dropwise 25% sodium methoxide in methanol (16 ml, 1.2 eq). 4-Methylthioacetophenone (Aldrich, 10 g, 0.06 mol) was added portionwise and the mixture stirred at ambient temperature overnight. 2N Hydrochloric acid (40 ml) was added cautiously and the organic phase separated, washed with brine and dried (Na2SO4) to give an orange solid. The orange solid was recrystallised from hot isopropanol to give the title compound as a yellow crystalline solid (11.25 g, 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[N:13][C:12](I)=[CH:11][N:10]=1.[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18]>C1CCCCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[N:13][C:12]([C:21]#[C:20][Si:17]([CH3:19])([CH3:18])[CH3:16])=[CH:11][N:10]=1
Reactant: C#C[Si](C)(C)C
Reactant: Clc1ccc(-c2cnc(I)cn2)c(Cl)c1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: C[Si](C)(C)C#Cc1cnc(-c2ccc(Cl)cc2Cl)cn1

Procedure:
The product was prepared analogously to Example 48.1c from 450 mg (1.28 mmol) of 2-(2,4-dichlorophenyl)-5-iodopyrazine and 0.20 mL (1.41 mmol) of trimethylsilylacetylene (using triethylamine as base). Yield: 300 mg (73% of theoretical); C15H14Cl2N2Si (M=321.276); calc.: molpeak (M+H)+:321/323/325 (2 Cl); found: molpeak (M+H)+:321/323/325 (2 Cl); Rf value: 0.6 (silica gel, cyclohexane/EtOAc 9:1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].CO[CH:22](OC)[N:23]([CH3:25])[CH3:24].N1CC[CH2:30][CH2:29]1.[OH-].[Na+]>CN(C)C=O>[CH3:19][N:16]1[CH2:15][CH2:14][N:13]([C:11]([C:4]2[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([CH:1]=[CH:25][N:23]3[CH2:22][CH2:30][CH2:29][CH2:24]3)[CH:3]=2)=[O:12])[CH2:18][CH2:17]1
Reactant: C1CCNC1
Reactant: Cc1cc(C(=O)N2CCN(C)CC2)ccc1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)c2ccc([N+](=O)[O-])c(C=CN3CCCC3)c2)CC1
Temperature: 0 °C

Procedure:
(3-Methyl-4-nitrophenyl)-(4-methylpiperazin-1-yl)methanone (3.8022 mmol, 1.0 grams) (obtained from, step (i)) was taken in a 25 mL two necked round bottomed flask attached with a condenser, under nitrogen atmosphere. To this, was added 3 mL of N,N-dimethylformamide, N,N-dimethylformamide dimethylacetal (5.7033 mmol) and pyrrolidine (5.7033 mmol) and refluxed for a period of 6 hours. After the completion of reaction, the reaction mixture was poured on to 20 grams of ice water, basified with 20% NaOH solution (pH to 10) and the mixture was extracted with ethyl acetate (2×30 mL). The combined ethyl acetate extracts were then washed with water (2×30 mL), brine (30 mL) and dried over anhydrous sodium sulfate. The volatiles were removed under reduced pressure to obtain thick syrupy mass. This thick syrupy mass was used for the next step of the reaction without purification.
Reaction SMILES: NC(N)=[S:3].[Cl:5][C:6]1[CH:24]=[CH:23][C:9]([CH2:10][N:11]2[CH2:16][CH:15]([CH3:17])[N:14]([CH2:18][CH2:19][CH2:20]Cl)[CH2:13][CH:12]2[CH3:22])=[CH:8][CH:7]=1.C(O)C.[OH-].[Na+]>O>[ClH:5].[ClH:5].[Cl:5][C:6]1[CH:24]=[CH:23][C:9]([CH2:10][N:11]2[CH:12]([CH3:22])[CH2:13][N:14]([CH2:18][CH2:19][CH2:20][SH:3])[CH:15]([CH3:17])[CH2:16]2)=[CH:8][CH:7]=1
Reactant: CC1CN(Cc2ccc(Cl)cc2)C(C)CN1CCCCl
Reactant: NC(N)=S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1CN(Cc2ccc(Cl)cc2)C(C)CN1CCCS
Product: Cl
Yield: 249.9 %

Procedure:
The procedure described in Example 1(b) was followed, using 12.7 g of thiourea and 26.0 g of 1-(4-chlorobenzyl)-2,5-dimethyl-4-(3-chloropropyl)piperazine in 250 ml of reagent ethanol. The hydrolysis was effected with 10.0 g of sodium hydroxide in 50 ml of water. Work-up, as described above, gave 26.5 g (83% of theory) of 3-[4-(4-chlorobenzyl)-2,5-dimethylpiperazin-1-yl]propanethiol dihydrochloride as a white crystalline solid, M.p. 168°-171° C.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:8]=2[CH2:21][CH3:22])=[C:4]([F:25])[CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([N:36]=[C:37]=[O:38])=[O:35])=[CH:29][CH:28]=1.C1(C)C=CC=CC=1>C1COCC1>[CH2:21]([C:8]1[C:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[N:10][CH:11]=[CH:12][C:7]=1[O:6][C:5]1[CH:23]=[CH:24][C:2]([NH:1][C:37]([NH:36][C:34](=[O:35])[CH2:33][C:30]2[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=2)=[O:38])=[CH:3][C:4]=1[F:25])[CH3:22]
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Reactant: CCc1c(Oc2ccc(N)cc2F)ccnc1NC(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCc1c(Oc2ccc(NC(=O)NC(=O)Cc3ccc(F)cc3)cc2F)ccnc1NC(=O)OC(C)(C)C

Procedure:
The title compound was prepared from tert-butyl 4-(4-amino-2-fluorophenoxy)-3-ethylpyridin-2-ylcarbamate (20 mg, 0.058 mmol) and 0.3 M solution of 2-(4-fluorophenyl)acetyl isocyanate in toluene (232 μL, 0.070 mmol) in THF in the same manner as Step D of Example 33. MS(ESI+): m/z 527.31 (M+H)+.