Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH3:9][O:10][CH:11]([C:17]([O-])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13].C1(N=C=NC2CCCCC2)CCCCC1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:17](=[O:18])[CH:11]([O:10][CH3:9])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(OC)C(=O)[O-]
Reactant: Nc1cccc(Cl)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CCOC(=O)C(OC)C(=O)Nc1cccc(Cl)c1
Yield: 30 %

Procedure:
3-Chloroaniline (2.82 grams, 0.02 mole), mono-ethyl methoxymalonate (3.58 grams, 0.02 mole), prepared in Example LIII Part B, and 1,3-dicyclohexylcarbodiimide (4.50 grams, 0.02 mole) were reacted in a manner similar to that described in Example LVII to give 1.60 grams (0.006 mole) of ethyl 3-[(3-chlorophenyl)amino]-2-methoxy-3-oxopropanoate having melting point of 43.50° C.-46.50° C.
Reaction SMILES: Br[C:2]1[C:3]([C:12]2[C:13]([F:22])=[CH:14][C:15]([Cl:21])=[C:16]([CH:20]=2)[C:17]([OH:19])=[O:18])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8].[H-].[Na+].[CH2:25]([Li])CCC.CI>C1COCC1>[Cl:21][C:15]1[CH:14]=[C:13]([F:22])[C:12]([C:3]2[C:2]([CH3:25])=[C:6]([C:7]([F:10])([F:9])[F:8])[N:5]([CH3:11])[N:4]=2)=[CH:20][C:16]=1[C:17]([OH:19])=[O:18]
Reactant: Cn1nc(-c2cc(C(=O)O)c(Cl)cc2F)c(Br)c1C(F)(F)F
Reactant: [Li]CCCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1c(-c2cc(C(=O)O)c(Cl)cc2F)nn(C)c1C(F)(F)F
Temperature: 60 °C

Procedure:
A solution of 30 g of 5-[4-bromo-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-2-chloro-4-fluorobenzoic acid in 800 mL of anhydrous THF was stirred with a mechanical stirrer and treated with 3.36 g of 80% NaH. The stirred mixture was kept under a nitrogen atmosphere and heated to 60° C. for one hour. After formation of the sodium carboxylate salt, the mixture was cooled to -110° C. and 32.3 mL of 2.5 M n-butyllithium in hexanes was added never allowing the temperature to exceed -100° C. The reaction was stirred at -110° C. for ten minutes, subsequently treated with 9.3 mL of methyl iodide and allowed to warm to room temperature. The mixture was quenched with 3N HCl and the volatiles removed. A precipitate formed which was collected and recrystallized from ethanol/water to give 24.5 g Of a white solid: mp 155.0° C.; 1HNMR (CDCl3) δ2.06 (m, 3H), 4.01 (s, 3H), 7.27 (d, 1H, J=9.6 Hz), 8.17 (d, 1H, J=7.6 Hz). Anal. Calcd for C13H9O2Cl1N2 F4 : C, 46.38; H, 2.69; N, 8.32. Found: C, 46.46; H, 2.65; N, 8.33.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@:10]1([CH3:30])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](Cl)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N:31]1[CH:36]=[CH:35][CH:34]=[C:33](B(O)O)[CH:32]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Si:1]([O:8][CH2:9][C@:10]1([CH3:30])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:33]5[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@]1(C)Cc2nnc(C3(c4ccc(Cl)cc4)CC3)n2CCS1
Reactant: OB(O)c1cccnc1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(C)[Si](C)(C)OC[C@@]1(C)Cc2nnc(C3(c4ccc(-c5cccnc5)cc4)CC3)n2CCS1
Temperature: 140 °C
Reaction time: 2 h
Yield: 90.7 %

Procedure:
The compound (460 mg, 0.99 mmol) obtained in Example 4-2), 3-pyridylboronic acid (135 mg, 1.09 mmol), tris(dibenzylideneacetone)dipalladium (45 mg, 0.05 mmol), tricyclohexylphosphine (33 mg, 0.12 mmol), and tripotassium phosphate (370 mg, 1.68 mmol) were dissolved in a mixed solvent of 1,4-dioxane (2 mL) and water (1 mL), and the mixture was stirred at 140° C. for 2 h under microwave irradiation. The reaction mixture was cooled to room temperature, then diluted with methylene chloride (100 mL), and separated into organic and aqueous layers by the addition of saturated aqueous sodium hydrogencarbonate (30 mL). The organic layer was washed with saturated sodium chloride solution and then dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: methanol/ethyl acetate=0% to 30%) to obtain the title compound (455 mg, 91%) in a yellow solid form.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[NH:11][C:10]3[CH:12]=[CH:13][C:14]([O:16][S:17]([C:20]4[CH:25]=[CH:24][C:23](F)=[CH:22][CH:21]=4)(=[O:19])=[O:18])=[CH:15][C:9]=3[N:8]=2)=[O:5])[CH2:3][CH2:2]1.[NH2:27][CH2:28][CH:29]1[CH2:33][CH2:32][CH2:31][N:30]1[CH2:34][CH3:35].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[CH:1]1([C:4]([NH:6][C:7]2[NH:11][C:10]3[CH:12]=[CH:13][C:14]([O:16][S:17]([C:20]4[CH:25]=[CH:24][C:23]([NH:27][CH2:28][CH:29]5[CH2:33][CH2:32][CH2:31][N:30]5[CH2:34][CH3:35])=[CH:22][CH:21]=4)(=[O:19])=[O:18])=[CH:15][C:9]=3[N:8]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: CCN1CCCC1CN
Reactant: O=C(Nc1nc2cc(OS(=O)(=O)c3ccc(F)cc3)ccc2[nH]1)C1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCN1CCCC1CNc1ccc(S(=O)(=O)Oc2ccc3[nH]c(NC(=O)C4CC4)nc3c2)cc1
Temperature: 110 °C
Yield: 69.2 %

Procedure:
Title compound was obtained by reacting 12 mg of 4-fluoro-benzenesulfonic acid 2-(cyclopropanecarbonyl-amino)-1H-benzoimidazol-5-yl ester (example 55) with 21 mg of 2-(aminomethyl)-1-ethylpyrrolidine and 50 mg cesium carbonate in 600 μl dimethylsulfoxide. Reaction was performed in a 24 well Inox plate for high pressure. The reaction mixture was put under 10 bars argon pressure and then heated to 110° C. for 50 hours. Cesium carbonate was filtered off and compound in DMSO was directly purified by LCMS triggered purification yielding 10.7 mg title compound. (LC/MS analysis: retention time=2.58 min, mass spectrum: 483.99, [M+H]+.
Reaction SMILES: C[C:2]([O:4][CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[Bi](Cl)(Cl)Cl.C(=O)(O)[O-].[Na+].[S-2].[Na+].[Na+]>O.CO.[N+](C)([O-])=O>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][O:4][CH3:2])[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cl[Bi](Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C[N+](=O)[O-]
Solvent: CO
Solvent: O
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 30 °C
Reaction time: 10 h

Procedure:
To 10 ml of nitromethane were added 2.72 g of 7-ACA, 2.2 g of methanol, 9.0 g of bismuth trichloride and 5.9 g of ferric chloride. The mixture was heated at 30° C. for 160 min to advance a reaction After completion of the reaction, the reaction mixture was cooled to 5° C. To the reaction mixture was added 50 ml of water. Then, the mixture was adjusted to pH 1 with sodium bicarbonate and, then, further adjusted to pH 7.5 with sodium sulfide while cooling on ice. The resulting precipitate was filtered off, and then washed with water. The filtrate was combined with the washings. The resulting mixture was adjusted to pH 3.5 with 36 % hydrochloric acid. To the mixture was added 50 ml of methanol, and the mixture was allowed to stand at 5° C. for 10 hours, thereby to form a precipitate. The precipitate was collected by filtration, and washed with 10 ml of cold water and, then, with 10 ml of cold methanol to obtain the desired product, namely 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid. The amount of the desired product was 1.37 g. The yield of the desired product was 56 %.
Reaction SMILES: [C:1]([O:4][CH:5]([O:16][C:17](=[O:19])[CH3:18])[C:6]1[CH:11]=[CH:10][C:9](S(Cl)(=O)=O)=[CH:8][CH:7]=1)(=[O:3])[CH3:2].C1(C)C=CC=C([S:26]([Cl:29])(=[O:28])=[O:27])C=1>>[C:17]([O:16][CH:5]([O:4][C:1](=[O:3])[CH3:2])[C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([S:26]([Cl:29])(=[O:28])=[O:27])[CH:11]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(OC(C)=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Product: CC(=O)OC(OC(C)=O)c1cccc(S(=O)(=O)Cl)c1

Procedure:
The same procedure was followed as for the preparation of compound 35 starting with m-toluenesulfonyl chloride (36). 1H NMR (CDCl3, 200 MHz): δ 8.19 (m, 1H), 8.1 (m, 1H), 7.9 (m, 1H), 7.65 (m, 1H), 2.16 (s, 6H)
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8]C(=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH:11]([O:16][CH3:17])([O:14][CH3:15])OC>CO.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>[C:1]([N:4]1[CH2:9][CH2:8][C:11]([O:14][CH3:15])([O:16][CH3:17])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(=O)CC1
Reactant: COC(OC)OC
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC1(OC)CCN(C(C)=O)CC1
Yield: 89.2 %

Procedure:
A solution of 1-acetyl-4-piperidone (17.0 g, 121 mmol), trimethyl orthoformate (26.4 mL, 241 mmol) and para-toluenesulfonic acid monohydrate (80 mg, 0.42 mmol) in dry methanol (34 mL) was refluxed for one hour. Then 1.0 M methanolic NaOMe (0.42 mL, 0.42 mmol) and excess of methanol and trimethyl orthoformate were removed by distillation (atmospheric pressure). Further distillation under reduced pressure afforded 1-acetyl-4,4-dimethoxy-piperidine (20.2 g, 89%) 1H NMR (DMSO) δ 3.45-3.32 (m, 4H), 3.10 (s, 6H), 1.99 (s, 3H), 1.72-1.62 (m, 2H), 1.61-1.52 (m, 2H).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:12](Cl)/[CH:13]=[CH:14]/[CH2:15]Cl.[OH-].[K+]>[Cl-].C(C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC)(=O)CCCCCCC.C(Cl)Cl>[CH:13]([CH:14]1[CH2:15][C:2]1([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[CH2:12]
Reactant: ClC/C=C/CCl
Reactant: CCOC(=O)CC(=O)OCC
Agent: CCCCCCCC(=O)C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC
Agent: [Cl-]
Agent: [K+]
Solvent: ClCCl
Product: C=CC1CC1(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Yield: 77.9 %

Procedure:
To demonstrate the ability to vary the method of addition, diethyl malonate (160 g; 1.0 mol) was slowly charged to a reactor with external cooling means containing 137.5 g (1.10 mol) trans 1,4-dichlorobutene-2, 125 g (2.0 mol) flaked KOH (90%), 300 cc methylene chloride and 21 g (5 mol %) of tricaprylylmethylammonium chloride. The reaction mixture was stirred during the addition and temperature maintained at 25° C. with external cooling. At the completion of the reaction the resulting crude product obtained following the usual workup procedure was fractionally distilled and 165.3 g diethyl 2-vinylcyclopropane-1,1-dicarboxylate (77.9% yield) recovered. The reaction was repeated using 1/2 and 1/4 the volume of methylene chloride and yields were 77.4% and 72.3%, respectively. While the reaction does proceed when no solvent is employed, the yield of the diethyl ester product is less than optimum.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[C:7]([CH3:16])=[CH:6][C:5]1([CH3:18])[CH3:17])(=[O:3])[CH3:2].[Al+3].[Cl-].[Cl-].[Cl-]>C1C=CC=CC=1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([CH3:16])[CH2:6][C:5]1([CH3:18])[CH3:17])(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1)C(C)=CC(C)(C)N2C(C)=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: COc1ccc2c(c1)C(C)(c1ccccc1)CC(C)(C)N2C(C)=O

Procedure:
Fiedel-Crafts alkylation of benzene (25 ml) with 1-acetyl-1,2-dihydro-6-methoxy-2,2,4-trimethylquinoline (1.8 g) in the presence of AlCl3 (3.0 g) was performed according to the method described in example 3.
Reaction SMILES: [CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][NH:14][C:15](=O)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:21])=O.C(#N)C.C(=O)(O)[O-].[Na+]>ClCCl.CN(C=O)C>[CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][N:14]=[C:15]([Cl:21])[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2c1CN(Cc1ccccc1)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: ClCCl
Product: Clc1ncnc2c1CN(Cc1ccccc1)CC2
Temperature: 70 °C
Yield: 57.8 %

Procedure:
A mixture of 6-benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one (5.0 g, 0.02 mol), phosphoryl chloride (3.30 mL, 0.035 mol) and acetonitrile (80 mL) and DMF (catalytic amount) was heated to at 70° C. for 1 hour. The mixture was reduced in vacuo and the remaining black residue was taken up in dichloromethane (250 ml) and poured over ice. The mixture was carefully neutralized with the addition of solid sodium bicarbonate. The layers were separated and the organic dried over sodium sulfate and reduced in vacuo. The mixture was chromatographed using an ethyl acetate:hexanes (0-100%) gradient on an isco flash chromatography system. The combined pure fractions were reduced in vacuo to yield the title compound as a yellow oil (3 g, 57.8%).
Reaction SMILES: [N:1]12[CH2:4][CH:3]1[CH2:2]2.Br.BrC(CBr)CN.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.S(=O)(=O)(O)O.[OH-].[Ca+2].[OH-]>C(O)C.O>[NH:1]1[CH2:4][CH:3]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH2:2]1
Reactant: C1C2CN12
Reactant: C1COCCN1
Agent: Br
Agent: NCC(Br)CBr
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: C1CN(C2CNC2)CCO1
Reaction time: 0.5 h
Yield: 33 %

Procedure:
A solution of 1-azabicyclo[ 1.1.0]butane, prepared from 2,3-dibromopropylamine hydrobromide (58.8 mmol) according to a known procedure described in Tetrahedron Lett. 40: 3761-64 (1999), was slowly added to a solution of morpholine (15.7 ml; 180 mmol) and sulfuric acid (3.3 g of 96% soln.) in anhydrous non-denaturated ethanol (250 ml) at 0° C. The reaction mixture was stirred on ice bath for 30 min., then at room temperature for 8 h. Calcium hydroxide (5.5 g) and 100 ml of water was added and the obtained slurry was stirred for 1 h and then filtered through a pad of cellite. The filtrate was concentrated and distilled at reduced pressure (20 mm Hg) to remove water and an excess of morpholine. The distillation residue was re-distilled at high vacuum using a Kugelrohr apparatus to obtain a pure 4-(azetidin-3-yl)morpholine in 33% yield (2.759 g) as a colorless oily liquid.
Reaction SMILES: [CH3:1][NH:2][CH:3]([CH3:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](N)=[CH:7][CH:6]=1.[F:13][B-](F)(F)F.[H+].N([O-])=O.[Na+].N([O-])=O>[Cu]Cl.O>[CH3:1][NH:2][CH:3]([CH3:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([F:13])=[CH:7][CH:6]=1
Reactant: CNC(C)Cc1ccc(N)cc1
Reactant: F[B-](F)(F)F
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [H+]
Solvent: O
Product: CNC(C)Cc1ccc(F)cc1
Reaction time: 0.5 h

Procedure:
A solution of 8.2 g. (0.05 mole) of (±)-N-methyl-2-(4-amino-phenyl)-1-methyl-ethyl amine (HU-PS 154,060) in 30 ml. 56% fluoroboric acid and 3.5 g. (0.051 mole) of sodium nitrite in 25 ml. water are simultaneously dropped into 100 ml. of 56% fluoro boric acid under stirring and cooling at -5°-(-7°)C. so that a small excess of nitrite solution is maintained in the reaction mixture during the addition. The mixture is then stirred for a further 30 minutes at -5°-(-7°)C. and in small portions 2.5 g. freshly prepared copper (I) chloride is added to the solution. The mixture is stirred for 2 hours at room temperature and stirred for 80°-90° C. for 2 hours. After cooling the mixture is extracted with ether and the aqueous acid layer is alkalized with conc. ammonium hydroxide and extracted with benzene. The benzene extract is evaporated after drying and the residue is distilled at 10 mmHg. As a main cut 5.6 g. (±)-N-methyl-2-(4-fluorophenyl)-1-methyl-ethyl-amine (boiling point: 87°-90° C./10 mmHg) obtained which are reacted according to Example 2 with propargyl bromide and processed according to Example 2. 3.8 g. (±)-N-methyl-N-propynyl-2-(4-fluoro-phenyl)-1-methyl-ethyl-amine are obtained. Bp.: 120°-123° C./2 mmHg, nD20 =1.5054.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].[CH:29]([C:31]1[CH:49]=[CH:48][C:34]([O:35][CH2:36][C:37]([NH:40]C(=O)OC(C)(C)C)([CH3:39])[CH3:38])=[CH:33][CH:32]=1)=O>>[NH2:40][C:37]([CH3:39])([CH3:38])[CH2:36][O:35][C:34]1[CH:48]=[CH:49][C:31]([CH2:29][CH2:2][CH2:1][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=2[C@@H:12]2[CH2:21][CH2:20][C:19]3[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=3[CH2:13]2)=[CH:32][CH:33]=1
Reactant: CC(C)(COc1ccc(C=O)cc1)NC(=O)OC(C)(C)C
Reactant: CCNc1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: COc1ccc([C@@H]2CCc3cc(O)ccc3C2)c(NCCCc2ccc(OCC(C)(C)N)cc2)c1
Yield: 36.5 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (33 mg) and tert-butyl [2-(4-formylphenoxy)-1,1-dimethylethyl]carbamate (125 mg) according to an analogous synthetic method to Example 238 and purified by LC-MS, the title compound (15 mg) was obtained.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([CH3:9])[C:3]=1[CH:10](O)[C:11]([F:14])([F:13])[F:12].[CH2:16]([NH2:19])[CH:17]=[CH2:18]>>[OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([CH3:9])[C:3]=1[CH:10]([NH:19][CH2:16][CH:17]=[CH2:18])[C:11]([F:14])([F:13])[F:12]
Reactant: C=CCN
Reactant: Cn1ccc(=O)c(O)c1C(O)C(F)(F)F
Product: C=CCNC(c1c(O)c(=O)ccn1C)C(F)(F)F
Yield: 42 %

Procedure:
In a similar manner, Apo7075 was prepared from 3-hydroxy-1-methyl-2-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-4(1H)-one (1.0 g, 4.5 mmol) and allylamine (0.67 mL, 9.0 mmol). The title compound Apo7075 (497 mg) was obtained after purification by flash chromatography (5% MeOH in CH2Cl2 as eluant). Yield=42%; 1H NMR (400 MHz, DMSO+a few drops of D2O) δ (ppm): 7.65 (d, J=7.1 Hz, 1H), 6.24 (d, J=7.4 Hz, 1H), 5.70-5.80 (m, 1H), 5.14 (d, J=17.4 Hz, 1H), 5.06 (d, J=10.1 Hz, 1H), 4.63 (q, J=8.2 Hz, 1H), 3.67 (s, 3H), 3.15-3.19 (m, 2H); MS m/z 263 [M+1]+, 206 (100%).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][C:7](=O)[C:6]2[CH:10]=[CH:11][C:12]3[C:17]([C:5]=2[S:4]1(=[O:19])=[O:18])=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH3:2].[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:1]([N:3]1[CH:8]=[C:7]([N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:6]2[CH:10]=[CH:11][C:12]3[C:17]([C:5]=2[S:4]1(=[O:19])=[O:18])=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH3:2]
Reactant: C1CCNC1
Reactant: CCN1CC(=O)c2ccc3ccccc3c2S1(=O)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCN1C=C(N2CCCC2)c2ccc3ccccc3c2S1(=O)=O
Reaction time: 24 h
Yield: 50.1 %

Procedure:
A mixture of 2 gm (7.3 millimols) of 2-ethyl-2H-naphtho[2,1-e]-1,2-thiazine-4(3H)-one-1,1-dioxide, 1.04 gm (14.6 millimols) of pyrrolidine, 200 mgm p-toluenesulfonic acid and 100 mlof benzene was refluxed for 24 hours in a vessel equipped with a water trap. Subsequently, another 1.04 gm (14.6 millimols) of pyrrolidine and 200 mgm of p-toluenesulfonic acid were added, and the reaction mixture wasrefluxed for 24 hours more. After cooling, the reaction mixture was evaporated, and the residue was extracted with ether several times. The combined ether extracts were washed twice with water, dried and evaporated. Recrystallization of the residue from methanol yielded 1.2 g (50% of theory) of the desired enamine, m.p. 115°-117° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([Cl:13])[C:3]=1[NH2:4].[N:14]([O-])=O.[Na+].C(=O)=O.C(O)(C)C.O.O.[Sn](Cl)Cl>C(O)(=O)C.S(=O)(=O)(O)O.Cl.[OH-].[NH4+]>[Cl:1][C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([Cl:13])[C:3]=1[NH:4][NH2:14]
Reactant: O=N[O-]
Reactant: Nc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=C=O
Solvent: CC(=O)O
Solvent: CC(C)O
Solvent: O
Product: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 55 °C
Reaction time: 1 h
Yield: 77.7 %

Procedure:
A solution of 125 g (0.543 mole) of 2,6-dichloro-4-trifluoromethylaniline in 662 mL of glacial acetic acid was placed in a flask equipped with a stirrer. This solution was warmed to 55° C., and to it was added a suspension of 43.3 g (0.628 mole) of sodium nitrite in 318 mL of concentrated sulfuric acid. The temperature was maintained at 62°-64° C. during the first half of this addition and then the temperature was maintained at 55°-62° C. during the second half of the addition. The total addition required about 100 minutes. Upon completion of addition, the reaction mixture was allowed to cool to 40° C. and then was cooled rapidly with a bath of dry ice/isopropanol to 0° C. At this temperature a solution of 473 g (2.10 moles) of tin(II) chloride dihydrate in 323 mL of concentrated hydrochloric acid was added dropwise while the temperature was kept between -5° C. and 5° C. This addition required about 50 minutes. After the white slurry was warmed to room temperature, it was filtered, yielding a moist, white solid which was immediately placed in 1.1 L of 30% ammonium hydroxide. This mixture was stirred at room temperature for one hour and then was warmed to 40° C. with stirring. The mixture was cooled to 28° C. before being filtered. The filter cake was triturated seven times with 400 mL of diethyl ether, decanting the ether extract each time. The combined ether extracts were then washed once with water, dried over anhydrous magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure, yielding 103.4 g of 2,6-dichloro-4-trifluoromethylphenylhydrazine as a crystalline product. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[N:10]2[CH:11]=[CH:12][C:13]3[C:18]([C:9]2=[N:8][C:7]=1[CH3:20])=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19].C(N(CC)CC)C.Cl[C:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[S:31](=[O:39])(=[O:38])[N:30]=1>C(O)C>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[CH:12]=[CH:11][N:10]1[C:6]([CH2:5][S:4][CH2:3][CH2:2][NH:1][C:29]3[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[S:31](=[O:38])(=[O:39])[N:30]=3)=[C:7]([CH3:20])[N:8]=[C:9]12
Reactant: O=S1(=O)N=C(Cl)c2ccccc21
Reactant: Cc1nc2c3cccc(Cl)c3ccn2c1CSCCN
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1nc2c3cccc(Cl)c3ccn2c1CSCCNC1=NS(=O)(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
To a mixture of 3-(2-aminoethyl)thiomethyl-7- chloro-2-methylimidazo[2,1-a]isoquinoline (1.5 g) and triethylamine (0.5 g) in ethyl alcohol (35 ml) was added portionwise 3-chloro-1,2-benzisothiazole-1,1dioxide (1.0 g). After being stirred at ambient temperature for 1 hour, the resulting precipitate was collected by filtration and washed several times with ethyl alcohol to give 3-[2-[(7-chloro-2-methylimidazo[2,1-a]isoquinolin-3-yl)methylthio]ethylamino]-1,2-benzisothiazole-1,1-dioxide (2.2 g).
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][C:9](=O)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:5]=[CH:4][N:3]=1.S(=O)(=O)(O)[OH:25].C([O-])(O)=O.[Na+]>CC(O)C>[C:10]1([C:9]2[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]3[N:5]=[CH:4][NH:3][C:2](=[O:25])[C:7]=3[N:8]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=S(=O)(O)O
Reactant: O=C(Nc1c(Cl)ncnc1Nc1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: O=c1[nH]cnc2c1nc(-c1ccccc1)n2-c1ccccc1
Temperature: 90 °C
Yield: 71.6 %

Procedure:
To a stirred solution of N-(4-chloro-6-(phenylamino)pyrimidin-5-yl)benzamide obtained in step 2 (35 g, 108 mmol) in 2-propanol (360 mL) was added sulfuric acid (18.2 mL, 323.3 mmol) at 0° C. The reaction mixture was heated to reflux at 90° C. overnight. After cooled to room temperature NaHCO3 (aq) was added to the resulting reaction mixture and stirred. The resulting mixture was filtered with water (600 mL). The collected solid was dried under reduced pressure to obtain the title compound (22.3 g, 72%) as white solid.