Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN1C(C)(C)CC[CH2:4][C:3]1(C)C.C#C.Cl[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:16]>CN(C)C1C=CN=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.ClCCl>[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])(=[O:16])[C:3]#[CH:4]
Reactant: CCCCOC(=O)Cl
Reactant: CN1C(C)(C)CCCC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C#C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C#CC(=O)OCCCC
Temperature: 40 °C
Yield: 85 %

Procedure:
0.42 g (0.36 mmol) of tetrakis(triphenylphosphine)palladium(0), 20 mg (0.16 mmol) of 4-dimethylamino-pyridine and 2.87 g (18.5 mmol) of 1,2,2,6,6-penta-methylpiperidine are introduced into 30 ml of dichloromethane in a 60 ml autoclave under argon. Then 10 bar of acetylene are injected, and the autoclave is heated to 40° C. 5 g (36.6 mmol) of n-butyl chloroformate are pumped in over the course of 10 min, and then acetylene is further injected to 20 bar. The amount of acetylene taken up is replenished hourly over the course of 24 h, and, after cooling, the reaction discharge is flushed with nitrogen and the reaction mixture is distilled. n-Butyl propiolate is isolated in 85% yield.
Reaction SMILES: S(O)(O)(=O)=O.N[C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:10][N:11]=1.N([O-])=O.[Na+].[ClH:22]>>[Cl:22][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:10][N:11]=1
Reactant: Nc1nnc(-c2ccccc2)s1
Reactant: Cl
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Clc1nnc(-c2ccccc2)s1
Temperature: 0 °C

Procedure:
A mixture of 2-amino-5-phenyl-1,3,4-thiadiazole sulphate (10.0 g, 56.4 mmol) and conc. hydrochloric acid (100 ml) was stirred at 0° C. Sodium nitrite (5.06 g, 69 mmol) was added at 0° C. The mixture was stirred for 9 days at room temperature. The crystals were filtered and resuspended in aqueous hydrochloric acid (150 ml, 1M), stirred overnight and filtered. Aqueous sodium hydroxide (100 ml, 4 M) was added and extracted with ethyl acetate. Yield 5.68 g.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][N:5]1[C:11](=[O:12])[C@@H:10]([NH2:13])[C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=2[C:7]2[CH:18]=[CH:19][CH:20]=[CH:21][C:6]1=2.[CH3:23][CH:24]([C:28]([NH:30][CH2:31][C:32]([F:38])([F:37])[C:33]([F:36])([F:35])[F:34])=[O:29])[C:25](O)=[O:26].ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.C(Cl)CCl>C1COCC1>[CH3:1][O:2][C:3](=[O:22])[CH2:4][N:5]1[C:11](=[O:12])[C@@H:10]([NH:13][C:25](=[O:26])[CH:24]([C:28](=[O:29])[NH:30][CH2:31][C:32]([F:37])([F:38])[C:33]([F:34])([F:36])[F:35])[CH3:23])[C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=2[C:7]2[CH:18]=[CH:19][CH:20]=[CH:21][C:6]1=2
Reactant: COC(=O)CN1C(=O)[C@@H](N)c2ccccc2-c2ccccc21
Reactant: CC(C(=O)O)C(=O)NCC(F)(F)C(F)(F)F
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COC(=O)CN1C(=O)[C@@H](NC(=O)C(C)C(=O)NCC(F)(F)C(F)(F)F)c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 70 %

Procedure:
((S)-7-Amino-6-oxo-6,7-dihydro-dibenzo[b,d]azepin-5-yl)-acetic acid methyl ester (25 mg, 0.85 mmol) were dissolved in THF and subsequently treated with 2-methyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid (25 mg, 0.1 mmol), 1-hydroxybenzotriazole (11.6 mg, 0.85 mmol), N-ethyldiisopropylamine (0.03 ml, 0.17 mmol) and EDC (16.5 mg, 0.85 mmol). After stirring for 2.5 h at ambient temperature, the reaction mixture is quenched with water and extracted with ethyl acetate. The aqueous phase is extracted twice with ethyl acetate and the combined organic layers are extracted with water (2×5 ml) and saturated aqueous sodium chloride (5 ml), combined, dried over anhydrous sodium sulfate and evaporated to dryness. Chromatography (silica, eluent cyclohexane/ethyl acetate 65/35) afforded the product as colorless solid (70%). MS: m/e=528 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([CH:9]([CH3:11])[CH3:10])[C:6]=1[CH:7]=[O:8].[BH4-].[Na+].O>CO>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([CH:9]([CH3:11])[CH3:10])[C:6]=1[CH2:7][OH:8]
Reactant: Cc1ncn(C(C)C)c1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1ncn(C(C)C)c1CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.7 %

Procedure:
To a 0° C. solution of 4-methyl-1-(propan-2-yl)-1H-imidazole-5-carbaldehyde (924 mg, 6.1 mmol) in anhydrous methanol (75 mL) was added sodium borohydride (425 mg, 11.2 mmol). The reaction mixture was stirred at room temperature for 3 hours. Water (20 mL) was added. Methanol was evaporated. The resultant mixture was extracted with EtOAc (1×20 mL) and 2-butanol (2×20 mL). The solution was dried over MgSO4, filtered, evaporated, and dried in vacuo, affording [4-methyl-1-(propan-2-yl)-1H-imidazol-5-yl]methanol (703 mg, 75% yield). The product was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:5]([C:8](OCC)=[O:9])=[N:6][CH:7]=1.[O-]CC.[Na+].C(OCC)(=O)C.C(O)(=O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[O:13][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:8]([OH:9])[C:5]2=[N:6][CH:7]=1
Reactant: CCOC(=O)COc1cc(Cl)cnc1C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1oc2cc(Cl)cnc2c1O
Yield: 47.5 %

Procedure:
To a solution of ethyl 5-chloro-3-(2-ethoxy-2-oxoethoxy)picolinate (385 mg, 1.34 mmol) in toluene (10 ml) at 23° C. was added sodium ethoxide (200 mg, 2.94 mmol) and the reaction mixture was stirred at reflux overnight. To the yellow suspension was added some ice, ethyl acetate and set to pH=4 with acetic acid. The organic layer was separated and washed with sat NaHCO3 solution. The aqueous layers were reextracted with ethyl acetate, then dried over Na2SO4, filtered and evaporated to give the crude ethyl 6-chloro-3-hydroxyfuro[3,2-b]pyridine-2-carboxylate (154 mg, 637 μmol, 47.6% yield) as a light brown solid. MS (ISN): m/z=240.1 [(M−H)−] and 242.3 [(M+2−H)−].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:22])[CH2:10][C@H:11]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:12]([O:14]C)=[O:13])=[CH:4][CH:3]=1.[OH-].[Na+]>CO.C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:22])[CH2:10][C@H:11]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:12]([OH:14])=[O:13])=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](CC(=O)Nc1ccc(Cl)cc1)C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(C[C@@H](C(=O)O)C1CCCCC1)Nc1ccc(Cl)cc1
Yield: 100.9 %

Procedure:
Methyl(2R)-4-((4-chlorophenyl)amino)-2-cyclohexyl-4-oxobutanoate (0.29 g) obtained in Example 5a) and 1 N sodium hydroxide (1.0 ml) were dissolved in methanol (12 ml) and THF (3 ml), and mixed at room temperature for 1 hour. Then, the reaction solution was concentrated under reduced pressure, acidified by adding 1 N hydrochloric acid to the concentrated solution and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound as pale brown powder (0.28 g, quantitative).
Reaction SMILES: [C:1]1(=[O:26])[N:5]([CH2:6][C:7]2[N:8]=[C:9]([N:12]3[CH2:15][CH:14](OS(C)(=O)=O)[CH2:13]3)[S:10][CH:11]=2)[C:4](=[O:21])[C:3]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:2]12.[C:27]([O-:30])(=[S:29])[CH3:28].[K+]>CN(C)C=O>[C:27]([S:29][CH:14]1[CH2:15][N:12]([C:9]2[S:10][CH:11]=[C:7]([CH2:6][N:5]3[C:1](=[O:26])[C:2]4=[CH:25][CH:24]=[CH:23][CH:22]=[C:3]4[C:4]3=[O:21])[N:8]=2)[CH2:13]1)(=[O:30])[CH3:28]
Reactant: CC([O-])=S
Reactant: CS(=O)(=O)OC1CN(c2nc(CN3C(=O)c4ccccc4C3=O)cs2)C1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(CN3C(=O)c4ccccc4C3=O)cs2)C1
Temperature: 90 °C
Reaction time: 6.5 h
Yield: 86.7 %

Procedure:
To a solution of 1-(4-phthalimidomethyl-1,3-thiazol-2-yl)-3-methanesulfonyloxyazetidine (726 mg, 1.85 mmol) (obtained as described in Reference Example 68(3)) in dimethylformamide (22 ml) was added potassium thioacetate (1.26 g, 11.1 mmol) at room temperature, and the mixture was stirred in an oil bath (90° C.) for 6.5 hours. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (1:1) as the eluant to afford 3-acetylthio-1-(4-phthalimidomethyl-1,3-thiazol-2-yl)azetidine (599 mg, yield 87%) as a pale brown solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Br[CH:23]([CH2:25][CH2:26][CH3:27])[CH3:24]>>[CH3:24][CH:23]([N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCC(C)Br
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: CCCC(C)N1CCC2(CC1)CSC1=C(O2)c2ccccc2C(=O)C1=O

Procedure:
Compound 127 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 2-bromopentane and conditions outlined in procedure V. M.p.=109-111° C.; 400 MHz 1H NMR (CDCl3) δ 8.05 (d, 1H), 7.75 (d, 1H), 7.65 (t, 1H), 7.5 (t, 1H), 2.9 (s, 2H), 2.8-2.6 (m, 5H), 2.1 (d, 2H), 1.85 (q, 2H), 1.55 (m, 1H), 1.4-1.15 (m, 3H), 1.0 (t, 3H), 0.9 (t, 3H); LCMS: 372 [M+H].
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:21](OC)=[O:22])=[CH:7][CH:8]=[C:9]2[C:18]=1[CH:17]=[C:16]([O:19]C)[C:15]1[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:4].[Na+].C(=O)([O-])O>O>[OH:19][C:16]1[C:15]2[C:10]([C:9]3[C:18]([CH:17]=1)=[C:5]1[C:3]([O:2][C:21](=[O:22])[C:6]1=[CH:7][CH:8]=3)=[O:4])=[CH:11][CH:12]=[CH:13][CH:14]=2
Reactant: COC(=O)c1ccc2c(cc(OC)c3ccccc32)c1C(=O)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C1OC(=O)c2c1ccc1c2cc(O)c2ccccc21
Temperature: 0 °C
Reaction time: 5 h
Yield: 88.4 %

Procedure:
9-methoxy phenanthrene-1,2-dicarboxylic acid dimethyl ester 8.11 g (0.025 mol) obtained in the example I-1 was dissolved in chloride methylene 100 ml, by ice-cooling and mixing under nitrogen gas airstreams, 1M 3 bromide boron/chloride methylene solution 100 ml (0.1 mol) was dropped for 60 minutes, and further a mixing reaction was performed for 5 hours under a room temperature. Then, reactants were poured into an ice, water was added, and further hydrogen carbonate sodium 8.4 g (0.1 mol) was added and mixed sufficiently, accordingly extracted crystals were filtered. Then, they were washed twice by 500 ml ion exchange water and dried under reduced pressure at the temperature of 60° C., thus 5.84 g (yield 88.4%) objective phenanthrene compound was obtained. An infrared absorption spectrum of this phenanthrene compound is shown in FIG. 5.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH2:14][OH:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:25]N(C)P(=O)(N(C)C)N(C)C.CI>O>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]([CH2:14][O:15][CH3:25])([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: OCC1(Nc2ccccc2)CCN(Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COCC1(Nc2ccccc2)CCN(Cc2ccccc2)CC1

Procedure:
A mixture of 72.5 g of 1-benzyl-4-anilino-4-piperidinemethanol, 11 g of sodium hydride (50% in mineral oil) and 427 g of hexamethylphosphoric triamide is stirred. Then 33 g of methyl iodide is added dropwise to the reaction mixture and the mixture is stirred overnight. The mixture is added to 2500 ml of water, extracted with six 500 ml portions of toluene, dried over anhydrous sodium sulfate and flash evaporated to give an oil. The oil is purified in a Waters Associates Prep LC/System 500, using a PrepPAK-500/SILICA column (40% ethyl acetate in hexane) to give 1-benzyl-4-methoxymethyl-4-anilinopiperidine.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][C@@H:8]([CH3:12])[CH2:9][O:10][CH3:11])=[O:6].[H-].[Na+].CCOC(C)=O>C1COCC1>[CH3:11][O:10][CH2:9][C@H:8]([N:7]1[CH2:2][CH2:3][NH:4][C:5]1=[O:6])[CH3:12]
Reactant: COC[C@H](C)NC(=O)NCCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC[C@@H](C)N1CCNC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A −20° C. solution of (S)-1-(2-chloroethyl)-3-(1-methoxypropan-2-yl)urea (393 mg, 2.019 mmol) in THF (10 mL) was treated portion-wise with NaH (60% in mineral oil, 178 mg, 4.44 mmol), warmed to RT and stirred overnight. The mixture was treated with EtOAc, washed with water, then brine, dried over Na2SO4 and concentrated to dryness to afford crude (R)-1-(1-methoxypropan-2-yl)imidazolidin-2-one (100% yield assumed) which was used without further purification. MS (ESI) m/z: 159.1 (M+H+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([OH:20])[CH2:19][CH2:18][C:13]4(OCC[O:14]4)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1>CC(C)=O.Cl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([OH:20])[CH2:11][CH2:12][C:13](=[O:14])[CH2:18][CH2:19]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: OC1(c2ccc3c(c2)OCO3)CCC2(CC1)OCCO2
Agent: Cl
Solvent: CC(C)=O
Product: O=C1CCC(O)(c2ccc3c(c2)OCO3)CC1

Procedure:
A solution of 8-(1,3-benzodioxol-5-yl)-1,4-dioxaspiro-[4.5]decan-8-ol (5.0 g, 1.8 mmole) in acetone (75 ml) and concentrated HCl (1 ml) was stirred for 2 hr. The insoluble product was collected and dried (96%, mp: 162-164° C.). Calc'd for C13H14O4 : C, 66.66%; H, 6.03%. Found: C, 65.69%; H, 5.95%.
Reaction SMILES: [C:1]([C:4]1[NH:5][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[Br:9]N1C(=O)CCC1=O>O1CCCC1.CO>[Br:9][C:6]1[NH:5][C:4]([C:1](=[O:3])[CH3:2])=[CH:8][CH:7]=1
Reactant: CC(=O)c1ccc[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)c1ccc(Br)[nH]1
Temperature: 25 °C
Yield: 22.4 %

Procedure:
2-Acetylpyrrole (2.00 g, 18.3 mmol) was dissolved in a mixed solvent of tetrahydrofuran (100 mL) and methanol (50 mL), and N-bromosuccinimide (3.26 g, 18.3 mmol) was added with stirring at room temperature under nitrogen atmosphere. After stirring for 1 hour, the solvent was distilled off under reduced pressure. A saturated aqueous sodium hydrogencarbonate solution (200 mL) was added, and extraction was carried out with ethyl acetate (300 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=10%-20%) to afford the desired compound (770 mg, yield 22%) as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][N:9]2[CH:14]=[CH:13][N:12]3[CH:15]=[CH:16][CH:17]=[C:11]3[CH2:10]2)[CH2:3][CH2:2]1.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24](Cl)=[O:25]>N1C=CC=CC=1>[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][N:12]3[CH2:15][CH2:16][CH2:17][CH:11]3[CH2:10]2)[CH2:3][CH2:2]1)=[O:25]
Reactant: O=C(Cl)c1ccccn1
Reactant: C1=Cn2cccc2CN1CCC1CCNCC1
Solvent: c1ccncc1
Product: O=C(c1ccccn1)N1CCC(CCN2CCN3CCCC3C2)CC1

Procedure:
In the manner of Example 2, 2-(4-piperidylethyl)pyrrolo[1,2-a]pyrazine and 2-pyridine carbonyl chloride will react in pyridine solution to give the title compound.
Reaction SMILES: [CH3:1][N:2]([C:6]1[S:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1)[C:3]#[C:4][CH3:5].[OH-].[K+].[I:17]I>CO.O>[CH3:1][N:2]([CH2:3][C:4]#[C:5][I:17])[C:6]1[S:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1
Reactant: CC#CN(C)c1nc2ccccc2s1
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(CC#CI)c1nc2ccccc2s1
Yield: 99.8 %

Procedure:
Compound (d) (2.02 g) was dissolved in a mixture of methanol (35 ml), water (10 ml) and 86% potassium hydroxide (1.4 g) and then iodine (2.66 g) was added in small portions with stirring under ice-cooling. The mixture was stirred at room temperature for 1.5 hours and then water was added thereto. The resultant crystals were filtered off, washed with water and dried to give 2-(N-methyl-3-iodo-2-propynylamino)benzothiazole (No.2) (3.27 g, yield 100%): mp. 100°-101° C. (decomp.) (acetone-hexane), Hydrochloride: mp. 156°-160° C. (decomp.), Nitrate: mp. 108°-109° C. (decomp.), Hydrobromide: mp. 158°-160° C. (decomp.).
Reaction SMILES: [OH:1][CH:2]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[C:3]#[C:4][C:5]([O:7][CH3:8])=[O:6]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([C:2]([C:3]#[C:4][C:5]([O:7][CH3:8])=[O:6])=[O:1])=[CH:14][CH:13]=1
Reactant: COC(=O)C#CC(O)c1ccc(OC)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COC(=O)C#CC(=O)c1ccc(OC)cc1
Reaction time: 0.5 h

Procedure:
A solution of 75 g (34 mmol) of methyl 4-hydroxy-4-(4-methoxyphenyl)-2-butynoate in 100 ml of methylene chloride was added dropwise at 0° to a suspension of 84.4 g (0.97 mol) of manganese dioxide in 150 ml of methylene chloride. The reaction mixture was stirred at 0° for 30 minutes, filtered over magnesium sulphate and concentrated. Crystallization of the residue from ether/hexane yielded methyl 3-(4-methoxybenzoyl)propiolate of melting point 68°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].C([O:12][C:13](=[O:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](O)=[O:21])C.[OH-].[Na+].Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C.O.B(O)(O)O.NC1C=CC(C)=CN=1>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([OH:9])=[C:2]([CH:7]=1)[NH:1][C:20](=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C:13]([OH:23])=[O:12]
Reactant: CCOC(=O)CCCCCCC(=O)O
Reactant: Nc1cc(Cl)ccc1O
Agent: Cc1ccc(N)nc1
Agent: Cl
Agent: OB(O)O
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)CCCCCCC(=O)Nc1cc(Cl)ccc1O
Temperature: 85 °C
Yield: 60 %

Procedure:
8-(5-chloro-2-hydroxyanilino)-8-oxooctanoic acid was prepared as follows. A suspension of 2 amino-4-chlorophenol (17.88 g, 124.5 mmol), 8-ethoxy-8-oxo-octanoic acid (25.19 g, 124.5 mmol), boric acid (0.385 g, 6.23 mmol), and 2-amino-5-picoline (0.675 g, 6.23 mmol) in 160 mL of dried toluene was heated at reflux (110° C.) under nitrogen for 4 hours during which water (2.5 mL) produced in the reaction was removed by azeotropic distillation in a Dean-Stark separation unit. Thin layer chromatography on silica gel with an eluant of ethylacetate and heptane at a molar ratio of 1:1 indicated the completion of the reaction. The mixture was cooled and a 2N aqueous solution of sodium hydroxide (125 mL, 250 mmol) was added. The mixture was heated at reflux (about 85° C.) for 4 hours and cooled. The cooled mixture was diluted with ethyl acetate (300 mL) and water (150 mL). The aqueous layer was washed with two portions of ethyl acetate (250 mL). After careful separation, the aqueous layer was chilled and acidified with a 10% (by weight) solution of hydrochloric acid (86.20 mL, 250 mmol) to yield a solid. The solid was filtered, washed with hexane, and dried under vacuum. Trituration with dichloromethane yielded the 8-(5-chloro-2-hydroxyanilino)-8-oxooctanoic acid (22.39 g, 60%) as an off-white solid. HPLC (Column: Higgins Kromasil 100 C18, water/acetonitile/acetic acid: 950/50/1, 3 mL/min, 220 nm) Rt 5.38 min.; melting point 123-124° C.; 1H NMR(DMSO d6, 300 MHz)δ: 1.28(m, 4H), 1.51 (m, 4H), 2.19 (t, 2H), 2.39 (t, 2H),6.83 (d, 1H), 6.93 (dd, 1H), 7.95 (d, 1H), 9.20 (s, 1H), 10.10 (s, 1H), 12.00 (br s, 1H); 13C NMR (DMSO d6, 75 MHz) δ: 24.29, 24.90, 28.20, 33.58, 35.90, 116.50, 121.02, 122.20, 123.41, 127.74, 148.23, 171.93, 174.26. MS m/z 300 (M+1)+. Anal. Calcd for C14H18ClNO4: C, 56.10; H, 6.05; Cl, 11.83, N, 4.67. Found: C, 56.07, H, 6.11, 11.98, N, 4.64.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[Si:9]([O:16][CH:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Si:9]([O:16][CH:17]1[CH2:18][CH2:19][CH:20]([NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[I:1])[CH2:21][CH2:22]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(=O)CC1
Reactant: Nc1ccccc1I
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CCC(Nc2ccccc2I)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
To a solution of 2-iodoaniline (2.5 g, 10.9 mmol) in dichloromethane (160 mL) was added 4-(tert-butyldimethylsilanyloxy)cyclohexanone (2.39 g, 10.9 mmol) and acetic acid (8 mL). After the reaction was stirred for 1 hour at room temperature, sodium triacetoxyborohydride (3.47 g, 16.4 mmol) was added and the reaction was stirred at room temperature overnight. The reaction was quenched with saturated sodium bicarbonate and extracted with dichloromethane. The organic solution was dried (MgSO4) and concentrated to give 4.47 g of the desired amine, which was used without further purification. LC-MS (C18H30INOSi calc'd 431) m/z 432 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]([OH:12])=[CH:4][CH:3]=1.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH2:18]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:18][C:14]2[S:13][CH:17]=[CH:16][CH:15]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: OCc1cccs1
Reactant: COC(=O)c1cc(Br)ccc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)ccc1OCc1cccs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55 %

Procedure:
Methyl 5-bromosalicylate [prepared by treating methyl 5-bromosalicyclic acid with methanol and sulphuric acid] (4.62 g, 20 mmol) was dissolved in THF (150 mL) and treated with thiophene methanol (2.28 g, 20 mmol) and triphenyl phosphine (10.4 g, 40 mmol). The reaction was cooled in an ice bath and treated with DEAD (6.96 g, 20 mmol). The resultant orange solution was allowed to stir at ambient temperature under argon for 18 hours. The reaction mixture was evaporated and the residue subjected to chromatography (eluant: diethyl ether/hexane) to give methyl 5-bromo-2-(2-thienylmethoxy)benzoate as a pink oil (3.6 g, 55%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:22][CH3:23])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[O:14])=[CH:8][C:7]=2[CH:21]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([O:37][CH3:38])[C:34]=1[O:35][CH3:36])[C:29](O)=[O:30].C(N(CC)CC)C.P(C#N)(=O)(OCC)OCC>C(OCC)(=O)C.O.CN(C)C=O>[CH3:1][O:2][C:3]1[C:4]([O:22][CH3:23])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:29](=[O:30])[C:28]4[CH:27]=[C:26]([O:25][CH3:24])[C:34]([O:35][CH3:36])=[C:33]([O:37][CH3:38])[CH:32]=4)[CH2:17][CH2:16]3)=[O:14])=[CH:8][C:7]=2[CH:21]=1
Reactant: COc1cc2c(cc1OC)CCCC(C(=O)N1CCNCC1)=C2
Reactant: COc1cc(C(=O)O)cc(OC)c1OC
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)CCCC(C(=O)N1CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)CC1)=C2
Yield: 85.2 %

Procedure:
To a mixture of 1-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl)piperazine (0.8 g), 3,4,5-trimethoxy benzoic acid (0.55 g), triethylamine (0.4 g) and N,N-dimethylformamide (10 ml) is added dropwise diethyl phosphorocyanidate (0.5 g) with stirring under ice-cooling. The reaction mixture is stirred for one hour at room temperature. To the reaction mixture are added water (60 ml) and ethyl acetate (50 ml), followed by shaking. The organic layer is separated, washed with water, dried and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent, ethyl acetate:hexane:acetone=10:5:8) to afford 1-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl)-4-(3,4,5-trimethoxybenzoyl)piperazine (1.1 g). This product is in agreement with the compound obtained by Example 62 in physico-chemical constants.