Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OCC)C.[CH3:6][C:7]([CH:14]=[CH:15][CH:16]=[C:17]([CH3:29])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:28])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])=[CH:8][C:9](OCC)=[O:10].C(Cl)(=O)OCC.[NH3:36]>C(N(CC)CC)C>[CH3:6][C:7]([CH:14]=[CH:15][CH:16]=[C:17]([CH3:29])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:28])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])=[CH:8][C:9]([NH2:36])=[O:10]
Reactant: CCOC(=O)C=C(C)C=CC=C(C)CCC=C(C)CCC=C(C)C
Reactant: N
Agent: CCOC(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)=CCCC(C)=CCCC(C)=CC=CC(C)=CC(N)=O
Reaction time: 0.17 h

Procedure:
In 20 ml. of diethyl ether was dissolved 3.0 g. of the above-obtained 3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid. To this solution was added 1 g. of triethylamine, and further added 1.1 g. of ethyl chlorocarbonate under stirring at room temperature. After 10 minutes, gaseous ammonia was introduced into the solution. The reaction liquid was washed with three 10 ml. portions of water, dried over magnesium sulfate, and evaporated to remove the solvent. The residue was purified by alumina column chromatography and crystallized from a mixture of acetone and n-hexane (1:2). There was obtained 1.7 g. of the desired product as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][N:10]([C:14](=[O:21])[CH2:15][NH:16][CH2:17][CH2:18][O:19][CH3:20])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[CH3:33])[C:27](O)=[O:28].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN1C(=O)CCC1>[Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][N:10]([C:14](=[O:21])[CH2:15][N:16]([CH2:17][CH2:18][O:19][CH3:20])[C:27](=[O:28])[C:26]3[CH:30]=[CH:31][C:32]([CH3:33])=[C:24]([OH:23])[CH:25]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(=O)O)cc1O
Reactant: COCCNCC(=O)N1CC(=O)N(c2cccc(Cl)c2C)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Product: COCCN(CC(=O)N1CC(=O)N(c2cccc(Cl)c2C)C1)C(=O)c1ccc(C)c(O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 4 mL vial was taken 100 mg of 3-(3-chloro-2-methyl-phenyl)-1-[2-(2-methoxy-ethylamino)-acetyl]-imidazolidin-4-one (0.31 mmol, 1.00 eq), 52 mg of 3-hydroxy-4-methylbenzoic acid (0.31 mmol, 1.00 eq), 163 mg BOP (0.37 mmol, 1.20 eq), 171 uL (1.23 mmol, 4.00 eq), and 1.5 mL NMP. The mixture was stirred overnight at room temperature and the crude product was purified by reversed phase HPLC (acetonitrile —H2O with 0.1% TFA as the eluent) to yield N-{2-[3-(3-chloro-2-methyl-phenyl)-4-oxo-imidazolidin-1-yl]-2-oxo-ethyl}-3-hydroxy-N-(2-methoxy-ethyl)-4-methyl-benzamide. MS (ES) M+H expected=480.0, found=480.1.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([Mg]Br)=[CH:3][CH:2]=1.C1(C)C=CC(Br)=CC=1.[Mg].[CH:19]12[O:25][CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24]2>O1CCCC1>[C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]2[OH:25])=[CH:3][CH:2]=1
Reactant: Cc1ccc([Mg]Br)cc1
Reactant: C1CCC2OC2C1
Agent: Cc1ccc(Br)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1ccc(C2CCCCC2O)cc1
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
A solution of p-tolyl-magnesium bromide, prepared from 17.1 g (100 mmol) p-tolyl bromide and 2.43 g (100 mmol) magnesium, in 100 ml abs. tetrahydrofuran was cooled to −20° C. and 1 g CuBr-dimethylsulfid complex was added and the mixture stirred at −20° C. for 10 min. To this a solution of 10 ml (9.80 g, 100 mmol) cyclohexene oxide in 10 ml abs. tetrahydrofuran was added drop-wise and the reaction warmed to 0° C. at which an exothermic reaction starts. With cooling the temperature was maintained below 25° C. The reaction mixture was stirred at 0 to 5° C. for additional 2h, then quenched with saturated aqueous ammonium chloride solution and extracted with tert.-butyl methyl ether. The organic extract was washed with water, dried over Na2SO4, filtered and evaporated. The residue, 18.25 g slightly yellow crystals was re-crystallizes from n-hexane: 9.91 g rac-2-p-tolyl-cyclohexanol as colorless crystals: m.p. 72.5–73° C., MS (EI): 190.1 M+.
Reaction SMILES: CO[C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[CH:12][O:13][CH:14]=2)[CH:5]=1.[C:16]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])[CH3:17].[Li]>>[C:20]([O:19][C:16](=[O:18])[CH2:17][C:3]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[CH:12][O:13][CH:14]=2)[CH:5]=1)=[O:15])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(=O)OC(C)(C)C
Reactant: COC(=O)c1cccc(-c2cocn2)c1
Agent: [Li]
Product: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cocn2)c1

Procedure:
3-Oxazol-4-yl-benzoic acid methyl ester (0.85 g) was treated with lithium tert.-butyl acetate according to the general procedure K (method b) to give crude 3-(3-oxazol-4-yl-phenyl)-3-oxo-propionic acid tert-butyl ester (1.46 g) as a pale-yellow oil.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]3[C:13]([C:14]4[C:15]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)=[N:16][O:17][C:18]=4[CH3:19])=[N:12][N:11]=[C:8]32)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1)CCC>CN(C=O)C>[CH3:19][C:18]1[O:17][N:16]=[C:15]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]=1[C:13]1[N:7]2[CH2:6][C:5]3[C:9]([C:8]2=[N:11][N:12]=1)=[CH:10][C:2]([C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1)=[CH:3][CH:4]=3
Reactant: Cc1onc(-c2ccccc2)c1-c1nnc2n1Cc1ccc(Br)cc1-2
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccc2)c1-c1nnc2n1Cc1ccc(-c3cccnc3)cc1-2
Temperature: 100 °C
Yield: 75.3 %

Procedure:
A mixture of 8-bromo-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole (100 mg) (as prepared in Example 4), 3-(tri-n-butylstannyl)pyridine (442 mg) and DMF (5 ml) was degassed with a stream of N2 for 0.5 h. Bis(triphenylphosphine)palladium(II) chloride (5 mg) was added and the reaction heated to 100° C. for 2 h. The mixture was concentrated under reduced pressure and the residue purified by column chromatography on silica, eluting with 2.5% MeOH/CH2Cl2 to give the title compound (75 mg, 64%). 1H NMR (400 MHz, CDCl3) δ 8.66 (1H, t, J=3.3 Hz), 8.23 (1H, d, J=1.4 Hz), 7.95–7.92 (1H, m), 7.63 (1H, dd, J=8.0, 1.7 Hz), 7.57–7.54 (2H, m), 7.49–7.38 (5H, m), 4.07 (2H, s), 3.97 (2H, s), 2.73 (3H, s), m/z (ES+) 392 (M+H)+.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:17]([NH2:18])=[N:16][C:10]2[N:11]=[C:12]([NH2:15])[N:13]=[CH:14][C:9]=2[CH:8]=1.[C:20]([N:24]=[C:25]=[O:26])([CH3:23])([CH3:22])[CH3:21].N>C>[NH2:15][C:12]1[N:13]=[CH:14][C:9]2[CH:8]=[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[CH3:19])[C:17]([NH:18][C:25]([NH:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])=[N:16][C:10]=2[N:11]=1
Reactant: Cc1ccccc1-c1cc2cnc(N)nc2nc1N
Reactant: CC(C)(C)N=C=O
Agent: C
Agent: N
Product: Cc1ccccc1-c1cc2cnc(N)nc2nc1NC(=O)NC(C)(C)C

Procedure:
The title compound was prepared from 6-o-tolyl-pyrido[2,3-d]pyrimidine-2,7-diamine from Example 90 and tert-butyl isocyanate according to Example 2. The product was purified by MPLC eluting with CHCl3 :EtOAc (1:1) afford the pure product; mp 195-197° C., CIMS (1% ammonia in methane): m/z (relative intensity) 351 (MH+ +1, 55), 352 (MH+ +2, 12), 84 (100).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:13][C:14]1[CH:15]=[C:16]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[C:17]([O:19]C)=[O:18])[CH2:9][CH2:10][CH2:11][CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>CO.O1CCCC1>[C:1]([O:5][C:6]([N:8]([CH2:13][C:14]1[CH:15]=[C:16]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[C:17]([OH:19])=[O:18])[CH2:9][CH2:10][CH2:11][CH3:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCN(Cc1cc(C)cc(C(=O)OC)c1)C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCCCN(Cc1cc(C)cc(C(=O)O)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 3-{[(tert-butoxycarbonyl)(butyl)amino]methyl}-5-methylbenzoate (70 mg, 0.21 mmol) in methanol (2 mL), tetrahydrofuran (1 mL), and water (1 mL) is added lithium hydroxide (88 mg, 2.1 mmol), and the reaction mixture stirred at room temperature for 2 h. The reaction mixture is concentrated under reduced pressure, dissolved in methylene chloride, filtered, and the filtrate concentrated under reduced pressure to provide the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([Cl:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([O:13][CH2:14][CH2:15][CH3:16])[N:3]=1.[F-:17].[Cs+]>CS(C)=O>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[C:4]([O:13][CH2:14][CH2:15][CH3:16])[N:3]=[C:2]2[F:17]
Reactant: [F-]
Reactant: CCCOc1cc2c(Cl)cccc2c(Cl)n1
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCCOc1cc2c(Cl)cccc2c(F)n1
Temperature: 140 °C

Procedure:
To a solution of 1,5-dichloro-3-propoxyisoquinoline (565 mg, 2.206 mmol) in DMSO (5 mL) was added CsF (369 mg, 2.427 mmol) and heated to 140° C. for 2 hrs. LC/MS showed the desired product. The reaction was diluted with Ethylacteate and washed with water, and brine. The organic phase was collected, dried over MgSO4, and concentrated under vacuum to give the crude product as a reddish brown solid. Crude material purified via silica gel chromatography (90 g column; 0-40% EtOAc:Hex) to get the product 5-chloro-1-fluoro-3-propoxyisoquinoline (440 mg, 83% yield) as a yellow solid. MS: MS m/z 240.05(M++1).
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[F:16][CH:17]([F:29])[CH2:18][O:19][C:20]1[N:25]=[CH:24][C:23]([CH2:26][NH2:27])=[CH:22][C:21]=1[CH3:28]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:27]([CH2:26][C:23]3[CH:24]=[N:25][C:20]([O:19][CH2:18][CH:17]([F:29])[F:16])=[C:21]([CH3:28])[CH:22]=3)[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: Cc1cc(CN)cnc1OCC(F)F
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: Cc1cc(CN2Cc3c(ccnc3Cl)C2=O)cnc1OCC(F)F
Yield: 44 %

Procedure:
The title compound is prepared in 44% yield (154 mg, pale yellow oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (279 mg, 1.0 mmol, Step-1 of Intermediate-1) and (6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methanamine hydrochloride (239 mg, 1.0 mmol, Amine-4) in a similar manner to Step-2 of Intermediate-1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25](OS(C)(=O)=O)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C.O>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: Oc1ccccc1Br
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2Br)CC1
Temperature: 80 °C
Yield: 62.2 %

Procedure:
To a stirred solution of 2-bromophenol (0.5 g, 0.00289 mole) in DMF (4 mL) was added potassium carbonate (0.478 g, 0.003468 mole), followed by 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (0.888 g, 0.00318 mole). The reaction mixture was heated at 80° C. for 6 hours. The mixture was then diluted with water and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography using silica gel 60-120 mesh (2% ethyl acetate in hexane) to afford 0.64 g (68%) of 4-(2-bromo-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester. LCMS: 356.08 (M+1)+, 99.56%. A solution of 4-(2-bromo-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (0.64 g, 0.0018 mole) in dichloromethane (6.4 mL) was stirred at 0-5° C. To the cold solution was added TFA (3.2 mL) dropwise and stirring was continued at ambient temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was washed with hexane to afford 0.64 g (96%) of 4-(2-bromo-phenoxy)-piperidine trifluoroacetate. LCMS: 370.02 (M+1)+, 91.37%. 1H NMR (CDCl3-D2O): δ 7.6-7.54 (d, 1H), 7.32-7.26 (d, 1H), 6.94-6.86 (d, 2H), 4.8-4.7 (bs, 1H), 3.5-3.4 (m, 2H), 3.3-3.2 (m, 2H), 2.2-2.1 (s, 4H).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][S:7][C:8]1[N:9]=[CH:10][N:11]2[CH:15]=[CH:14][S:13][C:12]=12)=[N+]=[N-].Cl.[H][H]>C1COCC1.C(O)C.O.[Pd]>[NH2:1][CH2:4][CH2:5][CH2:6][S:7][C:8]1[N:9]=[CH:10][N:11]2[CH:15]=[CH:14][S:13][C:12]=12
Reactant: [H][H]
Reactant: [N-]=[N+]=NCCCSc1ncn2ccsc12
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: NCCCSc1ncn2ccsc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
7-(3-Azidopropyl)thioimidazo[5,1-b]thiazole (1.46 g) was dissolved in 30 ml of THF ethanol and 6 ml of water, and 6.1 ml of a 1 N aqueous hydrochloric acid solution and 1.46 g of 10% Pd-C were added to the solution. The air in the reaction vessel was replaced by hydrogen, and the contents of the reaction vessel were stirred at room temperature for 24 hr. The catalyst was removed by filtration on Celite, and was washed with water. The filtrate was concentrated under the reduced pressure. A 1 N aqueous sodium hydroxide solution (20 ml) was added to the residue, and the mixture was extracted with dichloromethane five times. The extract was dried over anhydrous magnesium sulfate. The solvent was removed by distillation to prepare 1.15 g of 7-(3-aminopropyl)thioimidazo[5,1-b]thiazole.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=[O:20])[C:8]#[C:9][C:10]2([O:15][Si](C)(C)C)[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:3][CH:2]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.O>[OH:15][C:10]1([C:9]#[C:8][C:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[O:20])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C[Si](C)(C)OC1(C#CC(=O)c2ccncc2)CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: O=C(C#CC1(O)CCCC1)c1ccncc1
Reaction time: 1 h
Yield: 51.3 %

Procedure:
To a stirred solution of 1-(pyridin-4-yl)-3-(1-(trimethylsilyloxy)cyclopentyl) prop-2-yn-1-one (1.1 g, 3.8 mmol) in DCM (15 mL) was added PTSA (0.87 g, 4.6 mmol) at RT and the reaction mixture was stirred for 1 h. The reaction mixture was diluted with water (2 mL), the organic layer was washed with a saturated NaHCO3 solution, water, dried over Na2SO4, filtered and then concentrated in vacuo to afford 3-(1-hydroxycyclopentyl)-1-(pyridin-4-yl) prop-2-yn-1-one (0.42 g, 51%) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([CH2:8][OH:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=1.O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([O:10][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=2)[CH:3]=1
Reactant: OCc1cc(O)cc(Br)c1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OCc1cc(Br)cc(Oc2ccc(C(F)(F)F)cn2)c1
Temperature: 110 °C
Reaction time: 0.33 h
Yield: 107 %

Procedure:
To a solution of 3-bromo-5-(hydroxymethyl)phenol (3.0 g, 14.77 mmol) in DMF (15 mL) under a N2 atmosphere was added potassium carbonate (4.08 g, 29.55 mmol) and the mixture was stirred for 20 min. 2-Chloro-5-(trifluoromethyl)pyridine (2.68 g, 14.77 mmol) was added at RT and then the reaction was refluxed at 110° C. overnight. The reaction mixture was cooled and water was added. The mixture was extracted with ethyl acetate three times. The organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness to give the title compound (5.5 g) which was used in the next step without purification. 1H NMR (500 MHz, CDCl3): δ 8.44 (s, 1H), 7.92 (d, J=8.5 Hz, 1H), 7.41 (s, 1H), 7.24 (s, 1H), 7.19 (s, 1H), 7.04 (d, J=9 Hz, 1H), 4.71 (s, 2H); m/z (348, 349.9, M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:21](=[O:22])[C:20]3=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=[C:19]3[C:18]2=[O:28])[CH2:13][C:14](O)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:42][OH:43]>O1CCCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:21](=[O:22])[C:20]3=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=[C:19]3[C:18]2=[O:28])[CH2:13][C:14]([NH:42][OH:43])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: NO
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3cccc(C)c3C2=O)ccc1OC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)NO)N2C(=O)c3cccc(C)c3C2=O)ccc1OC
Yield: 89.9 %

Procedure:
3-(3-Ethoxy-4-methoxyphenyl)-N-hydroxy-3-(3-methylphthalimido)propionamide was prepared by the procedure of Example 1 from 3-(3-ethoxy-4-methoxyphenyl)-3-(3-methylphthalimido)propanoic acid (1.50 g, 3.91 mmol), carbonyldiimidazole (698 mg, 4.30 mmol) and hydroxylamine hydrochloride (330 mg, 4.75 mmol) in tetrahydrofuran (5 mL) to afford 3-(3-ethoxy-4-methoxyphenyl)-N-hydroxy-3-(3-methylphthalimido)propionamide as a white solid (1.4 g, 90% yield): mp, 165.0-166.5° C.; 1H NMR (DMSO-d6) δ1.32 (t, J=6.9 Hz, 3H, CH3), 2.61 (s, 3H, CH3), 3.10 (d, J=7.9 Hz, 2H, CH2), 3.72 (s, 3H, CH3), 3.98 (q, J=7.0 Hz, 2H, CH2), 5.66 (t, J=7.8 Hz, 1H, NCH), 6.87-6.90 (m, 2H, Ar), 7.02 (br s, 1H, Ar), 7.57-7.69 (m, 3H, Ar), 8.80 (br s, 1H, OH), 10.59 (br s, 1H, NH); 13C NMR (DMSO-d6) δ14.71, 16.99, 34.21, 49.95, 55.45, 63.73, 111.72, 112.38, 119.70, 120.76, 127.79, 131.27, 131.67, 134.06, 136.66, 137.29, 147.65, 148.51, 166.06, 167.55, 168.31; Anal Calcd for C21H22N2O6+H2O: C, 60.57; H, 5.81; N, 6.73. Found: C, 60.83; H, 5.72; N, 6.53.
Reaction SMILES: C(N(CC)CC)C.[CH:8]1[CH2:12][CH:11]=[CH:10][CH:9]=1.[Cl:13][CH:14]([Cl:18])[C:15](Cl)=[O:16]>CCCCCC>[Cl:13][C:14]1([Cl:18])[CH:8]2[CH:9]([CH2:10][CH:11]=[CH:12]2)[C:15]1=[O:16]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: C1=CCC=C1
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: O=C1C2CC=CC2C1(Cl)Cl
Reaction time: 15 h

Procedure:
Over a period of 1.5 hr 21.7 g of dry triethylamine in 200 ml of hexane was added to a vigorously stirred solution mixture of 27.2 g of freshly distilled cyclopentadiene (I), 30.5 g of dichloroacetyl chloride, and 200 ml of hexane (dried over molecular sieves). After stirring for 15 hours under an atmosphere of nitrogen, the reaction mixture was filtered and the filter cake was washed with hexane. The solvent was removed under vacuum, yielding a 35.2 g of liquid, which, when redistilled under vacuum, afforded 30 g of 7,7-dichlorobicyclo(3.2.0)hept-2-en-6-one (II).
Reaction SMILES: S(Cl)(Cl)=O.Cl.[N:6]1([CH2:11][CH:12]([N:14]2[C:27]3[CH:26]=[C:25]([C:28](O)=[O:29])[CH:24]=[CH:23][C:22]=3[S:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH3:13])[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH:31]1([CH2:36][NH2:37])[CH2:35][CH2:34][CH2:33][CH2:32]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(#N)C>[CH:31]1([CH2:36][NH:37][C:28]([C:25]2[CH:24]=[CH:23][C:22]3[S:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]([CH:12]([CH3:13])[CH2:11][N:6]4[CH2:10][CH2:9][CH2:8][CH2:7]4)[C:27]=3[CH:26]=2)=[O:29])[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(=O)O)cc21
Reactant: NCC1CCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(=O)NCC3CCCC3)cc21
Temperature: 15 °C
Reaction time: 3 h
Yield: 72.9 %

Procedure:
Thionyl chloride (2 cc) is added to a suspension, cooled to 5° C., of 10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxylic acid hydrochloride (1.6 g) in methylene chloride (50 cc). The suspension is stirred for 3 hours at 15° C. and then concentrated to dryness at 30° C. under reduced pressure (30 mm Hg; 4 kPa) to give a yellow residue which is taken up in methylene chloride (50 cc) at 5° C. Cyclopentylmethylamine (1.1 g) is added and the mixture is stirred for 12 hours at 25° C., and saturated sodium bicarbonate solution (150 cc) is then added. The mixture is extracted with ethyl acetate (2×100 cc). The organic phase is washed successively with distilled water (100 cc) and with brine (100 cc), dried over magnesium sulphate, filtered and concentrated to dryness at 40° C. under reduced pressure (30 mm Hg; 4 kPa). The yellow solid obtained (1.6 g) is dissolved in boiling acetonitrile (30 cc) and the solution is filtered. The filtrate is primed by scratching and then cooled with stirring for 1 hour. The solid is separated off by filtration, washed with acetonitrile (2×2 cc) and dried at 40° C. under reduced pressure (1 mm Hg; 0.13 kPa). N-Cyclopentylmethyl 10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxamide (1.3 g) is obtained in the form of white crystals, m.p. 124° C. 1 Proton NMR (250 MHz, CDCl3, δ in ppm, J in Hz)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Cl)[CH:7]=[C:6]2[CH:18]=[O:19].[I-:20].[Na+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][I:20])[CH:7]=[C:6]2[CH:18]=[O:19]
Reactant: [I-]
Reactant: COc1ccc2c(c1)c(C=O)cn2CCCCCCl
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc2c(c1)c(C=O)cn2CCCCCI
Temperature: 25 °C

Procedure:
A stirred solution of 5-methoxy-1-(5-chloropentyl)indole-3-carboxaldehyde and sodium iodide in acetonitrile under argon is heated under reflux for 18 h, cooled to room temperature and partitioned between ether and water. The combined organic extracts are washed (aqueous sodium metabisulfite solution, water, brine), dried (sodium sulfate) and concentrated in vacuo to give the product.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C@H:11]([C:15]1[NH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:30])[O:28][CH3:29])=[CH:22][C:21]=2[N+:31]([O-:33])=[O:32])=[CH:18][N:19]=1)[CH2:12][CH:13]=[CH2:14])=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:34][Si:35]([CH2:38][CH2:39][O:40][CH2:41]Cl)([CH3:37])[CH3:36]>C1COCC1>[C:3]([O:7][C:8]([NH:10][C@H:11]([C:15]1[N:19]([CH2:41][O:40][CH2:39][CH2:38][Si:35]([CH3:37])([CH3:36])[CH3:34])[CH:18]=[C:17]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:30])[O:28][CH3:29])=[CH:22][C:21]=2[N+:31]([O-:33])=[O:32])[N:16]=1)[CH2:12][CH:13]=[CH2:14])=[O:9])([CH3:4])([CH3:5])[CH3:6]
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)c1ncc(-c2ccc(NC(=O)OC)cc2[N+](=O)[O-])[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC[C@H](NC(=O)OC(C)(C)C)c1nc(-c2ccc(NC(=O)OC)cc2[N+](=O)[O-])cn1COCC[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A flame-dried 25 mL round bottom flask was charged with NaH (0.092 g, 2.295 mmol) and then THF (4.17 mL) was added to give a gray suspension. The suspension was cooled to 0° C. and then a clear, yellow solution of 135B (0.9 g, 2.086 mmol) in THF (4.17 mL) was added dropwise. The reaction mixture was stirred at 0° C. for 30 min and then allowed to warm to rt and stirring was continued at rt for additional 0.5 h. The yellow suspension was again cooled to 0° C. and then SEM-Cl (0.370 mL, 2.086 mmol) was added dropwise. The resulting cloudy reaction mixture was stirred at 0° C. After 1 h, the reaction was stopped and quenched with saturated NH4Cl followed by dilution with EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with saturated NaHCO3, brine, dried over Na2SO4, filtered, and concentrated. The yellow oil weighing 1.6 g was purified by silica gel chromatography. The desired product from the reaction was obtained as yellow foam (0.424 g, 36%). MS (ESI) m/z: 562.0 (M+H)+. 1D NOE confirmed the regioisomeric position of SEM on the imidazole ring.