Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-:1].[Li+].[C:3]([O:6][C:7]1[C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:25])[C@H:17](Br)[CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=[C:9]([O:27][CH3:28])[CH:8]=1)(=[O:5])[CH3:4].O>CN(C)C=O>[C:3]([O:6][C:7]1[C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:25])[C@@H:17]([Cl:1])[CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=[C:9]([O:27][CH3:28])[CH:8]=1)(=[O:5])[CH3:4]
Reactant: [Cl-]
Reactant: COc1cc2c(c(OC(C)=O)c1)[C@H]1CC[C@]3(C)C(=O)[C@H](Br)C[C@H]3[C@@H]1CC2
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(c(OC(C)=O)c1)[C@H]1CC[C@]3(C)C(=O)[C@@H](Cl)C[C@H]3[C@@H]1CC2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of lithium chloride (1.3 g, 31 mM) in 9 ml of anhydrous dimethylformamide is heated to 70° and then cooled to room temperature. 1-Acetoxy-16α-bromo-3-methoxyestra-1,3,5(10)-trien-17-one (0.50 g) is added to the solution as a solid using Gooch tubing. The resulting suspension is heated to 50° to effect solution. The solution is then stirred at room temperature for 5 hr, poured into 100 ml of H2O, filtered and dried in vacuo to give a white solid. Recrystallization from methanol gives 1-acetoxy-16β-chloro-3-methoxyestra-1,3,5(10)-trien-17-one, yield 0.40 g (89%); m.p. 164°-166°.
Reaction SMILES: C(S(C[C@@H](CC1C=CC=CC=1)C(N[C@@H:13]([CH2:32][C:33]1[N:34]=[CH:35][NH:36][CH:37]=1)[C:14]([NH:16][C@@H](CC1CCCCC1)[C@@H](O)C(C1CC1)=O)=[O:15])=O)(=O)=O)(C)(C)C.Cl.NO.C(N(CC)CC)C>CO>[NH:36]1[CH:37]=[C:33]([CH2:32][CH2:13][C:14]([NH2:16])=[O:15])[N:34]=[CH:35]1
Reactant: CC(C)(C)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)C(=O)C1CC1
Agent: Cl
Agent: NO
Solvent: CO
Solvent: CCN(CC)CC
Product: NC(=O)CCc1c[nH]cn1

Procedure:
A mixture of 62.8 mg (0.1 mmol) of (S)-α-[(S)-α-[(tert-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R)-1-(cyclohexylmethyl)-3-cyclopropyl-2-hydroxy-3-oxopropyl]imidazole-4-propionamide, 12 mg (0.2 mmol) of hydroxylamine hydrochloride and 0.027 ml (0.2 mmol) of triethylamine in 2.5 ml of methanol is heated to reflux for 20 hours. After the usual working-up the crude product obtained is purified by chromatography on 10 g of silica gel using a 8:1 mixture of methylene chloride and methanol as the eluting agent. There are obtained 28 mg of (S)-α-[(S)-α-[(tert-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R,E/Z=2:1)-1-(cyclohexylmethyl)-3-cyclopropyl-2-hydroxy-3-(hydroxyimino)propyl]imidazole-4-propionamide as an amorphous solid; MS: 644 (M+H)+.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:31]([CH3:32])=[CH:30][C:15]2[N:16]=[C:17]([C:19]3[CH:27]=[C:26]4C([C:23]([CH3:29])=[N:24][N:25]4C)=[CH:21][CH:20]=3)[S:18][C:14]=2[C:13]=1[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].CC1N2C=CC(B(O)O)=CC2=N[N:42]=1>>[C:1]([O:5][C@@H:6]([C:12]1[C:31]([CH3:32])=[CH:30][C:15]2[N:16]=[C:17]([C:19]3[CH:20]=[CH:21][N:42]4[C:23]([CH3:29])=[N:24][N:25]=[C:26]4[CH:27]=3)[S:18][C:14]=2[C:13]=1[C:33]1[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(C)nn(C)c4c3)sc2c1-c1ccc(Cl)cc1
Reactant: Cc1nnc2cc(B(O)O)ccn12
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccn4c(C)nnc4c3)sc2c1-c1ccc(Cl)cc1

Procedure:
Prepared in a manner similar to (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(1,3-dimethyl-1H-indazol-6-yl)-5-methylbenzo[d]thiazol-6-yl)acetate, but using 3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-ylboronic acid instead of 1,3-dimethyl-1H-indazol-6-ylboronic acid. 1H NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 7.94 (d, J=6.0 Hz, 1H), 7.91 (s, 1H), 7.75 (s, 1H), 7.58-7.49 (m, 3H), 7.49-7.44 (m, 1H), 5.17 (s, 1H), 4.26-4.16 (m, 2H), 2.81 (s, 3H), 2.61 (s, 3H), 1.26 (t, J=7.1 Hz, 3H), 0.98 (s, 9H).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[Cl-].[Al+3].[Cl-].[Cl-].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19]>Cl>[F:12][C:13]1[CH:18]=[C:17]([C:1](=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5])[CH:16]=[CH:15][C:14]=1[F:19]
Reactant: O=C1CCC(=O)O1
Reactant: Fc1ccccc1F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(O)CCC(=O)c1ccc(F)c(F)c1
Yield: 31.2 %

Procedure:
45 gm of succinic anhydride and 130.7 gm of aluminum chloride were added to 57 gm of difluorobenzene, and the mixture was heated under reflux for 4 hours. Upon the addition of 200 ml of 1% hydrochloric acid aqueous solution, the reaction mixture was extracted with chloroform, washed with water, and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was subjected to silica gel column chromatography using a chloroform-methanol (30:1) mixed solvent as an eluant to obtain fractions containing the target compound. The fractions were concentrated to produce 30 gm of the title compound.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:13]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[CH2:21][CH:22]([CH2:29][C:30]1([CH3:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[CH:23]2O>C1(C)C=CC=CC=1>[C:13]1([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[CH2:21][C:22]([CH2:29][C:30]1([CH3:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1)=[CH:23]2
Reactant: CC1(CC2Cc3c(-c4ccccc4-c4ccccc4)cccc3C2O)CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(CC2=Cc3cccc(-c4ccccc4-c4ccccc4)c3C2)CCCCC1
Temperature: 25 °C
Yield: 66.8 %

Procedure:
Mixture of p-toluene-sulfonic acid monohydrate (0.38 g, 2.0 mmol, 0.2 equiv), compound 22 (4.0 g crude, ˜9.88 mmol, 1.0 equiv) and toluene (100 mL) was refluxed for 1 hour. After cooling to room temperature, the mixture was washed sequentially with saturated sodium bicarbonate (100 mL) and saturated brine (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on an AnaLogix (25-80 g) column, eluting with a gradient of 0 to 10% ethyl acetate in heptanes to give compound 23 (2.5 g, 67% yield for 2 steps) as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:31])[C@:5]([F:30])([CH3:29])[C:6]([NH:8][C@@H:9]1[C:15](=[O:16])[N:14]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:13]2[CH:21]=[CH:22][CH:23]=[CH:24][C:12]=2[C:11]2[CH:25]=[CH:26][CH:27]=[CH:28][C:10]1=2)=[O:7])C.O.[OH-].[Li+]>O1CCCC1.O>[CH:18]1([CH2:17][N:14]2[C:15](=[O:16])[C@@H:9]([NH:8][C:6](=[O:7])[C@@:5]([F:30])([CH3:29])[C:4]([OH:31])=[O:3])[C:10]3[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=3[C:12]3[CH:24]=[CH:23][CH:22]=[CH:21][C:13]2=3)[CH2:20][CH2:19]1
Reactant: CCOC(=O)[C@@](C)(F)C(=O)N[C@@H]1C(=O)N(CC2CC2)c2ccccc2-c2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@](F)(C(=O)O)C(=O)N[C@@H]1C(=O)N(CC2CC2)c2ccccc2-c2ccccc21
Yield: 87.3 %

Procedure:
0.22g (0.52 mmol) (S)-N-((S)-5-cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2-fluoro-2-methyl-malonamic acid ethyl ester in 3 ml tetrahydrofurane was reacted with a solution of 0.02 g (0.52 mmol) lithium hydroxide monohydrate in 1 ml water at room temperature for 2 hours. Evaporation of the tetrahydrofurane, extraction with diethylether, acidification with 0.5 ml 1 N aqueous hydrochloric acid and extraction with ethylacetate gave 0.18 g (S)-N-((S)-5-cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2-fluoro-2-methyl-malonamic acid as white solid.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.O[CH2:14][C:15]1[N:16]2[CH:22]=[N:21][CH:20]=[C:17]2[S:18][CH:19]=1.[CH2:23]([O:26][C:27]([N-:29][S:30]([NH2:33])(=[O:32])=[O:31])=[O:28])[CH:24]=[CH2:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C.O1CCCC1>[CH2:23]([O:26][C:27]([N:29]([CH2:14][C:15]1[N:16]2[CH:22]=[N:21][CH:20]=[C:17]2[S:18][CH:19]=1)[S:30]([NH2:33])(=[O:32])=[O:31])=[O:28])[CH:24]=[CH2:25]
Reactant: OCc1csc2cncn12
Reactant: C=CCOC(=O)[N-]S(N)(=O)=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N(Cc1csc2cncn12)S(N)(=O)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 15.3 %

Procedure:
Under an argon atmosphere at -51° C., 0.71 ml of diethyl azodicarboxylate was added dropwise to 5 ml of an anhydrous tetrahydrofuran solution containing 463 mg of 3-hydroxymethylimidazo[5,1-b]thiazole, 811 mg of N-allyloxycarbonyl-N-aminosulfonylamide and 1180 mg of triphenylphosphine, and the mixture was then stirred at -51° C. to -37° C. for 15 minutes and further stirred for 70 minutes, while the solution was heated up to room temperature. The solvent was evaporated under reduced pressure to obtain an oil, and this oil was then dissolved in 50 ml of ethyl acetate. Further, the solution was extracted with 2N hydrochloric acid (30 ml×2), and the combined aqueous layer was then washed with 20 ml of ethyl acetate. After neutralized (pH 7) with sodium hydrogencarbonate, the neutralized solution was extracted with ethyl acetate (100 ml×2). The thus extracted organic layer was dried over anhydrous magnesium sulfate and then filtered, and the solvent was evaporated under reduced pressure. Afterward, the resulting oil was purified by a silica gel column chromatograph and successively Cephadex LH-20 to obtain 145.6 mg of the title compound in a milky white amorphous state.
Reaction SMILES: [C:1]1([CH:7]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C:18]2=[O:23])[CH2:8][C:9](=O)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.Cl>O>[C:10]1([C:9]2[CH:19]3[C:18](=[O:23])[CH:17]([CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:8]=2)[CH2:22][CH2:21][CH2:20]3)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(CC(c1ccccc1)C1CCCCC1=O)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C1C2CCCC1C(c1ccccc1)C=C2c1ccccc1
Temperature: 25 °C

Procedure:
Into a 1 L round bottom flask fifteen parts of 2-(α-phenyl-β-benzoylethyl)-cyclohexanone, 500 ml acetic acid and 100 mL of concentrated hydrochloric acid was added. Reaction mixture was heated under reflux for 45 hours. The hot reaction mixture was diluted with 250 ml of water (reaction mixture was cloudy). The reaction mixture was cool to room temperature to give a white solid which was filtered and dried under vacuum, to yield 11.75 g of product. The reaction proceeded as follows:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[CH3:10].Cl.[NH2:12][OH:13].C([O-])(=O)C.[Na+].O>C(O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:12][OH:13])=[CH:4][C:3]=1[CH3:10]
Reactant: NO
Reactant: Cc1cc(C=O)ccc1Br
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(C=NO)ccc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.9 %

Procedure:
To a solution of 4-bromo-3-methyl-benzaldehyde (4.3 g) (Example I1) in ethanol (50 ml), were added at ambient temperature hydroxylamine hydrochloride (1.75 g), sodium acetate (2.07 g) and water (15 ml). The reaction mixture was stirred at ambient temperature for 3 hours. The reaction mixture was concentrated and the residue partitioned between ethyl acetate and aqueous sodium hydroxide (2M). The phases were separated and the organic phase was washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 4:1) to give 4-bromo-3-methyl-benzaldehyde oxime (3.65 g) as a white solid. 1H-NMR (400 MHz, CDCl3): 8.05 (s, 1H), 7.50 (m, 2H), 7.25 (d, 1H), 2.40 (s, 3H) ppm.
Reaction SMILES: C(OC(=O)N[C:8]([CH3:29])(C)[CH2:9][C:10]1[C:18]2[C:13](=[C:14](OC3C(C#N)=CC=CN=3)[CH:15]=[CH:16][CH:17]=2)[NH:12]C=1)(C)(C)C.Cl.O1CCO[CH2:34][CH2:33]1>>[CH3:33][CH2:34][CH2:29][CH2:8][CH2:9][CH2:10][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][NH2:12]
Reactant: CC(C)(Cc1c[nH]c2c(Oc3ncccc3C#N)cccc12)NC(=O)OC(C)(C)C
Reactant: C1COCCO1
Agent: Cl
Product: CCCCCCCCCCCCN
Reaction time: 5 h
Yield: 83 %

Procedure:
{2-[7-(3-Cyano-pyridin-2-yloxy)-1H-indol-3-yl]-1,1-dimethyl-ethyl}-carbamic acid tert-butyl ester (119 mg, 0.293 mmol) is dissolved in 10 mL of 1,4 dioxane. The mixture is cooled to zero degrees Celsius in an ice/water bath. To the mixture is added 10 mL of 4N hydrochloric acid in 1,4 dioxane, and the resulting mixture is stirred at zero degrees, under nitrogen, for five hours. The solvent is evaporated, and the residue is taken up in water. The pH of the water is adjusted to 9 using sodium bicarbonate, and is extracted three times with 50 mL of ethyl acetate. The organic layers are combined, dried with sodium sulfate, filtered, and the solvent removed in vacuo to give 218 mg of the title amine (83%). FDMS m/e=307 (M++1).
Reaction SMILES: [CH3:1][CH:2]([CH2:7][CH2:8][CH:9]=[CH2:10])[CH2:3][C@@H:4]([OH:6])[CH3:5].[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([O:6][C@H:4]([CH2:3][CH:2]([CH3:1])[CH2:7][CH2:8][CH:9]=[CH2:10])[CH3:5])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C=CCCC(C)C[C@H](C)O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: C=CCCC(C)C[C@H](C)OS(=O)(=O)c1ccc(C)cc1
Reaction time: 0.17 h
Yield: 66.5 %

Procedure:
To a solution of (2S)-4-methyloct-7-en-2-ol (39 g, 0.274 moles) in pyridine (400 mL) was added 4-(dimethylamino)pyridine (DMAP, 1.67 g, 0.013 moles) and the solution was stirred for 10 min. P-toluenesulfonyl chloride (60 g, 0.315 moles) was added to the reaction mass at 0° C. The reaction mass was allowed to come to room temperature and stirred overnight. Pyridine was removed under reduced pressure and the residue was diluted with ethyl acetate (200 mL). The organic solution was washed with aqueous 1.5 N HCl solution, saturated aq. bicarbonate solution, brine solution, dried over anhydrous Na2SO4, filter, and concentrated under reduced pressure to get crude compound (2S)-4-methyloct-7-en-2-yl 4-methylbenzenesulfonate (54 g, 61%). The crude compound was taken to the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:34]C)=[C:6]([C:8]([CH3:33])([CH3:32])[CH2:9][C:10]([C:28]([F:31])([F:30])[F:29])([OH:27])[CH2:11][NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][C:17]([C:23]([F:26])([F:25])[F:24])=[N:18]3)[CH:7]=1.B(Br)(Br)Br.CO>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:34])=[C:6]([C:8]([CH3:32])([CH3:33])[CH2:9][C:10]([C:28]([F:29])([F:30])[F:31])([OH:27])[CH2:11][NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][C:17]([C:23]([F:26])([F:24])[F:25])=[N:18]3)[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cccc2nc(C(F)(F)F)ccc12)C(F)(F)F
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CC(C)(CC(O)(CNc1cccc2nc(C(F)(F)F)ccc12)C(F)(F)F)c1cc(F)ccc1O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
100 mg (0.20 mmol) of 4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-trifluoromethyl-1-(2-(trifluoromethyl)quinolin-5-ylamino)pentan-2-ol in 2.0 ml of dichloromethane is mixed at room temperature with 4.0 ml (4.0 mmol) of a 1 M boron tribromide solution. After 20 hours at room temperature, the reaction is brought to a halt by adding 20 ml of methanol. The reaction mixture is allowed to stir for 30 minutes at room temperature, and then the solvent is removed in a vacuum. After chromatography on silica gel with hexane-ethyl acetate (0-100%), 79 mg (80% of theory) of the product is obtained.
Reaction SMILES: [Na].[CH2:2]([O:4][C:5]1[CH:6]=[C:7]([CH:15]=[C:16]2[O:20][CH2:19][O:18][C:17]=12)[CH:8]=[C:9]([CH2:12][O:13][CH3:14])[C:10]#[N:11])[CH3:3].[CH3:21][OH:22]>>[CH3:14][O:13][CH:12]([O:22][CH3:21])[CH:9]([C:10]#[N:11])[CH2:8][C:7]1[CH:15]=[C:16]2[O:20][CH2:19][O:18][C:17]2=[C:5]([O:4][CH2:2][CH3:3])[CH:6]=1
Reactant: CCOc1cc(C=C(C#N)COC)cc2c1OCO2
Reactant: CO
Agent: [Na]
Product: CCOc1cc(CC(C#N)C(OC)OC)cc2c1OCO2

Procedure:
To 6.6 g. sodium dissolved in 96 ml. of methanol, 37.5 g. of 3-ethoxy-4,5-methylenedioxy-α-methoxymethylcinnamonitrile were added. The resulting mixture was refluxed for 24 hours. The solution was poured into 400 ml. water and was extracted with methylenechloride. Upon evaporation of the solvent, the product, 3-ethoxy-4,5-methylenedioxy-α-cyanodihydrocinnamaldehyde dimethylacetal, was vacuum distilled and had a b.p. of 191°/0.4 mmHg., nD23 = 1.5340.
Reaction SMILES: [C:1]([CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:11](=[O:15])[CH2:12][CH2:13][CH:14]=1)([OH:3])=[O:2].[C:16]1(C)C=CC(S(O)(=O)=O)=C[CH:17]=1>C(O)C>[C:1]([CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:11](=[O:15])[CH2:12][CH2:13][CH:14]=1)([O:3][CH2:16][CH3:17])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)COCCCCC1=CCCC1=O
Solvent: CCO
Product: CCOC(=O)COCCCCC1=CCCC1=O

Procedure:
In the manner described in Example 39, treatment of 2-(6-carboxy-5-oxahexyl)-2-cyclopentenone with p-toluenesulfonic acid in ethanol produces the subject product as a light yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:22])=[C:6]([CH:21]=1)[C:7]([NH:9][CH2:10][C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2)=[O:8].Cl.Cl[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]Cl>C1(C)C(C)=CC=CC=1>[Cl:22][C:5]1[CH:4]=[CH:3][C:2]([N:1]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:21][C:6]=1[C:7]([NH:9][CH2:10][C:11]12[CH2:12][CH:13]3[CH2:19][CH:17]([CH2:16][CH:15]([CH2:14]3)[CH2:20]1)[CH2:18]2)=[O:8]
Reactant: Nc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Reactant: ClCCNCCCl
Agent: Cl
Solvent: Cc1ccccc1C
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(N2CCNCC2)ccc1Cl
Temperature: 150 °C
Yield: 74 %

Procedure:
To a solution of 5-amino-2-chloro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (1.00 g, Example 4b) in xylene (20 ml) was added bis-(2-chloroethyl)amine hydrochloride salt (0.620 g). The mixture was heated at 150° C. for 12 h (a dark solution is obtained). The cold solution was washed with 2M HCl, the aqueous layer washed with ethyl acetate then basified with sodium bicarbonate and extracted twice with dichloromethane. The organic layer was dried over magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to give a foam. The crude material was purified on silica gel (0-10% ethanol/dichloromethane), to afford the title compound as a white solid (0.90 g).
Reaction SMILES: [ClH:1].Cl.[CH3:3][N:4]([CH3:13])[CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[Cl:14][C:15]1[CH:16]=[C:17]([O:21][CH2:22][CH2:23]Br)[CH:18]=[CH:19][CH:20]=1.C(N(CC)CC)C>CN(C=O)C>[ClH:14].[ClH:1].[Cl:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=1)[O:21][CH2:22][CH2:23][N:10]1[CH2:11][CH2:12][CH:7]([CH2:6][CH2:5][N:4]([CH3:3])[CH3:13])[CH2:8][CH2:9]1
Reactant: CN(C)CCC1CCNCC1
Reactant: Clc1cccc(OCCBr)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)CCC1CCN(CCOc2cccc(Cl)c2)CC1

Procedure:
A mixture of 4-(2-dimethylaminoethyl)piperidine dihydrochloride (7.0 g), 2-bromoethyl 3-chlorophenyl ether (7.2 g), triethylamine (12.75 ml) and DMF (50 ml) was heated on a steam bath for 16 hours then worked up as described in Example 16 to give 1-[2-(3-chlorophenoxy)ethyl]-4-(2-dimethylaminoethyl)piperidine dihydrochloride, m.p. 260°-264° C.
Reaction SMILES: [NH:1]([C:10]([CH3:12])=[O:11])[CH2:2][C:3]([NH:5][CH2:6][C:7](O)=[O:8])=[O:4].C1CCC(N=C=NC2CCCCC2)CC1.[NH2:28][C@H:29]([C:33]([NH2:35])=[O:34])[CH:30]([CH3:32])[CH3:31]>C(#N)C.O>[NH:1]([C:10]([CH3:12])=[O:11])[CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:28][C@H:29]([C:33]([NH2:35])=[O:34])[CH:30]([CH3:32])[CH3:31])=[O:8])=[O:4]
Reactant: CC(=O)NCC(=O)NCC(=O)O
Reactant: CC(C)[C@H](N)C(N)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Solvent: O
Product: CC(=O)NCC(=O)NCC(=O)N[C@H](C(N)=O)C(C)C
Temperature: 0 °C

Procedure:
1.75 g (10 mmoles) Ac-Gly-Gly-OH and 1.73 g (15 mmoles) HONSu were dissolved in 25 ml acetonitrile and cooled to 0° C. 2.46 g DCC (12 mmoles) were then added, the mixture allowed to warm to room temperature and stirred for 2 hours until complete formation of the active ester. After filtering off the DCU, 1.16 g of Val-NH2 free base (10 mmoles) in 25 ml H2O at pH 8 were added slowly and pH maintained above 7. At completion of the reaction the acetonitrile was removed under vacuum and a small residue filtered off from the aqueous phase. The product was then purified by reverse phase HPLC using water/ethanol/acetic acid buffers.
Reaction SMILES: CS[CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:10]=2)[NH:5][C:4]1=[O:18]>[Ni].O.O1CCCC1>[C:12]1([C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[NH:5][C:4](=[O:18])[CH2:3]3)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CSC1C(=O)Nc2ccc(-c3ccccc3)cc21
Agent: [Ni]
Solvent: O
Solvent: C1CCOC1
Product: O=C1Cc2cc(-c3ccccc3)ccc2N1

Procedure:
To a slurry of 11.2 g. (0.044 mole) of 3-methylthio-5-phenylindolin-2-one in 500 ml. of tetrahydrofuran was added 100 g. of a commercial Raney nickel/water preparation portionwise over a 2 hr. period. The mixture was filtered through celite and the filtrate was concentrated. A small amount of methylene chloride was added to the residue and the resulting solid was collected by filtration. This solid was recrystallized from toluene to give 6.2 g. (67%) of product as a tan solid, m.p. 214°-15° C.
Reaction SMILES: [I-].[Na+].O.O.O.C([O-])(=O)C.[Na+].[CH3:11][O:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>O>[CH3:11][O:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:15][CH:14]=1
Reactant: COc1ccc(N)cc1
Reactant: CCOC(=O)CBr
Agent: CC(=O)[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CNc1ccc(OC)cc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 75.5 %

Procedure:
To a solution of sodium iodide (122 g, 0.81 mol) and sodium acetate trihydrate (221 g, 1.62 mol) in water (200 mL) was added 4-methoxyaniline (3) (100 g, 0.81 mol) followed by ethyl 2-bromoacetate (90 mL, 812 mmol) the reaction was stirred at 90° C. for 3 h. The reaction mixture was cooled to RT and partitioned with EtOAc (1 L), the organic phase was separated, washed with water (400 mL), 1 M HCl (aq.) (3×500 mL), and the organic phase discarded. The combined acidic extracts were cooled to 0° C. and solid NaOH was added to pH 14 and the aqueous phase was extracted with EtOAc (3×400 mL). The combined organics were washed with brine (250 mL), dried (MgSO4), filtered and solvents removed in vacuo to give ethyl 2-((4-methoxyphenyl)amino)acetate (17) (128 g, 75%) as a purple oil that crystallised on standing: m/z 210 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 6.75-6.69 (m, 2H), 6.55-6.46 (m, 2H), 3.99 (t, J=6.5 Hz, 1H), 4.10 (q, J=7.1 Hz, 2H), 3.82 (d, J=6.5 Hz, 2H), 3.63 (s, 3H), 1.19 (t, J=7.1 Hz, 3H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=[O:10])[NH:2]1.[CH2:11]([N:17]=[C:18]=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[CH2:11]([NH:17][C:18]([N:2]1[C:3](=[O:10])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1]1)=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCN=C=O
Reactant: O=c1[nH]sc2ccccc12
Product: CCCCCCNC(=O)n1sc2ccccc2c1=O

Procedure:
Following the synthetic procedure of 6a as described in Example 1, compound 6e (82% yield) was synthesized from benzo[d]isothiazol-3-one and n-hexyl isocyanate as a white solid. mp 52-53° C.; IR(CHCl3) 3290, 1711, 1662, 1540 cm−1; 1H-NMR (CDCl3) δ0.80-0.87 (m, 3H), 1.21-1.35 (m, 6H), 1.53-1.61 (m, 2H), 3.34-3.40 (m, 2H), 7.36 (t, J=7.6 Hz, 1H), 7.51 (d, J=7.6 Hz, 1H), 7.63 (t, J=7.6 Hz, 1H), 7.95 (d, J=6.9 Hz, 1H), 8.81 (br s, 1H); ESIMS m/e 279 (M++1).