Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[N:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1CCCCC1.[Br:22][C:23]1[C:28]([F:29])=[CH:27][CH:26]=[C:25]([CH2:30]Br)[N:24]=1.Cl.[Cl-].[NH4+]>O1CCCC1>[Br:22][C:23]1[N:24]=[C:25]([CH2:30][C:11]2([C:14]#[N:15])[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]2)[CH:26]=[CH:27][C:28]=1[F:29]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Reactant: Fc1ccc(CBr)nc1Br
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C#N)(Cc2ccc(F)c(Br)n2)CC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 76 %

Procedure:
N-Boc-4-cyanopiperidine (5.35 g, 25.4 mmol) was dissolved in tetrahydrofuran (100 mL) and cooled to −78° C. Thereafter, to this, a cyclohexane solution (1.5 M, 16.5 mL, 24.8 mmol) of a lithium diisopropylamide/tetrahydrofuran complex was added while maintaining the inside temperature at −70° C. or less. The reaction mixture was stirred at −78° C. for 20 minutes. To the resultant reaction mixture, a THF solution (10 mL) of 2-bromo-6-(bromomethyl)-3-fluoropyridine (6.28 g, 23.4 mmol) was added while maintaining the inside temperature at −70° C. or less and then stirred at −78° C. for 20 minutes. To the reaction solution, a mixture of hydrochloric acid (5 M, 4.95 mL, 24.8 mmol) and a saturated aqueous ammonium chloride solution (95 mL) was added. After stirred at room temperature, the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate, then filtered and concentrated. A tar-like residue was dissolved in ethyl acetate (6 mL). To the mixture, heptane (50 mL) was added dropwise while stirring. A seed crystal was added and stirred at room temperature for one hour. To the resultant light yellow suspension solution, heptane (50 mL) was further added dropwise and stirred overnight. The resultant solid substance was collected by filtration, washed with a heptane solution of ethyl acetate and dried under reduced pressure to obtain the target product as an off-white solid substance (7.10 g, 17.8 mmol) (yield 76%). Note that the seed crystal was obtained from the tar-like residue by a purification method routinely used in silica gel column chromatography. Physical property values are shown below.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[NH2:11][C:12]1[S:13][C:14]2[C:20]([Cl:21])=[C:19]([Cl:22])[CH:18]=[C:17]([S:23][C:24]#[N:25])[C:15]=2[N:16]=1>CN(C)C=O>[Cl:22][C:19]1[CH:18]=[C:17]([S:23][C:24]#[N:25])[C:15]2[N:16]=[C:12]([NH:11][C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:10])[S:13][C:14]=2[C:20]=1[Cl:21]
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: N#CSc1cc(Cl)c(Cl)c2sc(N)nc12
Solvent: CN(C)C=O
Product: N#CSc1cc(Cl)c(Cl)c2sc(NC(=O)Nc3ccc(Cl)cc3)nc12
Reaction time: 5 h

Procedure:
p-Chlorophenyl isocyanate (15.3 g., 0.10 mole) was added in portions to a solution of 27.6 g. (0.10 mole) of 2-amino-6,7-dichloro-4-thiocyanatobenzothiazole in 300 ml. of dimethylformamide. The solution was heated at 120° with stirring for 5 hours and then cooled at 0° overnight. The solid was collected by filtration to give 22 g. (51%) of product. Recrystallization from ethanol gave an analytical sample, m.p. 238°-239° .
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=O)[C:10]3=[N:11][CH:12]=[C:13]([O:15][CH3:16])[CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:19]=1.FC1C=CC2CC[C:27]3[C:28](C(=O)C=2C=1)=[N:29][CH:30]=[CH:31][CH:32]=3>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[C:32]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:10]3=[N:11][CH:12]=[C:13]([O:15][CH3:16])[CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:19]=1
Reactant: O=C1c2cc(F)ccc2CCc2cccnc21
Reactant: COc1cnc2c(c1)CCc1cc(Cl)ccc1C2=O
Product: COc1cnc2c(c1)CCc1cc(Cl)ccc1C2=C1CCNCC1

Procedure:
By substituting in Preparative Example 2 step D, 8-chloro-3-methoxy-5,6-dihydro-11H-benzo[5,6]-cyclohepta[1 ,2-b]pyridin-11-one for 9-fluoro-5,6-dihydro-11H-benzo[5,6]-cyclohepta[1,2-b]pyridin-11-one and employing basically the same methods as steps D through H of Preparative Example 2, one obtains 8-chloro-3-methoxy-11-(4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]-cyclohepta[1,2-b]pyridine as a white solid (MH+ 340).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[H-].[Na+].Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:18][C@@H:17]([C:19]2[CH:30]=[CH:29][C:22]3[O:23][C:24]([CH3:28])([CH3:27])[O:25][CH2:26][C:21]=3[CH:20]=2)[O:16][C:15]1=[O:31].P([O-])([O-])([O-])=O>CN(C=O)C.O>[CH3:27][C:24]1([CH3:28])[O:23][C:22]2[CH:29]=[CH:30][C:19]([C@H:17]3[O:16][C:15](=[O:31])[N:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:3][CH2:2][CH2:1][OH:4])[CH2:18]3)=[CH:20][C:21]=2[CH2:26][O:25]1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCBr)C(=O)O3)ccc2O1
Reactant: OCCO
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCO)C(=O)O3)ccc2O1
Reaction time: 0.5 h

Procedure:
A solution of ethylene glycol (5.00 ml) in DMF (40 ml) under nitrogen at 0° was treated portionwise with sodium hydride (60% dispersion in mineral oil, 1.292 g) and the mixture was stirred at 0° for 15 min A solution of (5R)-3-(6-bromohexyl)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (7.40 g) in DMF (10 ml) was added. The mixture was stirred at 0° for 0.5 h then at 20° for 3 h. Phosphate buffer solution (pH 6.5, 40 ml) and water (160 ml) were added and the mixture was extracted with EtOAc (2×100 ml). The combined extracts were washed with water (2×150 ml), brine (50 ml) and were dried (Na2SO4). The solvent was evaporated in vacuo and the residue was purified by flash chromatography on silica gel. Elution with MeOH-EtOAc (1:9) gave the title compound (4.10 g). LCMS RT=2.90 min, ES+ve 394 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:27][CH2:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23]3)[C:8]2([NH:16][S:17]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:18])[C:11]([O:13][CH2:14][CH3:15])=C)=[CH:4][CH:3]=1.C(OC([O-])=O)(OC(C)(C)C)=[O:31]>CN(C1C=CN=CC=1)C.C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:27][CH2:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23]3)[C:8]2([NH:16][S:17]([C:19]([CH3:21])([CH3:22])[CH3:20])=[O:18])[C:11]([O:13][CH2:14][CH3:15])=[O:31])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: C=C(OCC)C1(NS(=O)C(C)(C)C)c2cc(Br)ccc2CC12CCC(OC)CC2
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)C1(NS(=O)C(C)(C)C)c2cc(Br)ccc2CC12CCC(OC)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.1 %

Procedure:
A mixture of compound 5 (50 mg, 0.11 mmol, 76% purity), tert-Butyl dicarbonate (48 mg, 0.22 mmol) and DMAP (27 mg, 0.22 mmol) in THF (5 mL) was stirred at ambient temperature overnight. The solvent was removed by evaporation in vacuo, the residue was purified by preparative TLC on silica gel eluting with petroleum ether:ethyl acetate=2:1 to give compound 6 (30 mg, 50%) as a white solid. LC-MS: 699-091-1B, tR=2.06 min in 3 min chromatography, MS (ESI) m/z=546.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[C:10]2[CH:11]=[CH:12][O:13][C:9]=2[CH:8]=[CH:7][CH:6]=1>C(O)C.O1CCCC1.[Pt](=O)=O>[O:13]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([O:4][C:3]3[CH:14]=[CH:15][C:16]([NH2:18])=[CH:17][C:2]=3[F:1])[C:10]=2[CH:11]=[CH:12]1
Reactant: O=[N+]([O-])c1ccc(Oc2cccc3occc23)c(F)c1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1ccc(Oc2cccc3occc23)c(F)c1
Reaction time: 2 h

Procedure:
Under argon, 150 mg (0.55 mmol) of 4-(2-fluoro-4-nitrophenoxy)-1-benzofuran (from example XXII) are initially charged in 5 ml of ethanol/tetrahydrofuran (1:1), platinum(IV) oxide is added and the mixture is hydrogenated under atmospheric pressure for 2 hours. The suspension is filtered off through CELITE (diatomaceous earth), the filtercake is washed with ethanol and the filtrate is concentrated using a rotary evaporator.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([N:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:9][CH2:10][C@H:11]([N:14]3[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN([C@H]2CC[C@H](c3ccc(F)cc3)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc([C@H]2CC[C@H](N3CCNCC3)CC2)cc1

Procedure:
This compound was prepared from trans 1,1-dimethylethyl 4-[4-(4-fluorophenyl)-1-cyclohexyl]-1-piperazine carboxylate (1.7 mmole) by treatment with TFA for 0.5 hr. The TFA was removed in vacuo and the residue dissolved in water. The solution was basified with NaOH and the basic mixture extracted with methylene chloride. The extracts were dried and concentrated in vacuo to give the product which was converted to the difumarate [95%, mp: 210° C. (dec)]. Calc'd for C16H23FN2.2C4H3O4.0.25H2O: C, 57.77%; H, 6.39%; N, 5.61%. Found: C, 57.69%; H, 6 23%; N, 5.60%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][CH2:22][C:23]([OH:25])=O)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.CCN=C=NCCCN(C)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][CH2:22][C:23]([N:30]3[CH2:31][CH2:32][CH:27]([OH:26])[CH2:28][CH2:29]3)=[O:25])[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)CCN1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Reactant: OC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CCC(=O)N2CCC(O)CC2)CC1
Reaction time: 4 h

Procedure:
A solution of 0.100 g (0.26 mmol) of 3-{4-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-propionic acid (intermediate 5) and 0.032 g (0.31 mmol) of 4-hydroxypiperidine in 5 ml of dichloromethane was treated at 0° C. with 0.060 g (0.31 mmol) of EDCI. The cooling bath was allowed to come to RT and after 4 h the reaction was extracted with aqueous 10% KHSO4/EtOAc (3×). The organic phases were washed with aqueous saturated NaHCO3, 10% NaCl and dried over Na2SO4 to yield after evaporation of the solvent 0.108 g (89%) of the titled compound as white solid. MS: 468.3 (MH+, 1Cl).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH:4]=1.[CH2:21]([O:23][P:24]([O:28]CC)[O:25][CH2:26][CH3:27])[CH3:22]>>[Si:14]([O:13][C:5]1[CH:4]=[C:3]([CH2:2][P:24]([O:25][CH2:26][CH3:27])([O:23][CH2:21][CH3:22])=[O:28])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: COC(=O)c1ccc(CBr)cc1O[Si](C)(C)C(C)(C)C
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1ccc(C(=O)OC)c(O[Si](C)(C)C(C)(C)C)c1)OCC
Temperature: 130 °C
Reaction time: 24 h
Yield: 66.1 %

Procedure:
A mixture of methyl 4-(bromomethyl)-2-{[tert-butyl(dimethyl)silyl]oxy}benzoate (0.30 g) and triethylphosphite (0.17 g) was mixed at 25° C. and then stirred at 130° C. for 24 hours. The reaction liquid was concentrated under reduced pressure and azeotroped with toluene twice (30 mL×2). The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=40:60 to 10:90) to obtain methyl 2-{[tert-butyl(dimethyl)silyl]oxy}-4-[(diethoxyphosphoryl)methyl]benzoate (0.23 g) as a colorless liquid
Reaction SMILES: CS(O[CH2:6][CH2:7][CH:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:9]1)(=O)=O.[OH:22][C:23]1([C:29]2[CH:34]=[CH:33][C:32]3[O:35][CH2:36][O:37][C:31]=3[CH:30]=2)[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:22][C:23]1([C:29]2[CH:34]=[CH:33][C:32]3[O:35][CH2:36][O:37][C:31]=3[CH:30]=2)[CH2:28][CH2:27][N:26]([CH2:6][CH2:7][CH:8]2[O:12][C:11](=[O:13])[N:10]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH2:9]2)[CH2:25][CH2:24]1
Reactant: OC1(c2ccc3c(c2)OCO3)CCNCC1
Reactant: COc1ccc(N2CC(CCOS(C)(=O)=O)OC2=O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(N2CC(CCN3CCC(O)(c4ccc5c(c4)OCO5)CC3)OC2=O)cc1

Procedure:
4.10 g of 5-(2-methanesulfonyloxyethyl)-3-p-methoxyphenyloxazolidin-2-one [m.p. 61°-64°; obtainable by reaction of 3,4-epoxy-1-butanol with N-benzyl-p-methoxyaniline to give 1-(N-benzyl-p-methoxyanilino)butane-2,4-diol (resin), hydrogenolysis to give 1-p-methoxyanilinobutane-2,4-diol (resin), reaction with diethyl carbonate to give 5-(2-hydroxyethyl)-3-p-methoxyphenyloxazolidin-2-one (m.p. 77°-78°) and reaction with CH3SO2Cl] are boiled together with 3.13 g of 4-hydroxy-4-(3,4-methylenedioxyphenyl)piperidine ("M"), 2.16 g of potassium iodide and 1.8 g of potassium carbonate in 100 ml of acetonitrile for 16 hours, the mixture is cooled, worked up as usual, to give 5-[2-(4-hydroxy-4-(3,4-methylenedioxyphenyl)piperidino)ethyl]-3-p-methoxyphenyloxazolidin-2-one, m.p. 128°-130°.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:5]([SH:13])=[N:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:21]1[S:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][N:25]=1>C(O)C>[OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:5]([S:13][C:21]2[S:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][N:25]=2)=[N:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Br)s1
Reactant: Oc1nnc(S)n1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=[N+]([O-])c1cnc(Sc2nnc(O)n2-c2ccccc2)s1
Yield: 18.7 %

Procedure:
The title compound was prepared by the general method described by Potts, K. T.(1961) Chem. Rev. 61:87. 4-Phenyl-3-thiosemicarbazide (4.18 g) (Aldrich) was dissolved in 50 mL of pyridine and treated with 2.71 g of ethyl chloroformate at 0° C. The reaction was stirred for 2 hours and then refluxed for 18 hours. Evaporation of the solvent and trituration with water gave 2.5 g of 3-hydroxy-5-mercapto-4-phenyl-1,2,4-triazole. 3-Hydroxy-5-mercapto-4-phenyl-1,2,4-triazole (1.93 g) was stirred in 10 mL of ethanol with 1.1 equivalent of potassium carbonate in 10 mL ethanol for one hour and then reacted with 2.09 g of 2-bromo-5-nitrothiazole as in Example 1. Crystallization from ethanol and water gave 0.6 g of 3-hydroxy-5-[(5-nitrothiazol-2-yl)mercapto]-4-phenyl-1,2,4-triazole, a dark yellow solid, M.P. 188°-190° C.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([N:14]=[C:15]=[S:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:18][NH:19][O:20][CH2:21][C:22]([OH:24])=[O:23].C(N(CC)CC)C>C(Cl)(Cl)Cl>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([N:19]([CH3:18])[O:20][CH2:21][C:22]([OH:24])=[O:23])=[S:16])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: S=C=Nc1ccc(Oc2ccccc2)cc1
Reactant: CNOCC(=O)O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN(OCC(=O)O)C(=S)Nc1ccc(Oc2ccccc2)cc1
Yield: 101.2 %

Procedure:
A mixture of 4-phenoxyphenyl-isothiocyanate (11.35 g), N-methyl aminooxy acetic acid hydrochloride (7.1 g), triethylamine (10.5 g) and chloroform (300 mL) was heated at reflux for three hours, then evaporated to dryness. The residue was dissolved in ethyl acetate (600 mL) and washed with 2N HCl (2×300 mL) then with water (300 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness to give (16.8 g) of [[[[(4-phenoxyphenyl)amino]thioxomethyl]methylamino]oxy]acetic acid as an oil. 1H-NMR (DMSO-d6; 300 Mhz) δ13.10 (br s, 1H), 10.50 (s, 1H), 7.50 (m, 2H), 7.38 (m, 2H), 7.12 (t, 1H), 6.98 (m, 4H), 4.63 (s, 2H), and 3.52 ppm (s, 3H). The acid (16.8 g) was dissolved in benzene (300 mL). Phosphorus pentachloride (10.4 g) was added in portions. The mixture was heated at reflux for one half hour then evaporated to dryness. The residue was dissolved in ethyl acetate (600 mL) and washed with sodium bicarbonate saturated solution (2×300 mL) then with water (300 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was chromatographed on silica gel (40% methylene chloride in hexane). The title compound (8.6 g) was obtained as a solid, m.p. 159-160° C. Mass spectrum (El, M.+) m/z 314. 1H-NMR (DMSO-d6; 400 MHz) δ7.43 (m, 2H), 7.19 (m, 3H), 7.09 (m, 2H), 7.00 (m, 2H), 5.07 (s, 2H), and 3.68 ppm (s, 3H).
Reaction SMILES: [OH-].[CH2:2]([N+:6]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][CH2:4][CH3:5].[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:21]=1[NH:27][C:28](=[O:34])/[CH:29]=[CH:30]\[C:31]([OH:33])=[O:32].C(O)(=O)C>CO>[CH2:15]([N+:6]([CH2:2][CH2:3][CH2:4][CH3:5])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:11][CH2:12][CH2:13][CH3:14])[CH2:16][CH2:17][CH3:18].[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:21]=1[NH:27][C:28](=[O:34])/[CH:29]=[CH:30]\[C:31]([O-:33])=[O:32]
Reactant: Cc1cccc(C)c1NC(=O)/C=C\C(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cccc(C)c1NC(=O)/C=C\C(=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 111.5 %

Procedure:
39 g (0.06 mole) of tetrabutylammonium hydroxide solution (40% in water) is added to the suspension of 13.15 g of N-(2,6-dimethylphenyl)-maleamic acid in 100 ml of methanol, and the reaction mixture is stirred for one hour at room temperature. The pH-value is adjusted to about 7.0 with acetic acid, and the solvent is removed in vacuo in a rotary evaporator to leave 30.8 g of N-(2,6-dimethylphenyl)-maleamic acid tetrabutylammonium salt in the form of yellow oil, which crystallises on prolonged standing.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.Cl[CH2:10][CH:11]=O>C(#N)C>[I:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:10]=[CH:11][N:1]=2)[CH:4]=1
Reactant: O=CCCl
Reactant: Nc1ccc(I)cn1
Solvent: CC#N
Product: Ic1ccc2nccn2c1
Yield: 66.1 %

Procedure:
Reflux a solution of 2-amino-5-iodo-pyridine (Tetrahedron 2002, 58, 2885-2890; 1.5 g, 6.82 mmol) and 50% aqueous chloroacetaldehyde (1.56 mL, 12.3 mmol) in acetonitrile (150 mL) for 14 h. Cool, concentrate, and dissolve the residue in 1:1 saturated aqueous sodium bicarbonate/dichloromethane. Extract the aqueous layer with dichloromethane, combine the organic layers, and concentrate. Flash chromatography using appropriate ethyl acetate/methanol mixtures gives 1.1 g (66%) of the subtitled compound as a light green solid. TOF MS ES+ exact mass calculated for C7H51N2 (p+1): m/z=244.9576; Found: 244.9564. 1H NMR (400 MHz, DMSO-d6) δ 8.9 (s, 1H), 7.86 (s, 1H), 7.52 (s, 1H), 7.40 (d, J=9 Hz, 1H), 7.36 (d, J=9.2, H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([C:9]([Cl:12])([Cl:11])[Cl:10])[CH:3]=1.[CH3:13][N:14]=[C:15]=[O:16]>CN(C)C=O.C(N(CC)CC)C>[CH3:13][NH:14][C:15](=[O:16])[O:8][C:6]1[CH:5]=[C:4]([C:9]([Cl:12])([Cl:10])[Cl:11])[CH:3]=[C:2]([Cl:1])[N:7]=1
Reactant: Oc1cc(C(Cl)(Cl)Cl)cc(Cl)n1
Reactant: CN=C=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)Oc1cc(C(Cl)(Cl)Cl)cc(Cl)n1

Procedure:
A solution was prepared by dissolving 7.4 g (0.03 m) of 6-chloro-4-(trichloromethyl)-2-pyridinol in 45 ml of dry dimethylformamide. To this solution was added 1.71 g (0.03 m) of methyl isocyanate and 7 drops of triethylamine. The mixture was allowed to stand, at room temperature, for ~30 hours. The reaction mixture was then poured over ice and the resulting solids were filtered out and taken up in hexane. The above-named product was recrystallized from the hexane and recovered in a yield of 3.8 g. The product melted at 95.5°-99.5° C. The structure of the compound was confirmed by its IR spectrum. Upon analysis, the product was found to have carbon, hydrogen, nitrogen and chlorine contents of 31.90, 2.10, 9.10 and 46.26 percent, respectively, as compared with the theoretical contents of 31.50, 1.99, 9.22 and 46.50 percent, respectively, as calculated for the above-named compound (Compound 2).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[C:10]([CH2:12][C:13]([NH:15][CH:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:17][CH2:18][CH3:19])=[O:14])[CH:9]=[CH:8][C:5]=1[CH2:6]Cl)[CH3:2].[H][H]>O1CCOCC1>[CH2:1]([O:3][C:4]1[CH:11]=[C:10]([CH2:12][C:13]([NH:15][CH:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)[CH2:17][CH2:18][CH3:19])=[O:14])[CH:9]=[CH:8][C:5]=1[CH3:6])[CH3:2]
Reactant: [H][H]
Reactant: CCCC(NC(=O)Cc1ccc(CCl)c(OCC)c1)c1ccccc1N1CCCCC1
Solvent: C1COCCO1
Product: CCCC(NC(=O)Cc1ccc(C)c(OCC)c1)c1ccccc1N1CCCCC1
Reaction time: 3 h

Procedure:
A mixture of 0.54 g (1.2 mmols) of 2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzyl chloride (melting point 114°-115° C., prepared from 2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl-benzyl alcohol and thionyl chloride in chloroform) and 10 ml of absolute dioxane was hydrogenated for 3 hours at 20° C. and a pressure of 5 bar hydrogen. The reaction mixture was then evaporated in vacuo, and the residue was taken up in a mixture of ethyl acetate and aqueous sodium carbonate. The organic phase was dried, filtered and evaporated in vacuo. The evaporation residue was purified by column chromatography on silica gel (chloroform/acetone=19/1).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]([CH:19]=O)=[C:9]([CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])[C:10]=1[CH3:11])=[O:5])C.[CH2:21]([O:23][C:24]1[CH:25]=[C:26]([C:30]2[CH:38]=[C:37]3[C:33]([CH2:34][C:35](=[O:39])[NH:36]3)=[CH:32][CH:31]=2)[CH:27]=[CH:28][CH:29]=1)[CH3:22]>N1CCCCC1.C(O)C>[C:14]([CH2:13][CH2:12][C:9]1[C:10]([CH3:11])=[C:6]([C:4]([OH:3])=[O:5])[NH:7][C:8]=1[CH:19]=[C:34]1[C:33]2[C:37](=[CH:38][C:30]([C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([O:23][CH2:21][CH3:22])[CH:25]=3)=[CH:31][CH:32]=2)[NH:36][C:35]1=[O:39])([OH:16])=[O:15]
Reactant: CCOc1cccc(-c2ccc3c(c2)NC(=O)C3)c1
Reactant: CCOC(=O)CCc1c(C=O)[nH]c(C(=O)OCC)c1C
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOc1cccc(-c2ccc3c(c2)NC(=O)C3=Cc2[nH]c(C(=O)O)c(C)c2CCC(=O)O)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
A mixture of 5-formyl-4-(2-ethoxycarbonylethyl)-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (281 mg), 6-(3-ethoxyphenyl)-2-oxindole (304 mg), and piperidine (2 drops) in ethanol (5 mL) were held at 90° C. overnight. The precipitate that formed was filtered, washed with ethanol. The precipitate, an orange solid, was stirred with potassium hydroxide (4 pellets) in ethanol (3 mL) at 90° C. for 2.5 hours. The reaction mixture was cooled and concentrated. The residue was dissolved into water and acidified with 2N hydrochloric acid to pH 2. The precipitate was filtered, washed with water, and dried in a vacuum oven overnight to give 370 mg of 4-(2-Carboxyethyl)-5-[6-(3-ethoxyphenyl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl]-3-methyl-1H-pyrrole-2-carboxylic acid.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:22]2[CH:26]=[C:25]([C:27]3[C:28]4[CH:35]=[CH:34][N:33]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:29]=4[N:30]=[CH:31][N:32]=3)[CH:24]=[N:23]2)[CH2:7][N:6]([C:8]2([CH3:21])[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[CH2:5]1)#[N:2].Cl>C1COCC1.O1CCOCC1>[CH3:21][C:8]1([N:6]2[CH2:7][C:4]([CH2:3][C:1]#[N:2])([N:22]3[CH:26]=[C:25]([C:27]4[C:28]5[CH:35]=[CH:34][N:33]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:42])([CH3:41])[CH3:43])[C:29]=5[N:30]=[CH:31][N:32]=4)[CH:24]=[N:23]3)[CH2:5]2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(N2CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CC1(N2CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 122.4 %

Procedure:
To a solution of tert-butyl 4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-4-methylpiperidine-1-carboxylate (30 mg, 0.05 mmol) in THF (2 mL) was added a 4 N solution of HCl in dioxane (2 mL). After being stirred at room temperature for 2 hours, the reaction mixture was evaporated under reduced pressure to give the title compound (31 mg, 99%), which was used for the next reaction. LC-MS found: 507.2 (M+H)+.