Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[C:9]3[N:17]=[C:16]([C:18]4[CH:19]=[C:20]([NH2:24])[CH:21]=[N:22][CH:23]=4)[CH:15]=[CH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:3][CH2:2]1.[Br:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[S:33](Cl)(=[O:35])=[O:34]>N1C=CC=CC=1.C(Cl)Cl>[Br:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[S:33]([NH:24][C:20]1[CH:21]=[N:22][CH:23]=[C:18]([C:16]2[CH:15]=[CH:14][C:10]3[N:11]=[CH:12][N:13]=[C:8]([O:7][CH:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)[C:9]=3[N:17]=2)[CH:19]=1)(=[O:35])=[O:34]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Br
Reactant: Nc1cncc(-c2ccc3ncnc(OC4CCOCC4)c3n2)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1cncc(-c2ccc3ncnc(OC4CCOCC4)c3n2)c1)c1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.1 %

Procedure:
To a solution of 5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-amine (Intermediate 12) (0.0500 g, 0.155 mmol) in pyridine (0.773 ml) was slowly added 2-bromo-4-fluorobenzene-1-sulfonyl chloride (0.0510 g, 0.186 mmol) at 0° C. After stirred for 1 hour at room temperature, the reaction mixture was diluted with DCM and quenched with 1N. aq HCl. The combined organic layers were washed brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was recrystallized from EtOAc-Hexane to give 2-bromo-4-fluoro-N-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzene-sulfonamide (0.0400 g, 46%) as a purple solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 2.02-2.11 (2H, m), 2.24-2.28 (2H, m), 3.69-3.75 (2H, m), 4.11-4.16 (2H, m), 5.65-5.71 (1H, m), 7.08-7.13 (1H, m), 7.46-7.49 (1H, m), 8.14-8.18 (1H, m), 8.22 (1H, d, J=8.8 Hz), 8.38 (1H, d, J=8.8 Hz), 8.55 (1H, s), 8.62 (1H, s), 8.84 (1H, s), 9.16 (1H, s). m/z=562.0 [M+1]+.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH2:10][CH2:9][CH2:8]2)=[O:4].[C:15]([NH:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C.Cl>CN(C)C=O>[CH2:11]1[C:12]2[C:7](=[CH:6][C:5]([C:3](=[O:4])[CH2:2][N:27]3[CH2:28][CH2:29][CH:24]([NH:23][C:15](=[O:22])[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:25][CH2:26]3)=[CH:14][CH:13]=2)[CH2:8][CH2:9][CH2:10]1
Reactant: O=C(CCl)c1ccc2c(c1)CCCC2
Reactant: O=C(NC1CCNCC1)c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CN1CCC(NC(=O)c2ccccc2)CC1)c1ccc2c(c1)CCCC2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 6-chloroacetyl-1,2,3,4-tetrahydro naphthalene (20.87 g.), 4-benzamidopiperidine (20.4 g.) and triethylamine (11.1 g.) in dimethylformamide (200 ml.). was stirred for 3 days at room temperature. The crystals which had formed during this time were then filtered off, washed and dried. A portion of this crystalline solid (4.0 g.) was dissolved in ethanol (50 ml.) and acidified with ethanolic hydrogen chloride to give 4.0 g. of the hydrochloride of the title compound, m.p. 270° C (decomp.). (Found: C, 69.5; H, 7.2; N, 6.8; C24H28N2O2.HCl requires C, 69.8; H, 7.1; N, 6.8%).
Reaction SMILES: [BH4-].[Na+].[Cl:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][C:9]=1[OH:17].[Na].[BH4-]>C(O)C.O1CCCC1>[Cl:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:15])[OH:16])=[CH:10][C:9]=1[OH:17]
Reactant: CC(=O)c1ccc(OCCCCl)c(O)c1
Agent: [BH4-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(O)c1ccc(OCCCCl)c(O)c1
Temperature: 10 °C
Reaction time: 3 h
Yield: 54.6 %

Procedure:
To a flask charged with sodium borohydride (1.5 g, 39.4 mmol) under nitrogen and chilled to 10° C. was added, slowly, a solution of 1-[4-(3-chloropropoxy)-3-hydroxyphenyl]ethanone (6.0 g, 26.2 mmol) dissolved in ethanol-tetrahydrofuran (120 ml, 2:1). After total addition, the ice bath was removed and the reaction was stirred at ambient temperature for 3 hours. An additional amount of sodium a borohydride (0.2 g, 5.3 mmol) was carefully added. After stirring at ambient temperature for one hour, the solvent was removed in vacuo. The resultant solid residue was diluted with water (100 ml) and left overnight. The product was isolated by vacuum filtration yielding 3.8 g. Two consecutive recrystallizations from toluene provided 3.3 g (55%) of 4-(3-chloropropoxy)-3-hydroxy-α-methylbenzene methanol as a light brown solid, m.p.=107°-109° C.
Reaction SMILES: C=O.[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[C:12]1[C:13]([NH2:29])=[N:14][CH:15]=[C:16]([C:18]2[CH:19]=[N:20][N:21]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH:22]=2)[CH:17]=1.[Na].[C:31](#N)C>CO.C(Cl)Cl>[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[C:12]1[C:13]([NH2:29])=[N:14][CH:15]=[C:16]([C:18]2[CH:19]=[N:20][N:21]([CH:23]3[CH2:24][CH2:25][N:26]([CH3:31])[CH2:27][CH2:28]3)[CH:22]=2)[CH:17]=1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ccccc2s1
Reactant: CC#N
Agent: C=O
Agent: [Na]
Solvent: ClCCl
Solvent: CO
Product: CN1CCC(n2cc(-c3cnc(N)c(-c4nc5ccccc5s4)c3)cn2)CC1
Reaction time: 0.5 h

Procedure:
37% Aqueous formaldehyde (0.060 ml) was added to a stirred solution of 3-(1,3-benzothiazol-2-yl)-5-[1-(4-piperidyl)pyrazol-4-yl]pyridin-2-amine (0.250 g) dissolved in methanol (2.5 ml) and DCM (2.5 ml). Sodium triacetoxyhydroborate (0.141 g) was added and the resulting solution was for 30 minutes. The mixture was concentrated. DCM and 7N methanol/ammonia were added. The mixture was concentrated on silica gel and the residue was purified by flash chromatography on silica gel eluting with 2 to 10% methanolic ammonia (7 N) in DCM. The solvent was evaporated to dryness to afford a solid. Acetonitrile (4 ml) was added and the solution was stirred overnight. The solid was filtered, and dried under vacuum. There was thus obtained 3-(1,3-benzothiazol-2-yl)-5-[1-(1-methyl-4-piperidyl)pyrazol-4-yl]pyridin-2-amine (0.198 g); Mass Spectrum: M+H+ 391; NMR Spectrum (DMSOd6): 8.48 (d, 1H), 8.33 (s, 1H), 8.16 (d, 1H), 8.15 (d, 1H), 8.10 (d, 1H), 7.93 (s, 1H), 7.88 (bs, 2H), 7.57 (dd, 1H), 7.49 (dd, 1H), 4.08-4.18 (m, 1H), 2.84-2.92 (m, 2H), 2.22 (s, 3H), 1.94-2.12 (m, 6H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][C@:6]([CH3:12])([C:8]([O:10][CH3:11])=[O:9])[NH2:7].[O-:16][C:17]#[N:18].[Na+]>C(O)(=O)C.O>[NH2:18][C:17]([NH:7][C@@:6]([CH3:12])([C:8]([O:10][CH3:11])=[O:9])[CH2:5][C:4]1[CH:13]=[CH:14][CH:15]=[C:2]([I:1])[CH:3]=1)=[O:16]
Reactant: COC(=O)[C@](C)(N)Cc1cccc(I)c1
Reactant: N#C[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)[C@@](C)(Cc1cccc(I)c1)NC(N)=O
Temperature: 20 °C
Reaction time: 48 h
Yield: 99 %

Procedure:
A mixture of methyl 3-iodo-α-methyl-D-phenylalaninate (0.73 g) in acetic acid (3 ml) and water (1 ml) was treated with sodium cyanate (0.4 g) and stirred for 2 days at 20° C. The solvents were removed under reduced pressure and the residue was diluted with EtOAc. The solution was washed with water, brine, dried (MgSO4) and evaporated to give the title compound (0.82 g) LCMS RT=2.74 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]#[N:12])[CH2:10][CH2:9]2)=[CH:4][C:3]=1Br.[CH3:14][C:15]1([CH3:24])[CH2:20][CH2:19][C:18](B(O)O)=[CH:17][CH2:16]1>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]#[N:12])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:18]1[CH2:19][CH2:20][C:15]([CH3:24])([CH3:14])[CH2:16][CH:17]=1
Reactant: N#CC1(c2ccc(N)c(Br)c2)CC1
Reactant: CC1(C)CC=C(B(O)O)CC1
Product: CC1(C)CC=C(c2cc(C3(C#N)CC3)ccc2N)CC1

Procedure:
The title compound was prepared from 1-(4-amino-3-bromo-phenyl)-cyclopropanecarbonitrile (as prepared in this step) and 4,4-dimethylcyclohexen-1-yl boronic acid using the conditions described in Example 1, step (e). 1H NMR (CD3OD; 400 MHz): δ 6.95 (dd, 1H, J=8.2, 2.3 Hz), 6.88 (d, 1H, J=2.3 Hz,), 6.71 (d, 1H, J=8.2 Hz), 5.62 (m, 1H), 2.52-2.23 (m, 2H), 1.98-1.97 (m, 2H), 1.55-1.51 (m, 4H), 1.31-1.28 (m, 2H), 1.01 (s, 6H).
Reaction SMILES: Cl.[C:2]([O:5][CH2:6][CH2:7][C@@H:8]([C:10]([OH:12])=[O:11])[NH2:9])(=[O:4])[CH3:3].C(=O)([O-])O.[Na+].Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>O>[CH2:22]([O:21][C:19]([NH:9][C@H:8]([C:10]([OH:12])=[O:11])[CH2:7][CH2:6][O:5][C:2](=[O:4])[CH3:3])=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(=O)OCC[C@H](N)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(=O)OCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reaction time: 3 h
Yield: 93.1 %

Procedure:
19.8 g (0.10 mol) of O-acetyl-L-homoserine hydrochloride are dissolved in 200 ml of water, and 35.0 g (0.42 mol) of sodium hydrogen carbonate are added at 0° C. 19.2 g (0.11 mol) of benzyl chloroformate are then added and stirring is carried out for 3 hours at room temperature. The mixture is then extracted twice using 100 ml of methyl isobutyl ketone each time, and the aqueous phase is adjusted to pH=2 using concentrated hydrochloric acid and extracted twice using 150 ml of methyl isobutyl ketone (MIBK) each time. The combined organic phases are washed with 50 ml of saturated sodium chloride solution and concentrated in vacuo. 27.5 g (93%) of N-benzyloxycarbonyl-O-acetyl-L-homoserine are obtained in the form of a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4](=[CH:9][OH:10])[C:5]([O:7][CH3:8])=[O:6].CO.Cl.[C:15](#N)C>>[CH3:8][O:7][C:5](=[O:6])[C:4](=[CH:9][O:10][CH3:15])[C:3]([O:2][CH3:1])=[O:11]
Reactant: CC#N
Reactant: COC(=O)C(=CO)C(=O)OC
Agent: Cl
Solvent: CO
Product: COC=C(C(=O)OC)C(=O)OC
Reaction time: 24 h
Yield: 79 %

Procedure:
160 g (1.0 mol) of hydroxymethylenemalonic acid dimethyl ester is dissolved in 288 g (9.0 mol) of methanol and 50 g of hydrogen chloride gas is introduced. Then 55.2 g (1.35 mol) of acetonitrile is added and the mixture is let stand for 24 hours at room temperature. Then the low-boiling substances are distilled out, dichloromethane is added to the residue, and ammonium chloride is filtered out. The filtrate is treated with 1.6 g of potassium bisulfate and heated while distilling the volatile components up to 130° C. 138 g (0.79 mol) of methoxymethylenmalonic acid dimethyl ester is obtained, corresponding to 79.3% of the theory.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:17]([C:18](O)=[O:19])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[NH2:36][C@H:37]([C:39]1[CH:48]=[CH:47][C:42]([C:43]([O:45][CH3:46])=[O:44])=[CH:41][CH:40]=1)[CH3:38]>ClCCl>[CH3:46][O:45][C:43]([C:42]1[CH:47]=[CH:48][C:39]([C@@H:37]([NH:36][C:18]([C@H:17]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:19])[CH3:38])=[CH:40][CH:41]=1)=[O:44]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@@H]1C(=O)O
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2Cc3ccccc3CN2C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 96.8 %

Procedure:
To a 0° C. mixture of (3R)-2-tert-butoxycarbonyl-3,4-dihydro-1H-isoquinoline-3-carboxylic acid (40.0 g, 141.4 mmol) and dichloromethane (784 mL), add triethylamine (21.7 mL, 155.5 mmol). Then add isobutyl chloroformate (20.3 mL, 155.5 mmol) in a dropwise fashion. After the end of the addition, stir the mixture at 0° C. for 20 minutes. Then, add methyl (S)-4-(1-aminoethyl)benzoate (27.9 g, 155.5 mmol), and stir the mixture at room temperature for 1 hour. Add water (400 mL), separate the layers, and wash the organic layer with 1 M aqueous KHSO4 (500 mL), followed by saturated aqueous NaHCO3 (500 mL). Dry the organic phase over MgSO4, filter to remove the solids, and concentrate the filtrate under reduced pressure to furnish the title compound as a white solid (60 g, 97% yield). Mass spectrum (m/z): 339 ([M+H−Boc]+), 383 ([M+H−t-Bu]+), 439 ([M+H]+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]([N:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[CH:17]1([CH3:27])[CH2:22]C[CH:20]([CH:23](C)[CH3:24])[CH:19](O)[CH2:18]1>CCO.CCO.CCO.CCO.[Ti]>[CH:23]1([CH3:24])[CH2:20][CH2:19][CH:18]([CH:17]([CH3:27])[CH3:22])[CH:9]([O:8][C:6](=[O:7])[CH:5]([N:11]2[CH:12]=[CH:13][CH:14]=[CH:15]2)[C:4]([O:3][CH2:1][CH3:2])=[O:16])[CH2:10]1
Reactant: CCOC(=O)C(C(=O)OCC)n1cccc1
Reactant: CC1CCC(C(C)C)C(O)C1
Agent: [Ti]
Solvent: CCO
Product: CCOC(=O)C(C(=O)OC1CC(C)CCC1C(C)C)n1cccc1
Temperature: 110 °C
Reaction time: 19 h
Yield: 31.8 %

Procedure:
To a mixture of 2-(pyrrol-1-yl)malonic acid diethyl ester (300.0 g) and (-)-menthol (417.0 g) was added tetraethyl titanate (10.0 g), and the resulting mixture was stirred at 110° C. for 19 hours. After removal of the (-)-menthol under reduced pressure, the residue was chromatographed on silica gel using n-hexane/ethyl acetate (50:1) as the eluent. Fractions containing the title compound were pooled and evaporated under reduced pressure to give the title compound (142.0 g, 31.8%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+].CO.O>Cl>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([C:16]([F:19])([F:17])[F:18])(=[O:14])=[O:15])=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(NS(=O)(=O)C(F)(F)F)ccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(NS(=O)(=O)C(F)(F)F)ccc1Cl
Yield: 81.5 %

Procedure:
A solution of methyl 2-chloro-5-{[(trifluoromethyl)sulfonyl]amino}benzoate (1.0 g, 3.15 mmol), sodium hydroxide (378 mg, 9.44 mmol), methanol (6 ml) and water (6 ml) was stirred for 1 hour. Removal of the volatiles by spin evaporation in vacuo gave a residue that was dissolved in 1 N aqueous hydrochloric acid. The aqueous solution was extracted with ethyl acetate (3 times) and the organic layers were combined, washed with water, and concentrated by spin evaporation in vacuo to give 2-chloro-5-{[(trifluoromethyl)sulfonyl]amino}benzoic acid as a crystalline solid (0.78 g, 82%). 1H-NMR (400 MHz, DMSO-d6): δ 7.63-7.60 (m, 1H), 7.59-7.54 (m, 1H), 7.40-7.35 (m, 1H). ES-LCMS m/z 304 (M+H).
Reaction SMILES: I[C:2]1[N:3]=[C:4]([CH3:16])[N:5]([C:8]2[CH:13]=[CH:12][N:11]([CH3:14])[C:10](=[O:15])[CH:9]=2)[C:6]=1[CH3:7].[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)#[CH:18]>>[F:25][C:21]1[CH:20]=[C:19]([C:17]#[C:18][C:2]2[N:3]=[C:4]([CH3:16])[N:5]([C:8]3[CH:13]=[CH:12][N:11]([CH3:14])[C:10](=[O:15])[CH:9]=3)[C:6]=2[CH3:7])[CH:24]=[CH:23][CH:22]=1
Reactant: C#Cc1cccc(F)c1
Reactant: Cc1nc(I)c(C)n1-c1ccn(C)c(=O)c1
Product: Cc1nc(C#Cc2cccc(F)c2)c(C)n1-c1ccn(C)c(=O)c1

Procedure:
The title compound, brown waxy solid, MS: m/e=322.1 (M+H+), was prepared in accordance with the general method of example 1c from 4-(4-iodo-2,5-dimethyl-imidazol-1-yl)-1-methyl-1H-pyridin-2-one and 1-Ethynyl-3-fluoro-benzene.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:26]#[C:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:8][C:9]=1[N:10]1[CH:15]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:14][CH2:13][C@H:12]([N:22]=[N+]=[N-])[C:11]1=[O:25])=[O:4].Cl[Sn]Cl.O[Li].O>CO>[NH2:22][C@H:12]1[CH2:13][CH2:14][CH:15]([CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[N:10]([C:9]2[CH:8]=[C:7]([C:26]#[C:27][C:28]([CH3:30])([CH3:31])[CH3:29])[S:6][C:5]=2[C:3]([OH:4])=[O:2])[C:11]1=[O:25]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N1C(=O)[C@@H](N=[N+]=[N-])CCC1C1CCCCC1
Agent: Cl[Sn]Cl
Agent: [Li]O
Solvent: CO
Solvent: O
Product: CC(C)(C)C#Cc1cc(N2C(=O)[C@@H](N)CCC2C2CCCCC2)c(C(=O)O)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 33.1 %

Procedure:
To the solution of 3-((S)-3-azido-6-cyclohexyl-2-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (40 mg, 0.09 mmol, 1 equiv) in MeOH (0.5 mL) was added SnCl2 (17 mg, 0.09 mmol, 1 equiv) and the resulting solution was stirred at room temperature for 18 hours. The solvent was then removed under vacuum. The residue was dissolved in THF/H2O/MeOH (0.5 mL/0.5 mL/1.0 mL) and to the solution was added LiOH.H2O (21 mg, 0.48 mmol, 5 equiv). The reaction mixture was stirred at 50° C. for 20 minutes. The organic solvents were removed under vacuum and the residue was acidified to pH=5 by addition of 3.0 N HCl aq. solution. The mixture was extracted with EtOAc. The organic layer was dried over Na2SO4, and concentrated under vacuum. The residue was purified by prep-HPLC (XBridge Prep C 18 5 um, 30×50 mm) in basic condition (0.1% NH4OH, 10%˜45% CH3CN/H2O, 10 min run, 40 ml/min) to give product 12 mg. MS: 403 [M+H+]. 1H-NMR (400 MHZ, CD3OD): δ 6.81 (s, 1H), 3.96 (br, 1H), 3.48 (m, 1H), 2.06 (m, 3H), 1.84 (m, 3H), 1.70 (br, 2H), 1.46 (m, 1H), 1.37 (m, 1H), 1.31 (s, 9H), 1.16 (m, 5H).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](Cl)=[O:7])(=[O:3])[CH3:2].[CH3:9][O:10][C:11]1[CH:55]=[C:54]([O:56][CH3:57])[CH:53]=[C:52]([O:58][CH3:59])[C:12]=1/[CH:13]=[CH:14]/[CH:15]([S:25]([CH:28](/[CH:38]=[CH:39]/[C:40]1[C:45]([O:46][CH3:47])=[CH:44][C:43]([O:48][CH3:49])=[CH:42][C:41]=1[O:50][CH3:51])[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([NH2:37])[CH:30]=1)(=[O:27])=[O:26])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([NH2:24])[CH:17]=1>>[CH3:59][O:58][C:52]1[CH:53]=[C:54]([O:56][CH3:57])[CH:55]=[C:11]([O:10][CH3:9])[C:12]=1/[CH:13]=[CH:14]/[CH:15]([S:25]([CH:28](/[CH:38]=[CH:39]/[C:40]1[C:41]([O:50][CH3:51])=[CH:42][C:43]([O:48][CH3:49])=[CH:44][C:45]=1[O:46][CH3:47])[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([NH:37][C:6](=[O:7])[CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH:30]=1)(=[O:27])=[O:26])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([NH:24][C:6](=[O:7])[CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH:17]=1
Reactant: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(N)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(N)c2)c(OC)c1
Reactant: CC(=O)OCC(=O)Cl
Product: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(NC(=O)COC(C)=O)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(NC(=O)COC(C)=O)c2)c(OC)c1
Yield: 90 %

Procedure:
A solution of acetoxyacetyl chloride (10 mmol) and (E)-2,4,6-trimethoxystyryl-3-amino-4-methoxy benzylsulfone (10 mmol) was reacted according to General Method A. The product obtained was purified column chromatography to give a 90% yield of the desired product. (m.p. 192-1 94° C.)
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])=[N:6][CH:7]=1.[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([OH:31])=[C:26](B(O)O)[CH:27]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([OH:31])=[C:24]([C:2]2[CH:3]=[N:4][C:5]([N:8]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])=[N:6][CH:7]=2)[CH:23]=1
Reactant: OB(O)c1cc(Cl)ccc1O
Reactant: CCS(=O)(=O)N(Cc1ccccc1)c1ncc(Br)cn1
Product: CCS(=O)(=O)N(Cc1ccccc1)c1ncc(-c2cc(Cl)ccc2O)cn1

Procedure:
The subtitle compound was prepared by the method of example 1 step (ii) using the product from step (i) and 5-chloro-2-hydroxyphenyl-boronic acid, yield 0.25 g.
Reaction SMILES: [Na].C([C:7]1([OH:18])[CH2:16][CH2:15][CH:14]2[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13]2)[CH:8]1[CH3:17])(OCC)=O.[CH2:19]([OH:21])C>O>[OH:21][CH2:19][CH2:17][CH:8]1[CH:9]2[CH:14]([CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:15][CH2:16][CH:7]1[OH:18]
Reactant: CCO
Reactant: CCOC(=O)C1(O)CCC2CCCCC2C1C
Agent: [Na]
Solvent: O
Product: OCCC1C(O)CCC2CCCCC21

Procedure:
86.25 g Of small pieces of sodium are added to 60 g of 2-carbethoxy-methyl-2-hydroxy-decalin and 900 ml of anhydrous ethyl alcohol. A vigorous reaction sets in which causes the reaction medium to reflux. Reflux is maintained for 1 hour. The mass is cooled, 1000 ml of water added, the alcohol distilled off and the residue is taken up in a little warm water. After cooling the mass is extracted three times with 250 ml of diethyl ether. The ethereal solutions are washed to neutrality and distilled; there are thus obtained 40 g of crude product which are rectified under 0.5 mm. This rectification gives 22 g of 2-hydroxyethyl-2-hydroxy-decalin (b.p.0.5 = 138°-140°C), which represents a conversion of about 42%.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:24]([N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25])[CH2:8][NH:9][C:10]([CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[CH2:14][CH2:13]1)=[O:11])=[O:5].[Cl:32][C:33]1[CH:34]=[C:35]([S:40](Cl)(=[O:42])=[O:41])[CH:36]=[CH:37][C:38]=1[Cl:39]>>[Cl:32][C:33]1[CH:34]=[C:35]([S:40]([NH:2][CH2:3][C:4]([NH:6][CH:7]([C:24]([N:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)=[O:25])[CH2:8][NH:9][C:10]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])=[O:5])(=[O:41])=[O:42])[CH:36]=[CH:37][C:38]=1[Cl:39]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: NCC(=O)NC(CNC(=O)C1CCN(c2ccncc2)CC1)C(=O)N1CCCCC1
Agent: Cl
Product: O=C(CNS(=O)(=O)c1ccc(Cl)c(Cl)c1)NC(CNC(=O)C1CCN(c2ccncc2)CC1)C(=O)N1CCCCC1
Yield: 27 %

Procedure:
Using an analogous procedure to that described in Example 2, 2-amino-N-{l-piperidinocarbonyl-2-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]ethyl}acetamide hydrochloride salt was reacted with 3,4-dichlorophenylsulphonyl chloride to give 2-(3,4-dichlorophenylsulphonamido)-N-{1-piperidinocarbonyl-2-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]ethyl}acetamide as a gum (0.17 g, 27%);
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH:10]=O)=[CH:2]1.C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15].N1CCCCC1>N1C=CC=CC=1>[S:1]1[CH:2]=[C:3]([CH:10]=[CH:13][C:14]([OH:16])=[O:15])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1csc2ccccc12
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1csc2ccccc12
Temperature: 110 °C

Procedure:
A suspension of 1-benzothiophene-3-carbaldehyde (4.9 g, 0.03 mol), malonic acid (6.6 g, 0.06 mol) and piperidine (1 mL) in 100 mL anhydrous pyridine was heated at 110° C. overnight. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was taken up in 100 mL of water and 1 N hydrochloric acid was added to adjust the pH of this solution to ca. 3. The suspension was filtered and the yellow solid was collected, washed with water (3×50 mL) and concentrated in vacuo to give the indicated product with 95% purity (5.65 g, 91%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([NH2:14])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[CH:16](=O)[CH2:17][CH2:18][CH2:19][CH3:20].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([NH:14][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cccc(N)c1C(=O)OC
Reactant: CCCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCCCNc1cccc(C(=O)OC)c1C(=O)OC
Reaction time: 0.08 h
Yield: 100 %

Procedure:
To a stirred solution of 3-amino-phthalic acid dimethyl ester (3.14 g, 15 mmol) in methylene chloride (50 ml) under a nitrogen atmosphere were added valeraldehyde (2.0 ml, 18.75 mmol) and acetic acid (5.18 ml, 90 mmol). The mixture was stirred for 5 minutes followed by addition of sodium triacetoxyborohydride (6.36 g, 30 mmol). The reaction was stirred for 30 minutes, diluted with methylene chloride (50 ml), washed with water (2×100 ml), saturated aqueous sodium bicarbonate (2×100 ml), brine (100 ml), and dried (MgSO4). The solvent was evaporated in vacuo to give 4.19 g of product (100%) that used without further purification. 1H NMR (DMSO-d6) d 7.31 (t, J=7.9 Hz, 1H), 6.81–6.75 (m, 2H), 3.85 (s, 3H), 3.82 (s, 3H), 3.15 (bs, 2H), 1.68–1.60 (m, 2H), 1.45–1.32 (m, 4H), 0.89 (t, J=6.9 Hz, 3H).