Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.Br[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=1.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[CH:24])[CH:18]=1>C(OCC)(=O)C.[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:15][C:13]1[CH:12]=[N:11][CH:10]=[C:9]([C:24]#[C:23][C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([Cl:16])[CH:18]=2)[CH:14]=1
Reactant: C#Cc1cccc(Cl)c1
Reactant: Brc1cncc(Br)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Clc1cccc(C#Cc2cncc(Br)c2)c1
Temperature: 50 °C
Reaction time: 18 h
Yield: 46.2 %

Procedure:
Add triethylamine (2.38 mL, 16.88 mmol), copper (I) iodide (80.4 mg, 0.422 mmol) and bis(triphenylphosphine)palladium (II) dichloride (148 mg, 0.211 mmol) to a solution of 3,5-dibromopyridine (1 g, 4.22 mmol) and 1-chloro-3-ethynylbenzene, (prepared as described in PREPARATION 12), (574 mg, 4.22 mmol) in ethyl acetate (4.22 mL). Stir under nitrogen at 50° C. for 18 h. Concentrate and purify the residue by silica gel chromatography, eluting with 100:0 to 0:100 hexanes:ethyl acetate, to give the title compound (571 mg, 46%).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[C:19](OC1C=CC=CC=1)=[O:20].Cl.Cl.[N:30]1([CH2:34][CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH2:33][CH2:32][CH2:31]1>O1CCCC1.C(N(CC)CC)C.CN(C)C=O>[N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:19]([N:38]3[CH2:39][CH2:40][CH:35]([CH2:34][N:30]4[CH2:33][CH2:32][CH2:31]4)[CH2:36][CH2:37]3)=[O:20])[CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C1CN(CC2CCNCC2)C1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1)N1CCC(CN2CCC2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
4-(4-Nitrophenoxy)pyridin-2-ylamine (60 mg) was dissolved in tetrahydrofuran (3 ml) under a nitrogen atmosphere, and then triethylamine (0.109 ml) and phenyl chloroformate (0.0975 ml) were added thereto while cooling in an ice water bath, followed by warming to room temperature and stirring for 1.5 hrs. The solution was partitioned between ethyl acetate (200 ml) and a saturated aqueous solution of sodium hydrogencarbonate (50 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (50 ml), water (50 ml), brine (100 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, to which was added N,N-dimethylformamide (3 ml). 4-(Azetidin-1-ylmethyl) piperidine dihydrochloride (207 mg) and triethylamine (0.254 ml) were added thereto, followed by stirring for 7 hrs. The reaction mixture was partitioned between ethyl acetate (100 ml) and a saturated aqueous solution of ammonium chloride (50 ml). The organic layer was washed with a saturated aqueous solution of ammonium chloride (50 ml), water (50 ml), and brine (50 ml), and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, heptane:ethyl acetate=1:1, then ethyl acetate). Fractions containing the target compound were concentrated to provide a crude product of the titled compound (70.4 mg) as a pale yellow solid.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[O:11]=[C:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[C@H:21]2[CH2:25][CH2:24][CH2:23][N:22]2[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[NH:13]1.Cl.[CH2:34]([N:41]([CH2:45][CH2:46]Cl)[CH2:42][CH2:43]Cl)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1COCC1>[CH2:34]([N:41]1[CH2:45][CH2:46][C:20]2([C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[C@H:21]3[CH2:25][CH2:24][CH2:23][N:22]3[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[NH:13][C:12]2=[O:11])[CH2:43][CH2:42]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1c1cccc2c1CC(=O)N2
Reactant: ClCCN(CCCl)Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1c1cccc2c1C1(CCN(Cc3ccccc3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 32.8 %

Procedure:
NaHMDS (5.0 mL, 5.0 mmol) was added into a solution of (R)-tert-butyl 2-(2-oxoindolin-4-yl)pyrrolidine-1-carboxylate (300 mg, 0.992 mmol) in THF (10 mL) at −78° C. The mixture was stirred for 20 minutes at that temperature. N-benzyl-2-chloro-N-(2-chloroethyl)ethanamine HCl salt (300 mg, 1.12 mmol) was added into the solution at −78° C. The reaction mixture was allowed to warm up to room temperature and was heated to reflux for 12 hours. The reaction was quenched by pouring the reaction mixture into water (10 mL) and was extracted with EtOAc (100 mL). The organic layer was washed with brine, dried with Na2SO4, filtered and concentrated. The residue was purified with flash chromatography to afford the product (R)-tert-butyl 2-(1′-benzyl-2-oxospiro[indoline-3,4′-piperidine]-4-yl)pyrrolidine-1-carboxylate (150 mg, 0.325 mmol, 32.8%) as a solid. 1H NMR (CDCl3, 400 MHz) δ 7.20-7.45 (m, 6H), 7.10 (t, 1H), 6.80 (d, 1H), 6.60-6.70 (m, 1H), 5.40-5.80 (m, 1H), 3.50-3.80 (m, 4H), 3.00-3.20 (m, 2H), 2.90-3.00 (m, 2H), 2.75-2.85 (m, 2H), 2.60-2.70 (m, 1H), 2.20-2.50 (m, 2H), 1.90-2.00 (m, 1H), 1.80-1.90 (m, 1H), 1.70-1.80 (m, 1H), 1.60-1.70 (m, 1H), 1.50-1.60 (m, 1H), 1.00-1.50 (m, 9H). MS (APCI+) [M+H]+ 462.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:12][C:13]([NH:15][C:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1)([CH3:18])[CH3:17])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN(C)C=O.ClCCl>[CH2:5]([O:12][C:13]([NH:15][C:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([Cl:3])=[O:24])=[CH:21][CH:20]=1)([CH3:18])[CH3:17])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)(NC(=O)OCc1ccccc1)c1ccc(C(=O)O)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(NC(=O)OCc1ccccc1)c1ccc(C(=O)Cl)cc1

Procedure:
Thionyl chloride (0.21 ml) and dimethylformamide (2 drops) were added to a solution of 4-(1-benzyloxycarbonylamino-1-methylethyl)-benzoic acid (780 mg) in dichloromethane (10 ml), and the mixture was refluxed under heating for 1 hour. After the reaction, the solvent was evaporated under reduced pressure to give 4-(1-benzyloxycarbonylamino-1-methylethyl)benzoyl chloride as crystals. Then, the crystals were dissolved in acetonitrile (10 ml), and the solution was dropwise added to a solution of 4-aminopyridine (195 mg) and diisopropylethylamine (0.5 ml) in acetonitrile (10 ml) under ice-cooling. The mixture was stirred at room temperature for 5 hours. After the reaction, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated under reduced pressure, and the obtained crystals were recrystallized from ethyl acetate-hexane to give 750 mg of N-(4-pyridyl)-4-(1-benzyloxycarbonylamino-1-methylethyl)benzamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:35][N:36]1[CH:40]=[C:39]([S:41](Cl)(=[O:43])=[O:42])[N:38]=[CH:37]1.O>ClCCl.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:19]([NH:21][S:41]([C:39]4[N:38]=[CH:37][N:36]([CH3:35])[CH:40]=4)(=[O:43])=[O:42])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: C[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](NS(=O)(=O)c1cn(C)cn1)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Reaction time: 18 h

Procedure:
To (1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenylpropan-2-amine (1a, 60 mg, 0.14 mmol) 130 μmol) in dichloromethane (6 mL) was added triethylamine (55 μl), followed by 1-methylimidazole-4-sulfonyl chloride (36 mg, 200 μmol) and DMAP (2 mg, 17 μmol). The stirring was continued for 18 hours at room temperature and the reaction mixture was poured into water and extracted with dichloromethane. The combined organic phases were washed with brine, died over sodium sulphate, the solvent was removed i.vac., and the product purified by chromatography on silica gel.
Reaction SMILES: C([Mg]Cl)(C)C.[Br:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10](Br)=[CH:9][N:8]=1.N1(C=O)CC[O:18][CH2:17]C1.O>C1COCC1>[Br:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([CH:17]=[O:18])=[CH:9][N:8]=1
Reactant: O=CN1CCOCC1
Reactant: Cc1cc(Br)cnc1Br
Agent: CC(C)[Mg]Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C=O)cnc1Br
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
Under an argon atmosphere, a solution of 2 M isopropylmagnesium chloride in THF (5.5 ml) was cooled to −78° C., and a solution of 2,5-dibromo-3-methylpyridine (2.5 g) in THF (10 ml) was added dropwise. After stirring at the same temperature for 30 minutes, a solution of morpholine-4-carboaldehyde (1.26 g) in THF (5 ml) was added dropwise thereto, followed by elevating the temperature to 0° C. over 30 minutes, followed by stirring at 0° C. for 2 hours. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was dried over Na2SO4 and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain 6-bromo-5-methyl nicotine aldehyde (1.42 g).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH:16]([CH3:18])[CH3:17])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C(O)CCC>[NH3:7].[CH:16]([N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[N:7][C:2]([NH:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:3][CH:4]=2)=[O:9])[CH2:11][CH2:12]1)([CH3:18])[CH3:17]
Reactant: CC(C)N1CCN(C(=O)c2ccc(Cl)nc2)CC1
Reactant: NCCN1CCCCC1
Solvent: CCCCO
Product: CC(C)N1CCN(C(=O)c2ccc(NCCN3CCCCC3)nc2)CC1
Product: N
Yield: 2 %
Yield: 37.1 %

Procedure:
A solution of (6-chloro-pyridin-3-yl)-(4-isopropyl-piperazin-1-yl)-methanone (0.20 g, 0.75 mmol) and 1-(2-aminoethyl)-piperidine (0.16 mL, 1.13 mmol) in 1-butanol (10 mL) was heated at reflux temperature. After 18 h the reaction was concentrated, treated with 1 N aq. NaHCO3 (25 mL), and extracted with DCM (3×25 mL). The organic layers were combined, dried (Na2SO4), and concentrated. Chromatography of the residue (SiO2: 2-5% 2 M NH3 in MeOH/DCM) gave the title compound as an oil (0.050 g, 20%). MS (ESI): exact mass calcd. for C20H33N5O, 359.3; m/z found, 360.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.20 (d, J=1.8, 1H), 7.54 (dd, J=8.6, 2.3, 1H), 6.40 (d, J=9.0, 1H), 5.49 (br s, 1H), 3.65 (br s, 4H), 3.39-3.35 (m, 2H), 2.74-2.70 (m, 1H), 2.59-2.57 (m, 2H), 2.53 (br s, 4H), 2.42 (br s, 4H), 1.62-1.56 (m, 4H), 1.46-1.45 (m, 2H), 1.04 (d, 6.5, 6H).
Reaction SMILES: C(O)(=O)C[SH:3].[H-].[Na+].Cl[C:9]1[N:14]=[C:13]([Cl:15])[N:12]=[C:11]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[CH3:24])[N:10]=1.Cl.[CH2:26]([O:28]CC)[CH3:27]>CN(P(N(C)C)(N(C)C)=O)C>[Cl:15][C:13]1[N:12]=[C:11]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[CH3:24])[N:10]=[C:9]([CH2:27][C:26]([OH:28])=[S:3])[N:14]=1
Reactant: CCOCC
Reactant: Cc1cccc(Nc2nc(Cl)nc(Cl)n2)c1C
Reactant: O=C(O)CS
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cc1cccc(Nc2nc(Cl)nc(CC(O)=S)n2)c1C

Procedure:
To a solution of thioglycolic acid (0.076 ml) in hexamethylphosphortriamide (2 ml), 100% sodium hydride (46 mg) is added, at room temperature, stirring for 15'. Then 2,4-dichloro-6-(2,3-xylidino)-1,3,5-triazine (0.26 g) in hexamethylphosphorotriamide (1.5 ml) is added, stirring for 30' more. The reaction mixture is then diluted with ethyl ether (15 ml), added with 10% HCl (7 ml) and stirred for 10'. The orgaic phase is separated, washed with water to neutrality and dried over Na2SO4. By evaporation of the solvent an oil (0.24 g) is obtained which crystallizes from ethyl acetate/hexane. Yield: 0.18 g of the title compound (V, 43).
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]1[CH2:14][N:13]([C:15]([O:17]C(C)(C)C)=O)[C@H:12]([C:22]([OH:24])=O)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:25]([CH2:32]C(Cl)=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[CH2:36]([N:38]1[C:50]2[CH:49]=[CH:48][C:47]([NH2:51])=[CH:46][C:45]=2[C:44]2[C:39]1=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH3:37]>>[CH2:1]([O:8][N:9]=[C:10]1[CH2:14][N:13]([C:15](=[O:17])[CH2:32][O:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@H:12]([C:22]([NH:51][C:47]2[CH:48]=[CH:49][C:50]3[N:38]([CH2:36][CH3:37])[C:39]4[C:44]([C:45]=3[CH:46]=2)=[CH:43][CH:42]=[CH:41][CH:40]=4)=[O:24])[CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(=NOCc2ccccc2)C[C@H]1C(=O)O
Reactant: O=C(Cl)COc1ccccc1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Product: CCn1c2ccccc2c2cc(NC(=O)[C@@H]3CC(=NOCc4ccccc4)CN3C(=O)COc3ccccc3)ccc21

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, phenoxyacetyl chloride, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 65% purity by LC/MS. MS(ESI+): m/z=561.4.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7](C#CC3C=CC(CO)=CN=3)[CH:8]=2)[O:3]1.[C:25]([OH:28])(=[O:27])[CH3:26].[CH:29]1([N:35]=[C:36]=NC2CCCCC2)[CH2:34][CH2:33][CH2:32][CH2:31]C1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][C:2]1([CH3:24])[CH2:11][C:10]([CH3:12])([CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:29]3[CH:34]=[CH:33][C:32]([CH2:31][O:27][C:25](=[O:28])[CH3:26])=[CH:36][N:35]=3)[CH:8]=2)[O:3]1
Reactant: CC1(C)CC(C)(C)c2cc(C#Cc3ccc(CO)cn3)ccc2O1
Reactant: CC(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCc1ccc(-c2ccc3c(c2)C(C)(C)CC(C)(C)O3)nc1

Procedure:
A solution of 3.09 g (10 mmol) of 2,2,4,4-tetramethyl-6-[2-(5-hydroxymethylpyrid-2-yl)ethynyl]chroman (Compound 50) 600 mg (10 mmol) of glacial acetic acid, 2.06 g (10 mmol) of dicyclohexylcarbodiimide and 460 mg (3.765 mmol) of 4-dimethylaminopyridine in 150 ml methylene chloride is stirred at room temperature for 48 hours. The reaction mixture is then filtered and the residue washed with 50 ml of methlene chloride. The filtrate is then concentrated in vacuo and the residue is purified by chromatography followed by recrystallization to give the title compound.
Reaction SMILES: C(O)=O.[C:4]1(=[O:13])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5]1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl>[CH:4]1([OH:13])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5]1
Reactant: O=C1CCc2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=CO
Solvent: CCN(CC)CC
Product: OC1CCc2ccccc21
Temperature: 30 °C
Reaction time: 19 h

Procedure:
Formic acid (7.2 mL, 190.7 mmol) was added dropwise to a stirred solution of 1-indanone (5.09 g, 38.5 mmol), (S,S)-TsDPEN Ru (p-cymene) Cl (231 mg, 0.36 mmol) and triethylamine (26 mL, 186.5 mmol) in dichloromethane (50 mL) at 30° C. (internal) under a nitrogen atmosphere over a period of 30 minutes. The internal temperature reached 35° C. during the addition. After stirring for 19 hours at 30° C., 1H NMR analysis indicated a conversion of 80%. Additional (S,S)-TsDPEN Ru (p-cymene)Cl (47 mg, 0.07 mmol) was added to the reaction mixture followed by formic acid (3 mL, 79.5 mmol) dropwise over 30 minutes. After stirring for 21 hours at 35° C. (internal), 1H NMR analysis indicated complete conversion. The reaction was allowed to cool to room temperature before saturated aqueous sodium hydrogen carbonate solution (100 mL) was added. The two layers were separated then the aqueous layer was further extracted with dichloromethane (80 mL). The combined organic layers were washed with water (80 mL), dried (MgSO4), filtered and concentrated under reduced pressure. The crude material was purified by passage trough a pad of silica using methyl tert-butyl ether as eluant to afford the S-enantiomer of the title compound as a red solid. (5.06 g, 98%). 1H NMR (400 MHz, d6-DMSO) δ ppm 7.37-7.34 (1H, m, Ar), 7.26-7.19 (3H, m, Ar), 5.23 (1H, d, J6, OH), 5.06 (1H, dt, J6 and 6, CH), 2.97-2.90 (1H, m, CHH), 2.77-2.69 (1H, m, CHH), 2.39-2.31 (1H, m, CHH) and 1.84-1.75 (1H, m, CHH). Analysis of this material by chiral GC indicated it to be 98% e.e.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([O:7][C:8]2[CH:9]=[C:10]([CH2:14][OH:15])[CH:11]=[CH:12][CH:13]=2)=[CH:5][N:6]=1.[C:16]([Si:20]([CH3:23])([CH3:22])Cl)([CH3:19])([CH3:18])[CH3:17].N1C=CN=C1>CN(C=O)C>[Si:20]([O:15][CH2:14][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[O:7][C:4]1[S:3][C:2]([NH2:1])=[N:6][CH:5]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:23])[CH3:22]
Reactant: Nc1ncc(Oc2cccc(CO)c2)s1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cccc(Oc2cnc(N)s2)c1
Temperature: 60 °C
Yield: 39.1 %

Procedure:
[3-(2-aminothiazol-5-yl)oxyphenyl]methanol (1.70 g, 7.575 mmol), tert-butyldimethylchlorosilane (1.38 g, 9.189 mmol), and imidazole (0.625 g, 9.189 mmol) was taken in 20 mL of dry DMF and heated at 60° C. for overnight. TLC showed consumption of starting material. The reaction mixture was cooled to room temperature and poured into water and extracted with ethyl acetate. The combined organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to get the crude product which was purified by column chromatography using 5-30% ethyl acetate in hexanes to get pure title compound (0.998 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21](I)[S:22][C:13]=12.[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)#[CH:25].CO>C(N(CC)CC)C.C1C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21]([C:25]#[C:24][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[S:22][C:13]=12
Reactant: COc1cc(Nc2c(C#N)cnc3cc(I)sc23)c(Cl)cc1Cl
Reactant: C#Cc1ccccn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1cc(Nc2c(C#N)cnc3cc(C#Cc4ccccn4)sc23)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 32.4 %

Procedure:
A mixture of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-iodothieno[3,2-b]pyridine-6-carbonitrile (300 mg, 0.63 mmol), 2-ethynylpyridine (90 μL, 0.82 mmol), 7.3 mg of tetrakis(triphenylphosphine)palladium(0) and 3 mg of copper(I) iodide in 2 mL of triethylamine and 7 mL of benzene is heated at reflux overnight. The mixture is cooled to room temperature and 5 mL of methanol are added. The solvents are removed in vacuo and the residue is treated with 10 mL of ethyl acetate. The insoluble material is removed by filtration, washing with ethyl acetate. The filtrate is washed with 10% aqueous hydrochloric acid, water, and saturated aqueous sodium chloride. The combined aqueous layers are extracted with dichloromethane. The organic layer is washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated in vacuo. The aqueous layer is adjusted to pH 6 and extracted with chloroform. The organic layer is washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The residues are combined and purified by flash column chromatography eluting with 5% methanol in dichloromethane. The fractions containing product are combined and concentrated. The resultant solid is recrystallized from ethyl acetate and hexane to provide 92 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(pyridin-2-ylethynyl)thieno[3,2-b]pyridine-6-carbonitrile as light brown crystals, mp 237–239° C.; 1H NMR (DMSO-d6) δ 3.86 (s, 3H), 7.35–7.52 (m, 2H), 7.73 (d, J=8 Hz, 1H), 7.80 (s, 1H), 7.83–7.92 (m, 2H), 8.60–8.72 (m, 2H), 9.89 (s, 1H); MS 449.1, 450.9 (M−H)−.
Reaction SMILES: C(O[C:4](=[N:6][C:7](=O)[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([O:16][CH3:17])[CH:9]=1)[CH3:5])C.[NH:19]([C:21]1[N:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1)[NH2:20].O>ClCCl.CO>[CH3:15][O:14][C:12]1[CH:13]=[C:8]([C:7]2[N:19]([C:21]3[N:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[N:20]=[C:4]([CH3:5])[N:6]=2)[CH:9]=[C:10]([O:16][CH3:17])[CH:11]=1
Reactant: NNc1ccc(S(N)(=O)=O)cn1
Reactant: CCOC(C)=NC(=O)c1cc(OC)cc(OC)c1
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: COc1cc(OC)cc(-c2nc(C)nn2-c2ccc(S(N)(=O)=O)cn2)c1
Reaction time: 8 h
Yield: 63.2 %

Procedure:
N-(1-ethoxy-ethylidene)-3,5-dimethoxy-benzamide 536 mg (2.09 mmol) was dissolved in a mixed solvent of dichloromethane 20 ml and methanol 10 ml, and 6-hydrazinopyridine-3-sulfonic acid amide 433 mg (2.23 mmol) was added to the solution and stirred for 8 hours. After completing the reaction, water 20 ml was added to the reacting solution and extracted two times with dichloromethane, and then, the collected organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting product was re-crystallized in acetone and hexane phase. As a result, 6-[5-(3,5-dimethoxy-phenyl)-3-methyl-[1,2,4]triazole-1-yl]-pyridine-3-sulfonic acid amide (496 mg, yield: 62%) was obtained as a solid phase.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:23])[CH3:22])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24]([C:26]1[CH:36]=[CH:35][C:29]([CH:30]=[CH:31][C:32]([OH:34])=[O:33])=[CH:28][CH:27]=1)=O.[OH-].[K+]>O1CCOCC1.CCO.O>[C:1]([N:9]1[CH2:10][CH2:11][N:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21](=[O:23])/[CH:22]=[CH:24]/[C:26]3[CH:27]=[CH:28][C:29](/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33])=[CH:35][CH:36]=3)=[CH:19][CH:20]=2)[CH2:13][CH2:14]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(C=CC(=O)O)cc1
Reactant: CC(=O)c1ccc(N2CCN(C(=O)c3ccccc3)CC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCO
Product: O=C(O)/C=C/c1ccc(/C=C/C(=O)c2ccc(N3CCN(C(=O)c4ccccc4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.8 %

Procedure:
1-[4-(4-Benzoyl-piperazin-1-yl)-phenyl]-ethanone (500 mg, 1.62 mmol) was dissolved in 1,4-dioxane (3 ml) and added to a stirred solution of 4-formylcinnamic acid (286 mg, 1.62 mmol) and 1.7 M KOH (1.9 ml) in EtOH (5 ml) and water (5 ml). The resulting mixture was stirred overnight at room temperature and then heated to 40° C. for 4 h. The reaction was then quenched with 10% HCl, the resulting precipitate was filtered and washed with EtOH. The resulting green solid was dried in vacuo to give 240 mg of (E)-3-(4-{(E)-3-[4-(4-benzoyl-piperazin-1-yl)-phenyl]-3-oxo-propenyl}-phenyl)-acrylic acid as its hydrochloride salt.