Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:33][CH:34]=[CH2:35])=[C:4]([CH:26]=[CH:27][C:28]=1[C:29]([NH:31][CH3:32])=[O:30])[O:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([CH2:23][CH2:24][CH3:25])=[C:12]([CH:20]=[CH:21][CH:22]=1)[O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].[OH-].[K+].S(OC)(O[CH3:42])(=O)=O>C1COCC1>[CH3:42][O:1][C:2]1[C:3]([CH2:33][CH:34]=[CH2:35])=[C:4]([CH:26]=[CH:27][C:28]=1[C:29]([NH:31][CH3:32])=[O:30])[O:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([CH2:23][CH2:24][CH3:25])=[C:12]([CH:20]=[CH:21][CH:22]=1)[O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: COS(=O)(=O)OC
Reactant: C=CCc1c(OCCCOc2cccc(OCC(=O)OCC)c2CCC)ccc(C(=O)NC)c1O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=CCc1c(OCCCOc2cccc(OCC(=O)OCC)c2CCC)ccc(C(=O)NC)c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound of Example 51 (120 mg, 0.247 mmol), potassium hydroxide (16.6 mg, 0.285 mmol) and dimethyl sulfate (46.7 mg, 0.37 mmol) were added to 5.0 ml of THF, and the reaction mixture was stirred at room temperature overnight. The solvent was removed under vacuum, and 10 ml of water was added. The solution was extracted three times with ethyl acetate, the combined extracts were dried, and the solvent was removed under vacuum to give an oil. Chromatography of the oil on silica gel using 50/50 ethyl acetate/hexane as eluant gave the product as a colorless gum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]4[NH:20][CH:19]=[CH:18][N:16]4[N:17]=3)[CH:10]=[N:9]2)=[CH:5][CH:4]=1.Br[C:24]1[CH:25]=[C:26]([NH:31][C:32](=[O:43])[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=2)[CH:27]=[CH:28][C:29]=1[CH3:30].C(=O)([O-])[O-].C([N+](CC)(CC)CC)C.C([N+](CC)(CC)CC)C.OC1C=CC=C2C=1N=CC=C2>CN(C=O)C.O.[Cu]I>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]4[N:20]([C:24]5[CH:25]=[C:26]([NH:31][C:32](=[O:43])[C:33]6[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:41])([F:40])[F:42])[CH:34]=6)[CH:27]=[CH:28][C:29]=5[CH3:30])[CH:19]=[CH:18][N:16]4[N:17]=3)[CH:10]=[N:9]2)=[CH:21][CH:22]=1
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Br
Reactant: COc1ccc(Cn2cc(-c3cc4[nH]ccn4n3)cn2)cc1
Agent: [Cu]I
Agent: CC[N+](CC)(CC)CC
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc(-c3cc4n(-c5cc(NC(=O)c6cccc(C(F)(F)F)c6)ccc5C)ccn4n3)cn2)cc1
Temperature: 160 °C

Procedure:
55 mg (0.19 mmol) of the compound of Example 5A and 74 mg (0.21 mmol) of the compound of Example 45A were dissolved in 1.24 ml of DMF and 0.12 ml of water, and 126 mg (0.39 mmol) of bis(tetraethylammonium) carbonate were added carefully. The mixture was degassed with argon, and 14.3 mg (0.08 mmol) of copper(I) iodide and 10.9 mg (0.08 mmol) of 8-hydroxyquinoline were then added. The reaction was then heated in a microwave oven (Biotage Initiator, with Dynamic Field Tuning) at 160° C. for 1 h. After cooling, the mixture was poured into 10 ml of water and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution and concentrated under reduced pressure. The residue was purified by preparative HPLC (Method 11). The product fractions were concentrated and the residue was dried under high vacuum. This gave 26 mg (57% pure, 14% of theory) of the title compound which was reacted further in this form.
Reaction SMILES: [CH3:1][C:2]([OH:6])([CH:4]=[CH2:5])[CH3:3].C(N(CC)CC)C.[C:14](OC(=O)C)(=[O:16])[CH3:15].O>C(Cl)Cl>[C:14]([O:6][C:2]([CH3:3])([CH:4]=[CH2:5])[CH3:1])(=[O:16])[CH3:15]
Reactant: C=CC(C)(C)O
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: C=CC(C)(C)OC(C)=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
To a stirred solution of 2-methyl-3-buten-2-ol (86.13 g, 1.0 mole), triethylamine (101.19 g, 1.3 mole), and 4-dimethylaminopropyridine (25.0 g, 0.2 mole) at 0° C. is added dropwise acetic anhydride (102.09 g, 1.15 mole) in CH2Cl2 (700 ml). The mixture is stirred at 0° C. for 5 hours and at room temperature overnight. Water is then added and the CH2CL2 layer separated. The aqueous layer is extracted with CH2Cl2 (3×300 ml) and the combined CH2Cl2 solution is washed with cold 1N HCl (300 ml), water (330 ml) and dried over anhydrous MgSO4. Distillation of the CH2Cl2 solution gives 2-methyl-3-buten-2-yl acetate (113.07 g), 88 percent, boiling point 59° C. (80 mm Hg).
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[C:24](N1C=CN=C1)=[O:25])[CH2:4][CH3:5])[CH3:2].[CH3:31][Mg]Br.C(OCC)C>C(Cl)Cl>[CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[C:24](=[O:25])[CH3:31])[CH2:4][CH3:5])[CH3:2]
Reactant: C[Mg]Br
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C(=O)n1ccnc1
Solvent: CCOCC
Solvent: ClCCl
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C(C)=O

Procedure:
The title compound was prepared by reacting [4-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]-imidazol-1-yl-methanone with methylmagnesium bromide/ethyl ether in methylene chloride. 1H NMR(CDCl3) d 9.7(d,1H), 6.88(s,2H), 6.10(s,1H), 3.32(m,1H), 2.73(s,3H), 2.31(s,3H), 2.10(s,3H), 2.09(s,6H), 1.5–1.7(m,4H), 0.95(t,6H)ppm.
Reaction SMILES: [CH:1]([Li])([CH2:3][CH3:4])[CH3:2].[CH2:6]=[CH:7][C:8](=[CH2:10])[CH3:9]>C1C=CC=CC=1>[CH2:6]=[CH:7][C:8](=[CH2:9])[CH3:10].[CH2:2]=[CH:1][CH:3]=[CH2:4]
Reactant: [Li]C(C)CC
Solvent: c1ccccc1
Solvent: C=CC(=C)C
Product: C=CC=C

Procedure:
A 3-arm star isoprene/butadiene block copolymer was synthesized using standard high vacuum techniques, M. Morton et al., J. Rubber Chem. and Technol., 48, 359 (1975). A brief summary of the polymerization procedure is as follows: Ampules containing sec-butyl lithium solution (in benzene) and benzene were released into a 250 ml all-glass high-vacuum apparatus, magnetic stirring was commenced, and sufficient isoprene was added from an ampule to form oligomeric chains five (5) units long. After stirring for 40 hours at 25° C., the mixture was frozen, and an amount of butadiene was distilled into the reaction mixture to add a block of 95 units to the living isoprene oligomers. The reaction mass was then thawed and stirred for 60 hours at room temperature. During this time, a slight increase in viscosity was noted, but the mixture remained clear and water-white. At this point, the living chains were linked with a stoichiometric amount of trichloromethyl silane, followed by precipitation into methanol. Work-up was completed by redissolution of the polymer into hexanes, washing the solution three times with water, drying the solution over MgSO4, and finally removal of the solvent using a Rotovap.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([CH3:15])[C:11]([O:13]C)=[O:12])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].O1CCCC1.O.[OH-].[Na+]>C(OCC)(=O)C.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([CH3:15])[C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: COC(=O)C(C)c1ccc(C#N)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C(=O)O)c1ccc(C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 110.5 %

Procedure:
To a stirred solution of methyl 2-(3-chloro-4-cyanophenyl)propanoate (642 mg, 2.87 mmol) in co-solvent with tetrahydrofuran and water (1:1) were added sodium hydroxide (287 mg, 7.175 mmol). The reaction mixture was stirred for 15 h at room temperature, then acidified to pH 3-4 with acetic acid. The residue dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography. 2-(3-Chloro-4-cyanophenyl)propanoic acid (665 mg) was obtained as 99% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH:13]1[CH2:17][CH2:16][C:15](=O)[CH2:14]1)([O-:3])=[O:2].CC(O)=O.[CH2:23]([NH2:25])[CH3:24].Cl.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH2:23]([NH:25][CH:15]1[CH2:16][CH2:17][CH:13]([C:7]2[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[NH:9][CH:8]=2)[CH2:14]1)[CH3:24]
Reactant: O=C1CCC(c2c[nH]c3ccc([N+](=O)[O-])cc23)C1
Reactant: CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCNC1CCC(c2c[nH]c3ccc([N+](=O)[O-])cc23)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(5-nitro-1H-indol-3-yl)cyclopentanone (1.6 g, 6.55 mmol) in 1,2-dichloroethane (50 mL) was added AcOH (0.40 mL, 6.55 mmol), EtNH2.HCl (0.53 g, 6.55 mmol) and NaBH(OAc)3 (2.1 g, 9.83 mmol) and the mixture left to stir overnight at room temperature. The reaction mixture was extracted with 2N NaOH (10 mL) and washed with dichloromethane (2×10 mL). The dichloromethane layer was separated and evaporated. The crude material was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 1:9) to obtain the product as a yellow solid as a mixture of diastereomers (1.2 g, 67%). 1H-NMR (CDCl3) δ 1.10-1.16 (m, 6H), 1.45-1.92 (m, 10H), 1.96-2.13 (m, 3H), 2.13-2.36 (m, 3H), 2.50-2.58 (m, 1H), 2.65-2.76 (m, 4H), 3.28-3.43 (m, 3H), 3.49-3.60 (m, 1H), 7.11 (d, 1H, J=1.8 Hz), 7.15 (d, 1H, J=1.5 Hz), 7.35 (s, 1H), 7.38 (s, 1H), 8.08 (d, 1H, J=2.1 Hz), 8.11 (d, 1H, J=2.1 Hz), 8.32 (brs, 1H, NH), 8.41 (brs, 1H, NH), 8.61 (d, 1H, J=2.1 Hz), 8.63 (d, 1H, J=2.1 Hz); EI-MS (m/z, %) 273 (M+, 90).
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[CH2:3][CH:4]([C:6]1[S:7][CH:8]=[CH:9][C:10]=1[N+:11]([O-])=O)[CH3:5].[Sn](Cl)(Cl)(Cl)Cl.Cl.[OH-].[Na+]>C(O)C>[CH3:1][CH:2]([CH3:14])[CH2:3][CH:4]([C:6]1[S:7][CH:8]=[CH:9][C:10]=1[NH2:11])[CH3:5]
Reactant: CC(C)CC(C)c1sccc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)CC(C)c1sccc1N
Temperature: 70 °C
Yield: 38.8 %

Procedure:
After dissolving 0.33 g of 2-(4-methylpentan-2-yl)-3-nitrothiophene in 6 ml of ethanol, 0.88 g of tin chloride (II) and 0.97 g of concentrated hydrochloric acid were added thereto, and the reaction solution was heated to 70° C. and stirred for an hour. After cooling the solution to room temperature, 1 mol/l of an aqueous sodium hydroxide was added thereto, and the solution stirred for five minutes. The resultant was filtered on cellite, and the filterate was extracted with ethyl acetate. The organic layer was washed with 1 mol/l of aqueous sodium hydroxide and saturated saline. Then, the organic layer was dried with magnesium sulfate and concentrated, and then purified by silica gel chromatography (hexane/ethyl acetate=8/1), thereby obtaining 0.11 g of 2-(4-methylpentan-2-yl)-3-aminothiophene (yield: 39.0%).
Reaction SMILES: C(O[C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)C=C.CCCCC.C([Li])(C)(C)C.[CH:22]([C:24]1[CH:33]=[CH:32][C:27](C(OC)=O)=[CH:26][C:25]=1O)=[O:23].[Cl-].[NH4+]>O1CCCC1.O>[C:24]1([CH:22]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[OH:23])[CH:33]=[CH:32][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc(C=O)c(O)c1
Reactant: C=CCOc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: O
Solvent: CCCCC
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 108.8 %

Procedure:
To a solution of 1-allyloxy-4-bromobenzene (3.1 g) in tetrahydrofuran (70 mL) was added 1.45 mol/L tert-butyllithium n-pentane solution (11 mL) under an argon atmosphere at −78° C. After the mixture was stirred at −78° C. for 5 minutes, a solution of methyl 4-formyl-3-hydroxybenzoate (0.89 g) in tetrahydrofuran (15 mL) was added to the reaction mixture. After the mixture was stirred for 30 minutes under ice-cooling, a saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=3/1) to give a diphenylmethanol compound (0.99 g). The obtained diphenylmethanol compound (0.99 g) was dissolved in methanol (10 mL), and 10% palladium-carbon powder (0.30 g) was added to the solution. After the mixture was stirred under a hydrogen atmosphere at room temperature for 24 hours, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=3/1) to give methyl 3-hydroxy-4-(4-propoxybenzyl)benzoate (0.50 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][C:43]=1F)[C:5]1[C:10]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]4[N:25]([CH:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)[C:24]5[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=5[N:22]=4)[CH:17]=3)[N:12]=2)=[CH:9][C:8]([O:39][CH3:40])=[CH:7][CH:6]=1.[CH3:45]OC(C1C=CC2N(C3CCCCC3)C(C3C=C4C(=CC=3)N=C(C3C=C(OC)C=CC=3Br)C=C4)=NC=2C=1)=O.C1(C)C=CC=C(B(O)O)C=1>>[CH:26]1([N:25]2[C:24]3[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=3[N:22]=[C:21]2[C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([C:10]2[C:5]([C:4]4[CH:41]=[CH:42][CH:43]=[C:2]([CH3:45])[CH:3]=4)=[CH:6][CH:7]=[C:8]([O:39][CH3:40])[CH:9]=2)[CH:20]=[CH:19]3)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: COC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(OC)ccc4Br)ccc3c1)n2C1CCCCC1
Reactant: COc1ccc(-c2ccc(F)c(Cl)c2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Agent: Cc1cccc(B(O)O)c1
Product: COc1ccc(-c2cccc(C)c2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Yield: 27 %

Procedure:
Following the full procedure and workup for Compound 366, Compound 365b (100 mg, 0.175 mmol) was reacted with m-tolylboronic acid (36 mg, 0.2625 mmol) to produce the title compound (27 mg, 27% yield).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][C:15]([C:17]2[N:18]=[CH:19][S:20][CH:21]=2)=[O:16])[CH2:10][C@H:9]1[C:22]([N:24]1[CH2:28][CH2:27][S:26][CH2:25]1)=[O:23])=O)(C)(C)C.Cl.O1CCOCC1>CO.O>[S:26]1[CH2:27][CH2:28][N:24]([C:22]([C@H:9]2[NH:8][CH2:12][C@@H:11]([CH2:13][NH:14][C:15]([C:17]3[N:18]=[CH:19][S:20][CH:21]=3)=[O:16])[CH2:10]2)=[O:23])[CH2:25]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CNC(=O)c2cscn2)C[C@H]1C(=O)N1CCSC1
Agent: Cl
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: O=C(NC[C@@H]1CN[C@H](C(=O)N2CCSC2)C1)c1cscn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of Example 55A (4.8 g, 11.3 mmol) in anhydrous methanol (10 mL) a solution of 4 M HCl in dioxane (22.5 mL, 90 mmol) was slowly added via addition funnel at 0° C. over 30 minutes. The mixture was stirred for 4 hours at room temperature and concentrated under reduced pressure to provide a yellow oil. The oil was dissolved in water, frozen, and lyophilized to provide a white power as the titled product. MS (ESI) m/e 327 (M+H)+, 325 (M−H)−; 1H NMR (500 MHz, CD3OD) δ ppm 1.80 (m, 1H), 2.74 (m, 1H), 2.84 (m, 1H), 3.09 (m, 1H), 3.16 (t, 1H), 3.24 (m, 1H), 3.52 (dd, 2H), 3.55 (m, 1H), 3.74 (m, 1H), 3.88 (m, 1H), 4.51 (m, 1H), 4.65 (d, 1H), 4.70 (d, 1H), 8.33 (s, 1H) 9.11 (s, 1H).
Reaction SMILES: C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:29]1[CH:30]=[C:31]([C:36]2[O:37][C:38]3[C:39]([N:44]=2)=[N:40][CH:41]=[CH:42][CH:43]=3)[C:32]([NH2:35])=[N:33][CH:34]=1.[CH3:45][N:46]([CH3:67])[CH2:47][CH2:48][NH:49][C:50](=[O:66])[C:51]1[CH:56]=[CH:55][C:54](B2OC(C)(C)C(C)(C)O2)=[CH:53][CH:52]=1>O1CCOCC1.O>[NH2:35][C:32]1[N:33]=[CH:34][C:29]([C:54]2[CH:55]=[CH:56][C:51]([C:50]([NH:49][CH2:48][CH2:47][N:46]([CH3:45])[CH3:67])=[O:66])=[CH:52][CH:53]=2)=[CH:30][C:31]=1[C:36]1[O:37][C:38]2[C:39]([N:44]=1)=[N:40][CH:41]=[CH:42][CH:43]=2
Reactant: CN(C)CCNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Nc1ncc(Br)cc1-c1nc2ncccc2o1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CN(C)CCNC(=O)c1ccc(-c2cnc(N)c(-c3nc4ncccc4o3)c2)cc1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
The following conditions were used. Tris(dibenzilideneacetone)dipalladium (47.2 mg), tricyclohexylphosphine (28.9 mg) and potassium phosphate (656 mg) were added to a degassed solution of 5-bromo-3-oxazolo[4,5-b]pyridin-2-yl-pyridin-2-amine (300 mg, 1.03 mmol), N-(2-dimethylaminoethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (361 mg, 1.13 mmol) in 1,4-dioxane (2 ml) and water (0.400 ml) under nitrogen atmosphere. The suspension was stirred at 90° C. for 4 hours. The mixture was filtered and the solvent was removed. The mixture was adsorbed on silica gel, the crude product was purified by flash chromatography on silica gel eluting with 10% methanol in dichloromethane follow by 10% methanolic ammonia (7 N) in dichloromethane. The solvent was evaporated to dryness to afford 4-(6-amino-5-oxazolo[4,5-b]pyridin-2-yl-3-pyridyl)-N-(2-dimethylaminoethyl)benzamide after stirring overnight in acetonitrile. NMR Spectrum: (DMSO-d6) 2.19 (s, 6H), 2.42 (t, 2H), 3.35-3.42 (m, 2H), 7.50 (dd, 1H), 7.84 (d, 2H), 7.91 (bs, 2H), 7.95 (d, 2H), 8.26 (dd, 1H), 8.45 (t, 1H), 8.56 (dd, 1H), 8.61 (d, 1H), 8.73 (d, 1H); Mass spectrum: M+H+ 403
Reaction SMILES: [OH-].[Li+].C[O:4][C:5]([CH2:7][N:8]([C:26](=[O:35])/[CH:27]=[CH:28]/[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:9]1[CH:14]=[CH:13][C:12]([O:15]C(=O)/C=C/C2C=CC=CC=2)=[CH:11][CH:10]=1)=[O:6].Cl>O.C1COCC1.CO>[OH:15][C:12]1[CH:13]=[CH:14][C:9]([N:8]([CH2:7][C:5]([OH:6])=[O:4])[C:26](=[O:35])/[CH:27]=[CH:28]/[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)CN(C(=O)/C=C/c1ccccc1)c1ccc(OC(=O)/C=C/c2ccccc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)CN(C(=O)/C=C/c1ccccc1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
Lithium hydroxide (119 mg, 4.96 mmol) in water (10 mL) was added to a solution of (E)-3-phenylacrylic acid 4-{methoxycarbonylmethyl-[(E)-(3-phenylacryloyl)]-amino}phenyl ester 12 (734 mg, 1.66 mmol) in THF (30 mL) and methanol (10 mL). The reaction mixture was stirred at room temperature for 2 h. A further quantity of lithium hydroxide (119 mg, 4.96 mmol) in water (5 mL) was added and the reaction mixture stirred for a further 1 h. It was then acidified to pH1 with conc. hydrochloric acid and concentrated in vacuo. The aqueous mixture was extracted with ethyl acetate (×2) and the organic layers combined, washed with brine, dried (Na2SO4) and evaporated. The resultant residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate, to afford the title compound (0.37 g, 75%). 1HNMR (300 MHz) (d6-DMSO) δ 4.07 (2H, br s), 6.37 (1H, d, J=15 Hz), 6.78 (2H, d), 7.22 (2H, d), 7.34 (5H, m) and 7.44 (1H, d, J=15 Hz).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:10]=[CH:9][C:8]=1[C:17](=[O:27])[CH2:18][C:19]([NH:21][C:22]1[S:23][CH:24]=[CH:25][N:26]=1)=[O:20])=O>CN(C)C1C=CN=CC=1.O1CCCC1>[OH:27][C:17]1[C:8]2[C:7](=[C:12]([C:13]([F:16])([F:15])[F:14])[CH:11]=[CH:10][CH:9]=2)[N:6]=[C:4]([CH2:3][O:2][CH3:1])[C:18]=1[C:19]([NH:21][C:22]1[S:23][CH:24]=[CH:25][N:26]=1)=[O:20]
Reactant: COCC(=O)Nc1c(C(=O)CC(=O)Nc2nccs2)cccc1C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COCc1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1
Temperature: 20 °C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
5.03 g of 4-dimethylamino-pyridine were added to a solution of 16.5 g of the product of Step B in 205 ml of tetrahydrofuran and the mixture was stirred at 20° C. for 41/2 hours. The tetrahydrofuran was distilled off under reduced pressure at 40° C. and the dry residue wsa taken up in 500 ml of water. 42 ml of N hydrochloric acid were added to the mixture and the suspension was stirred at 20° C. for 30 minutes and was vacuum filtered. The product was washed with water, dried under reduced pressure at 70° C. and was crystallized from 310 ml of dioxane. The mixture was vacuum filtered at 15° C. and the product was washed with 30 ml of dioxane and dried under reduced pressure at 70° C. to obtain 13.3 g of 4-hydroxy-2-methoxymethyl-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline-carboxamide melting at 260° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]2=[O:14].[NH4+].[Cl-].[CH2:17]1[CH2:21][O:20][CH2:19][CH2:18]1>>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]2([OH:14])[C:11]1[CH:12]=[CH:4][CH:5]=[C:17]([CH3:18])[C:21]=1[O:20][CH3:19]
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Product: COc1c(C)cccc1C1(O)C(=O)Nc2ccc(Cl)cc21
Reaction time: 1 h

Procedure:
Under nitrogen atmosphere, to a solution of 6.00 g of NaH in THF (130 ml) was added 12.4 g of 5-chloroisatin and the reaction mixture was stirred for one hour. The solution prepared beforehand was added dropwise over 10 minutes at the same temperature. A saturated aqueous solution of NH4Cl was added, the solution was extracted with EtOAc; the organic layer was washed with saturated brine and dried over Na2SO4, then, the drying agent was separated by filtration and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silicagel 60N; mobile phase: CHCl3/MeOH=100/1 to 20/1; v/v), the obtained solid was further washed by stirring in EtOAc (30 ml), then, the solid was collected by filtration to obtain 2.45 g of the title compound.
Reaction SMILES: [OH:1][CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[O-:12][C:13]#[N:14].[K+].C(O)(=O)C.O>CC(O)C>[CH3:11][C:2]1[O:1][C:13](=[O:12])[NH:14][C:3]=1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: N#C[O-]
Reactant: CC(O)C(=O)c1ccccc1
Agent: [K+]
Solvent: CC(C)O
Solvent: CC(=O)O
Solvent: O
Product: Cc1oc(=O)[nH]c1-c1ccccc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 36.9 %

Procedure:
To a solution of 2-hydroxy-1-phenylpropan-1-one (1.00 g, 6.66 mmol) and potassium cyanate (1.08 g, 13.3 mmol) in 2-propanol (15 mL) was added dropwise acetic acid (960 mg, 16.0 mmol) at 50° C. over 1 hr. The mixture was stirred at 50° C. for 5 hr, and the reaction mixture was poured into water. The resulting precipitate was collected by filtration and recrystallized from isopropyl ether-hexane to give the title compound (430 mg, yield 37%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[C:13]3([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[NH:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[S:20](=[O:24])(=[O:23])([OH:22])[OH:21]>>[S:20]([OH:24])([OH:23])(=[O:22])=[O:21].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]3([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[NH:12][CH2:11][CH2:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: OC1(c2ccc(Cl)cc2)CCCNC12CCCCC2
Agent: O=S(=O)(O)O
Product: Clc1ccc(C2=CCCNC23CCCCC3)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5-(4-Chlorophenyl)-5-hydroxy-1-azaspiro[5.5]undecane (5.9 g, prepared as described in Example C) was dissolved in concentrated sulphuric acid (75 ml) and stirred at ambient temperature for 3 hours. The mixture was then poured slowly into ice-water (300 ml) and the resulting solid collected by filtration, washed with a little water and dried in vacuo at ambient temperature over phosphorus pentoxide to give 5-(4-chlorophenyl)-1-azaspiro[5.5]undec-4-ene sulphate as a white solid. Yield 6.2 g, mp 228°-233° C.