Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[NH2:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=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.O1CCCC1>[Cl:1][C:2]1[N:11]=[C:10]([C:35]2[CH:36]=[C:31]([NH2:30])[CH:32]=[CH:33][CH:34]=2)[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: COc1cc2nc(Cl)nc(Cl)c2cc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1cc2nc(Cl)nc(-c3cccc(N)c3)c2cc1OC
Temperature: 60 °C
Yield: 92.6 %

Procedure:
Twenty-five grams of 2,4-dichloro-6,7-dimethoxyquinazoline was suspended in 2.25 L of a mixed solution consisting of toluene:tetrahydrofuran:a 2 N sodium carbonate solution=1:1:1. To the reaction mixture was added 21.5 g of 3-aminophenyl boronic acid ½ sulfate, and the mixture was degassed, the atmosphere in the reaction vessel was replaced with nitrogen. To the reaction mixture was added 2.23 g of tetrakis(triphenylphosphine)palladium(0), followed by stirring at 60° C. under a nitrogen atmosphere. Eighteen hours after initiation of the reaction, 1.2 g of tetrakis(triphenylphosphine)palladium(0) was added to the reaction mixture, and the stirring was continued. Thirty hours later, 1.2 g of tetrakis(triphenylphosphine)palladium(0) was further added to the reaction mixture, and stirring was further continued. Forty-eight hours after initiation of the reaction, the reaction mixture was cooled, and it was then transferred into a separatory funnel, so as to separate an organic layer. The obtained organic layer was washed with 300 mL of brine, and was then dried over anhydrous magnesium sulfate. The desiccant was removed by passing it through 250 g of silica gel. The silica gel was washed with 1.5 L of ethyl acetate, and the obtained organic layers were combined and concentrated to dryness. The residue was triturated with 200 mL of ethyl acetate, and the obtained solid was then filtrated. The solid was washed with 100 mL of diethyl ether and 200 mL of a mixed solution consisting of n-heptane:ethyl acetate=1:1, and dried under aeration to yield 28.2 g of a target product. Yield: 92.5%
Reaction SMILES: [CH3:1][NH:2][OH:3].[C:4](Cl)(=[O:13])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C([N+]([O-])=O)CCCCCCCCC>>[CH3:1][N:2]([C:4](=[O:13])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[OH:3]
Reactant: CNO
Reactant: CCCCCCCCC(=O)Cl
Agent: CCCCCCCCCC[N+](=O)[O-]
Product: CCCCCCCCC(=O)N(C)O

Procedure:
The starting N-methyl nonanohydroxamic acid was prepared by acylation of methyl hydroxylamine with nonanoyl chloride and was a white, waxy solid, M.P. 29° C., represented by the formula C10H21NO2.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:3]=1.[C:14](OCC)(=[O:19])[CH2:15][C:16]([CH3:18])=O.[OH-].[Na+]>O>[CH3:1][C:2]1[C:6]2[C:14]([OH:19])=[CH:15][C:16]([CH3:18])=[N:7][C:5]=2[N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:3]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: Cc1cc(N)n(-c2ccccn2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(O)c2c(C)nn(-c3ccccn3)c2n1
Temperature: 130 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
A mixture of 3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-amine (1.8 g, 10 mmol) and polyphosphoric acid (4.2 g) was heated at 130° C. The mixture was stirred thoroughly at the same temperature, while ethyl acetoacetate (1.3 mL, 10 mmol) was added dropwise thereto, and the resulting mixture was stirred at the same temperature for 1 hour. The mixture was cooled to room temperature, iced water was added thereto. The mixture was neutralized with an aqueous sodium hydroxide solution, and organic matter was extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (chloroform:methanol=50:1 to 20:1), and recrystallized from ethyl acetate to give the title compound (0.72 g, 30% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([C:24]([F:27])([F:26])[F:25])=[C:14]([N:17]3[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18]3)[CH:15]=2)[NH:10][C:9](=[O:28])[C:8]1=[O:29])=[O:5])[CH3:2].[Cl-].[OH:31][NH3+:32].C([O-])(=O)C.[Na+]>O.CCO>[CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([C:24]([F:27])([F:26])[F:25])=[C:14]([N:17]3[CH:21]=[CH:20][C:19]([CH:22]=[N:32][OH:31])=[CH:18]3)[CH:15]=2)[NH:10][C:9](=[O:28])[C:8]1=[O:29])=[O:5])[CH3:2]
Reactant: [NH3+]O
Reactant: CCOC(=O)Cn1c(=O)c(=O)[nH]c2cc(C(F)(F)F)c(-n3ccc(C=O)c3)cc21
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)Cn1c(=O)c(=O)[nH]c2cc(C(F)(F)F)c(-n3ccc(C=NO)c3)cc21
Yield: 130 %

Procedure:
1.2 g (2.9 mmol) of the compound from Example 70, 0.4 g (6 mmol) of hydroxylammonium chloride and 0.48 g (6 mmol) of sodium acetate in 45 ml of H2O/EtOH (2:1) were refluxed for 30 minutes. The organic solvent was removed under reduced pressure, and the resulting aqueous phase was extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure. The residue was recrystallized from ethanol to yield 1.6 g (70%) of the product. Melting point >250° C.
Reaction SMILES: [C:1]1([C:7]([CH2:18][C:19]([CH3:21])=[CH2:20])([C:13](OCC)=O)[C:8]([O:10]CC)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CCO.O>[CH3:13][C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([CH2:18][C:19]([CH3:21])=[CH2:20])[C:8]([OH:10])=[O:9]
Reactant: C=C(C)CC(C(=O)OCC)(C(=O)OCC)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=C(C)CC(C)(C(=O)O)c1ccccc1
Reaction time: 24 h

Procedure:
A solution of diethyl 2-phenyl-2-(2-methyl-2-propenyl)malonate (1.63 g, 5.6 mmole) in 20 mL of EtOH and 5 mL of H2O was treated with NaOH (2 g), and refluxed for 3 hours. The reaction was cooled, diluted with H2O, and washed with Et2O. The aqueous layer was acidified and extracted with CH2Cl2. The extracts were dried and evaporated. The residue was dissolved in 5 mL of dimethylacetamide and heated to 125° for 1 hour. The reaction was cooled, diluted with H2O, acified, and extracted with Et2O. The extracts were washed with H2O, dried, and the solvent removed. The residue was dissolved in 10 mL of MEOH, a drop of concentrated H2SO4 was added, and stirred for 24 hours. The reaction was diluted with H2O, and extracted with Et2O. The extracts were washed with H2O, aqueous NaHCO3, dried and the solvent removed, and gave the titled compound, 953 mg (83%). MS (ESI) 205 (MH+)
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:10][C:11]([O:13]CC)=O)=O.O.[NH2:17][NH2:18]>CCO>[NH2:17][N:18]1[C:3](=[O:2])[C:5]2[S:6][CH:7]=[CH:8][C:9]=2[NH:10][C:11]1=[O:13]
Reactant: NN
Reactant: CCOC(=O)Nc1ccsc1C(=O)OC
Solvent: CCO
Solvent: O
Product: Nn1c(=O)[nH]c2ccsc2c1=O
Temperature: 90 °C
Yield: 61.9 %

Procedure:
To a solution of 3-ethoxycarbonylamino-thiophene-2-carboxylic acid methyl ester (3.43 g, 15.0 mmol) in EtOH (100 mL) was added hydrazine monohydrate (7.98 mL, 164.6 mmol). After heating at 90° C. for 12 h, the mixture was filtered to afford a fine yellow powder (1.70 g), which was used in the next step without further purification. MS: 184.2. 1H NMR (400 MHz, CD3OD) 8 ppm 7.93 (d, J=5.3 Hz, 1H), 6.95 (d, J=5.3 Hz, 1H).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7](N)[CH:6]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:4]=1.N([O-])=[O:21].[Na+]>C(O)(=O)C>[CH3:1][S:2][C:3]1[N:8]=[C:7]([OH:21])[CH:6]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:4]=1
Reactant: CSc1nc(N)cc(-c2cccc(C(F)(F)F)c2)n1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CSc1nc(O)cc(-c2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86.9 %

Procedure:
2-Methylsulfanyl-6-(3-trifluoromethylphenyl)-pyrimidin-4-ylamine (2.42 g) was heated to 40° C. in acetic acid (6 ml) until dissolved. A solution of sodium nitrite (1.17 g in 5 ml water) was added dropwise and stirring continued for 30 minutes at 40° C. and 90 minutes at 90° C. The reaction mixture was allowed to cool to room temperature and filtered. The cake was washed with water then dissolved in ethyl acetate (200 mL) and washed with saturated sodium bicarbonate (2×300 ml). Organics were separated, dried over sodium sulphate and solvent was evaporated under reduced pressure to yield product 2-methylsulfanyl-6-(3-trifluoromethyl-phenyl)-pyrimidin-4-ol (2.11 g) as a pale yellow solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[C:3](=[O:7])[CH2:4][C:5]#[N:6].[OH-].[Na+].S(O)(O)(=O)=O.[NH2:16]O.Cl>CCOC(C)=O.O>[CH:2]([C:3]1[O:7][N:6]=[C:5]([NH2:16])[CH:4]=1)([CH3:8])[CH3:1]
Reactant: NO
Reactant: CC(C)C(=O)CC#N
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)c1cc(N)no1
Temperature: 40 °C
Reaction time: 72 h

Procedure:
To a mixture of 4-methyl-3-oxopentanenitrile (11 g, 99 mmol) and water (200 mL) is added NaOH (4.95 g, 124 mmol). Once the NaOH pellets are completely dissolved, hydroxylamine sulfate (8.93 g, 109 mmol) is added and after 5 min the pH is measured (pH 7-8). The reaction is warmed to 40° C. and stirred for 72 h. At this point HCl (13.0 mL, 158 mmol, 37%) is added in one portion and the reaction warmed to 50° C. for 2.5 h. The reaction is removed from the oil bath and allowed to cool to rt. At this point a solution of NaOH (30% in H2O) is added to give a solution of pH 11. EtOAc is then added and the layers separated. The water layer is extracted with EtOAc (3×) until no more product appears in the LCMS of the water layer. The combined organics are dried (Na2SO4) and evaporated to give 5-isopropyl-isoxazol-3-ylamine. MS (ESI) m/z 127.2 (M+1).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH:20]([CH3:22])[CH3:21])=[N:5][C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[CH:2].CC(N=NC(C#N)(C)C)(C#N)C.[I:35]I>C([SnH](CCCC)CCCC)CCC.CCOCC>[F:19][C:16]1[CH:15]=[CH:14][C:13]([C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH:20]([CH3:22])[CH3:21])[C:3]=2/[CH:1]=[CH:2]/[I:35])=[CH:18][CH:17]=1
Reactant: C#Cc1c(C(C)C)nc2ccccc2c1-c1ccc(F)cc1
Reactant: II
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: CCOCC
Product: CC(C)c1nc2ccccc2c(-c2ccc(F)cc2)c1/C=C/I
Temperature: 120 °C
Reaction time: 2.5 h

Procedure:
A mixture of 3-Ethynyl-4-(4-fluorophenyl)-2-(1-methylethyl)quinoline (1.500 gm, 5.18 mmol) (the preparation of which is described in Example 8) and AIBN (15 mg) in tri-n-butylstannyl hydride (2.1 ml) was rapidly heated to 120° C. After 3 minutes of heating, the mixture was treated with additional Bu3SnH (0.6 ml) and the temperature of the reaction was raised to 130° C. Approximately 15 mg of AIBN was added to the reaction mixture of 0.5, 1, and 2 hours after heating was initiated. After 2.5 hours, the mixture was cooled to room temperature, diluted with Et2O (30 ml) and treated with solid I2 (3.86 gm, 15.2 mmol). The dark reaction mixture was stirred for 1 hour, then quenched with 10% Na2SO3 in saturated NaHCO3. The layers were shaken and separated. The ethereal layer was washed with brine, dried (Na2 SO4), filtered and stripped to yield a liquid/solid residue. The residue was chromatographed (flash, Merck SiO2, 4% EtOAc in hexane) to give slightly impure (E)-4-(4-Fluorophenyl)-3-(2-iodoethenyl)-2-(1-methylethyl)-quinoline as a solid. Recrystallization of the solid from hot hexane gave (E)-4-(4-Fluorophenyl)-3-(2-iodoethenyl)-2-(1-methylethyl)quinoline (1.725 gm, 80%) as light yellow crystals.
Reaction SMILES: [OH-].[Na+].[C:3]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[C:22]([CH3:24])[C:21]([CH:25]([CH2:30][CH2:31][CH3:32])[C:26]([O:28]C)=[O:27])=[C:20]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)[N:19]=2)[CH2:14][CH2:13]1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[C:3]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[C:22]([CH3:24])[C:21]([CH:25]([CH2:30][CH2:31][CH3:32])[C:26]([OH:28])=[O:27])=[C:20]([C:33]3[CH:34]=[CH:35][C:36]([CH3:39])=[CH:37][CH:38]=3)[N:19]=2)[CH2:14][CH2:13]1)(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(N2CCC(NC(=O)c3ccccc3)CC2)nc1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(N2CCC(NC(=O)c3ccccc3)CC2)nc1-c1ccc(C)cc1
Temperature: 100 °C
Yield: 50.4 %

Procedure:
A solution of sodium hydroxide 5N (1 mL) was added to a mixture of methyl 2-(2-(4-benzamidopiperidin-1-yl)-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (0.049 g; 0.0979 mmol) in methanol (1.5 mL). The mixture was heated in a sealed tube at 100° C. for 18 h and then concentrated under reduced pressure. The residue was dissolved in water and the pH of the solution was adjusted between 3 and 4 by addition of a solution of hydrochloric acid 6N. The precipitate was collected by filtration and was purified by preparative HPLC (HPLC method 4) furnished 0.024 g (51%) of the title compound as a white solid.
Reaction SMILES: N12CCN(CC1)CC2.[CH2:9]([O:11][C:12]([C:14]1[C:19](=[O:20])[NH:18][C:17]2[CH:21]=[CH:22][S:23][C:16]=2[C:15]=1Cl)=[O:13])[CH3:10].[N:25]1([C:31]([C:33]2[S:34][CH:35]=[CH:36][CH:37]=2)=[O:32])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>CC(N(C)C)=O>[CH2:9]([O:11][C:12]([C:14]1[C:19](=[O:20])[NH:18][C:17]2[CH:21]=[CH:22][S:23][C:16]=2[C:15]=1[N:28]1[CH2:29][CH2:30][N:25]([C:31]([C:33]2[S:34][CH:35]=[CH:36][CH:37]=2)=[O:32])[CH2:26][CH2:27]1)=[O:13])[CH3:10]
Reactant: CCOC(=O)c1c(Cl)c2sccc2[nH]c1=O
Reactant: O=C(c1cccs1)N1CCNCC1
Agent: C1CN2CCN1CC2
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2sccc2[nH]c1=O
Temperature: 120 °C
Yield: 95.8 %

Procedure:
1,4-Diazabicyclo[2.2.2]octane (224 mg, 2 mmol) was added to a solution of 7-chloro-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester (4) (240 mg, 1 mmol) and piperazin-1-yl-thiophene-2-yl-methanone (215 mg, 1.1 mmol) in dry DMA. The solution was heated at 120° C. for 2 h. The solution was cooled and poured into ice water. The solids formed were filtered, washed by water, and dried to yield 5-oxo-7-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester (400 mg, 96%) as white solids. MP 252° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.27 (t, J=7.2 Hz, 3H), 3.31 (m, 4H), 3.77 (m, 4H), 4.24 (q, J=7.2 Hz, 2H), 6.97 (d, J=5.6 Hz, 1H), 7.15 (dd, J=3.6, 4.8 Hz, 1H), 7.47 (dd, J=1.2, 3.6 Hz, 1H), 7.80 (dd, J=1.2, 4.8 Hz, 1H), 7.96 (d, J=5.6 Hz, 1H), 12.10 (s, 1H) ppm; MS m/z=418 amu (M++1).
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][O:8][NH:9][C:10]([C:12]2[S:20][C:15]3=[CH:16][N:17]=[CH:18][CH:19]=[C:14]3[C:13]=2[NH:21][C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:23]=2[F:29])=[O:11])[CH2:4][O:3]1>Cl.CO>[OH:6][C@H:5]([CH2:4][OH:3])[CH2:7][O:8][NH:9][C:10]([C:12]1[S:20][C:15]2=[CH:16][N:17]=[CH:18][CH:19]=[C:14]2[C:13]=1[NH:21][C:22]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:23]=1[F:29])=[O:11]
Reactant: CC1(C)OC[C@H](CONC(=O)c2sc3cnccc3c2Nc2ccc(Br)cc2F)O1
Agent: Cl
Solvent: CO
Product: O=C(NOC[C@H](O)CO)c1sc2cnccc2c1Nc1ccc(Br)cc1F
Yield: 27.4 %

Procedure:
A solution 3-(4-bromo-2-fluoro-phenylamino)-thieno[2,3-c]pyridine -2-carboxylic acid ((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-amide (61 mg, 0.12 mmol) and 1 drop of concentrated HCl in methanol (2 ml) was stirred at ambient temperature for 2 hours. The solvent was evaporated in vacuo and the resultant residue partitioned between dichloromethane (20 ml), water (10 ml) and saturated NaHCO3 solution (3 ml). The organic phase was dried over sodium sulfate and concentrated in vacuo to afford a yellow oil. The resultant yellow oil was purified by flash chromatography (Si-SPE, DCM:MeOH, gradient 99:1 to 92:8) followed by trituration with methanol/acetonitrile to afford the title compound as an off-yellow solid (15 mg, 26%): LCMS (method A): RT=6.01 min, M+H+=456/458. 1H NMR (d4-MeOH, 400 MHz) 9.16 (d, J=0.8 Hz, 1H), 8.38 (d, J=5.8 Hz, 1H), 7.37-7.46 (m, 2H), 7.17 (ddd, J=8.6 Hz, 2.3 Hz, 2.2 Hz, 1H), 6.72 (dd, J=8.7 Hz, 8.7 Hz, 1H), 4.00-4.05 (m, 1H), 3.84-3.96 (m, 2H), 3.53-3.64 (m, 2H).
Reaction SMILES: [C:1]1([N:7]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:8]([C:10]2[CH:11]=[CH:12][C:13]3[S:17][C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=4)=[N:15][C:14]=3[CH:28]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:35].C(O)C.C(=O)([O-])[O-].[NH4+:43].[NH4+]>C(O)(=O)C.C(Cl)Cl.C(O)C>[ClH:35].[C:1]1([N:7]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:8]([C:10]2[CH:11]=[CH:12][C:13]3[S:17][C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:43])[NH2:27])=[CH:22][CH:21]=4)=[N:15][C:14]=3[CH:28]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CN(C(=O)c1ccc2sc(CNc3ccc(C#N)cc3)nc2c1)c1ccccc1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)CN(C(=O)c1ccc2sc(CNc3ccc(C(=N)N)cc3)nc2c1)c1ccccc1
Yield: 82 %

Procedure:
Prepared analogously to Example 9 from 2-[N-(4-cyanophenyl)-aminomethyl]-benzothiazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbonylmethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 82% of theory, C26H25N5O3S (487.58) Rf value: 0.21 (silica gel; methylene chloride/ethanol=4:1+a few drops of acetic acid) EKA mass spectrum: (M+H)+ =488
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].O>C1(C)C=CC=CC=1>[CH3:1][S:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[CH2:5][OH:6]
Reactant: CSc1ccccc1C(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CSc1ccccc1CO
Reaction time: 5 h
Yield: 100.3 %

Procedure:
5 g of 2-methylsulfanylbenzoic acid were dissolved in 50 ml of toluene, treated in portions at 20° C. with 14.5 ml of a solution of sodium dihydridobis(2-methoxy-ethoxy)aluminate (Red-AI®; 65% strength in toluene) and stirred for 5 h. The reaction mixture was added to 200 ml of water and extracted three times with 100 ml each of EA. The combined organic phases were dried with magnesium sulfate and the solvent was removed in vacuo. 4.6 g of the crude title compound were obtained as a brown oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:35][O:36][C:37]1[C:42]2[N:43]=[C:44]([NH2:46])[O:45][C:41]=2[C:40]([CH:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)=[CH:39][CH:38]=1>C1COCC1.O1CCOCC1.CN(C=O)C>[CH3:35][O:36][C:37]1[C:42]2[N:43]=[C:44]([NH:46][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][N:10]=[C:2]([CH3:1])[CH:3]=3)[O:45][C:41]=2[C:40]([CH:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)=[CH:39][CH:38]=1
Reactant: COc1ccc(C2CCOCC2)c2oc(N)nc12
Reactant: Cc1cc(C(=O)O)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: COc1ccc(C2CCOCC2)c2oc(NC(=O)c3ccnc(C)c3)nc12

Procedure:
From 2-methylisonicotinic acid, HATU and N-diethylisopropylamine in THF, then treatment with 4-methoxy-7-(tetrahydro-pyran-4-yl)-benzooxazol-2-yl-amine in dioxane and DMF. ES-MS m/e (%): 368 (M+H+, 100).
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:22][C:23]#[N:24])[C:15]=2[C:14]2[C:9]1=[C:10]([F:25])[CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.CSC>C1COCC1>[CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:22][CH2:23][NH2:24])[C:15]=2[C:14]2[C:9]1=[C:10]([F:25])[CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCOc1cccc2c1c1cccc(F)c1n2Cc1ccccc1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: NCCOc1cccc2c1c1cccc(F)c1n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 43.3 %

Procedure:
A mixture of 2-[(9-benzyl-8-fluoro-9H-carbazol-4-yl)oxy]acetonitrile (0.7685 g, 0.0023 mol), dry THF (20 mL) and borane-methyl sulfide (0.71 mL, 0.0075 mol) is stirred at room temperature for 3.5 h. Additional borane-methyl sulfide (0.20 mL, 0.0021 mol) is added and the mixture is stirred overnight. The excess borane is cautiously quenched with methanol and the mixture is concentrated under reduced pressure. Methanol and dichloromethane are added to the residue and the solution is again concentrated under reduced pressure (repeated twice). The solids are then dissolved in methanol/dichloromethane and conc. HCl (3 mL) is added. After the mixture stirred for 50 min, the solvent is removed under reduced pressure and the residue is partitioned between dichloromethane and aq. sodium bicarbonate. The combined organic layers are dried over sodium sulfate and concentrated to dryness. The residue is chromatographed on silica gel (100 mL) using methanol/dichloromethane (2/98 and 4/96) and recrystallized from ethyl acetate/dichloromethane/heptane to give 0.333 g (43%) of the title compound; mp 122.25-123° C.; MS (ESI+) for C21H19FN2O m/z 335.2 (M+H)+; IR (drift) 1602, 1577, 1498, 1456, 1443, 1352, 1337, 1325, 1269, 1254, 1242, 1228, 1141, 792, 736 cm−1; 1H NMR (CDCl3) δ3.30, 4.28, 5.30, 6.70, 7.01, 7.11, 7.22, 7.36, 8.10, NH2 not seen. Anal. Calcd for C21H19FN2O: C, 75.43; H, 5.73; N, 8.38. Found: C, 75.25; H, 5.79; N, 8.28.
Reaction SMILES: Br[CH:2]([C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[CH2:3][C:4]([O-:6])=[O:5].[OH:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[S:22])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(C)C>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]2([OH:15])[CH:2]([CH2:3][C:4]([OH:6])=[O:5])[S:22][C:21]([C:20]3[CH:24]=[CH:25][C:17]([OH:16])=[CH:18][CH:19]=3)=[N:23]2)=[CH:9][CH:10]=1
Reactant: O=C([O-])CC(Br)C(=O)c1ccc(Cl)cc1
Reactant: NC(=S)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: O=C(O)CC1SC(c2ccc(O)cc2)=NC1(O)c1ccc(Cl)cc1

Procedure:
3-Bromo-3-(4-chlorobenzoyl)propionate acid and an equimolar amount of 4-hydroxythio-benzamide are stirred in isopropyl alcohol solvent containing sodium carbonate to give 4-(4-chlorophenyl)-4-hydroxy-2-(4-hydroxyphenyl)-2-thiazolin-5-acetic acid. This compound is dehydrated by heating to give the title compound.