Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1B(O)O.Br[C:18]1[S:19][CH:20]=[CH:21][CH:22]=1>C1(C)C=CC=CC=1.C(O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[C:8]1([CH3:7])[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:18]1[S:19][CH:20]=[CH:21][CH:22]=1
Reactant: Brc1cccs1
Reactant: Cc1ccccc1B(O)O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccccc1-c1cccs1
Temperature: 25 °C
Yield: 344.3 %

Procedure:
Sodium carbonate (5 ml., 2M aqueous solution) followed by 2-methylphenylboronic acid (0.294 g, 2.4 mmol) were added to a solution of 2-bromothiophene (0.542 g, 2 mmol) and tetrakis(triphenylphosphine)palladium(O) (100 mg) in toluene (5 ml) and ethanol (5 ml) under nitrogen. The mixture was refluxed for 2 hours, cooled to room temperature and extracted with ethyl acetate (2×50 ml). The combined organic layers was dried over MgSO4 and evaporated. The residue was flash chromatographed on silica gel using hexane as eluent to afford 1.2 g of 2-(2-tolyl)thiophene as a colorless gum.
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][C@H:14]2[C@H:10]([CH:11]=[CH:12][C:13]2=[O:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.[Rh]>[CH2:1]([N:8]1[CH2:15][C@H:14]2[C@H:10]([CH2:11][CH2:12][C:13]2=[O:16])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C=C[C@@H]2CN(Cc3ccccc3)C[C@H]12
Reactant: [H][H]
Agent: [Rh]
Solvent: CCOC(C)=O
Product: O=C1CC[C@@H]2CN(Cc3ccccc3)C[C@H]12
Yield: 83.1 %

Procedure:
5% Rhodium-on-alumina (700 mg) was added to a solution of (1R,5S)-7-benzyl-2-oxo-7-azabicyclo[3.3.0]oct-3-ene (1.57 g, 7.34 mmol) in ethyl acetate (50 ml), and the mixture was vigorously stirred in a hydrogen atmosphere for 3.5 hours. The insoluble matter was removed by Celite filtration, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to give 1.31 g (6.10 mmol, 83%) of the title compound as a colorless oily substance.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[CH:13]=[C:12]([O:14][CH:15]3[CH2:20][CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16]3)[CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClCCl>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[CH:13]=[C:12]([O:14][CH:15]3[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]3)[CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1
Reactant: Cc1csc(Nc2cc(OC3CCCN(C(=O)OC(C)(C)C)C3)ccn2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1csc(Nc2cc(OC3CCCNC3)ccn2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.6 %

Procedure:
A 100 mL round bottom flask was charged with tert-butyl 3-(2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)piperidine-1-carboxylate (1.65 g, 4.23 mmol) in dichloromethane (10 mL), and 2,2,2-trifluoroacetic acid (0.977 mL, 12.7 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. A saturated solution of NaHCO3 was added, and the solution was extracted with EtOAc and dichloromethane. The combined organic layers were filtered and concentrated to provide 4-methyl-N-(4-(piperidin-3-yloxy)pyridin-2-yl)thiazol-2-amine as a light yellow solid. (0.70 g, 53.6% yield). Mass spectrum (apci) m/z=291 (100) (+H).
Reaction SMILES: [CH2:1]([C:8]1([N:15]([CH3:17])[CH3:16])[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B([O-])=O.[Na+].P([O-])([O-])([O-])=O>C(O)(C)C>[CH2:1]([C:8]1([N:15]([CH3:16])[CH3:17])[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C1(Cc2ccccc2)CCC(=O)CC1
Agent: O=B[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: CN(C)C1(Cc2ccccc2)CCC(O)CC1
Reaction time: 8 h
Yield: 93.4 %

Procedure:
40.0 g of 4-benzyl-4-dimethylamino-cyclohexanone were suspended in 250 ml of isopropanol; 19.9 g of sodium boranate were added, while cooling with an ice bath, and stirring was carried out overnight at room temperature. 65 ml of phosphate buffer (pH 7, Merck-Darmstadt) were added dropwise and the mixture was concentrated. The residue was taken up in water and dichloromethane and rendered alkaline with potassium hydroxide. The phases were separated and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. 37.7 g of 4-benzyl-4-dimethylaminocyclohexanol were obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14](OCC)=[O:15])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([N:8]1[CH:12]=[C:11]([CH3:13])[C:10]([CH2:14][OH:15])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nn(Cc2ccccc2)cc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cn(Cc2ccccc2)nc1CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
Into a 100-mL 3-neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of ethyl 1-benzyl-4-methyl-1H-pyrazole-3-carboxylate (compound 268.1, 2.3 g, 9.42 mmol) in THF (30 mL). The solution was cooled to 0° C., then LiAlH4 (360 mg, 9.49 mmol, 1.00 equiv) was carefully added in portions. The resulting mixture was stirred for 1 h at room temperature, then carefully quenched by drop-wise addition of water (400 μL), then aqueous NaOH (10%, 400 μL), followed by additional water (1.2 mL). The solids were removed by filtration and the filtrate was dried (Na2SO4), filtered and concentrated under reduced pressure to obtain the tile compound as a yellow oil (1.7 g, 89%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:15]([CH2:16][CH2:17][CH2:18][O:19][CH:20]([CH3:22])[CH3:21])[C:14]([CH2:23][O:24][CH2:25][CH3:26])=[N:13][C:7]=3[C:8]([NH2:12])=[N:9][C:10]=2[CH:11]=1.[NH:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]1=[O:33].CNCCNC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu]I.O1CCOCC1>[NH2:12][C:8]1[C:7]2[N:13]=[C:14]([CH2:23][O:24][CH2:25][CH3:26])[N:15]([CH2:16][CH2:17][CH2:18][O:19][CH:20]([CH3:22])[CH3:21])[C:6]=2[C:5]2[CH:4]=[CH:3][C:2]([N:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]3=[O:33])=[CH:11][C:10]=2[N:9]=1
Reactant: O=c1cccc[nH]1
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCOC(C)C
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CCOCc1nc2c(N)nc3cc(-n4ccccc4=O)ccc3c2n1CCCOC(C)C
Temperature: 110 °C
Yield: 49 %

Procedure:
7-Bromo-2-ethoxymethyl-1-(3-isopropoxypropyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.75 g), 2(1H)-pyridone (0.20 g), copper(I) iodide (68 mg), N,N′-dimethylethylenediamine (75 μL), potassium phosphate (0.79 g) and dioxane (2.7 mL) were added to a scintillation vial. The vial was flushed with nitrogen, sealed with a Teflon-lined cap, placed in an oil bath, and heated to 110° C. for 60 hours. The reaction was cooled to ambient temperature, diluted with chloroform and filtered through a bed of CELITE filter agent. The solvent was evaporated and the residue was purified by column chromatography on a Biotage Horizon™ High-Performance Flash Chromatography instrument using a silica gel cartridge. The purification was carried out eluting with chloroform:CMA in a gradient from 99:1 to 75:25. Additional purification by recrystallization from acetonitrile provided 0.38 g of 1-[4-amino-2-ethoxymethyl-1-(3-isopropoxypropyl)-1H-imidazo[4,5-c]quinolin-7-yl]-1H-pyridin-2-one as a tan solid, mp 161-163.5° C.
Reaction SMILES: [CH2:1]([C:11]1[S:15][C:14]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C([Li])CCC.CN([CH:29]=[O:30])C.[Cl-].[NH4+]>CCCCCC.C1COCC1>[CH2:1]([C:11]1[S:15][C:14]([C:16]2[S:17][C:18]([CH:29]=[O:30])=[CH:19][CH:20]=2)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCc1ccc(-c2cccs2)s1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCCCCCc1ccc(-c2ccc(C=O)s2)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
5-Decyl-2,2′-bithiophene (39.0 g, 0.127 mol) prepared above and THF (300 ml) were placed in a 1000-ml three-necked flask equipped with a 200-ml dropping funnel and a reflux tube. The solution was cooled in an ice bath to 0° C., and a solution (80 ml) of n-butyllithium (1.6 M) in n-hexane was added dropwise to the cooled solution over a period of about one hr. After the completion of the dropwise addition, the mixture was stirred for about one hr. DMF (13.9 g, 0.191 mol) was added dropwise thereto at 0° C. over a period of about one hr. After the completion of the dropwise addition, the reaction temperature was raised to room temperature, and, at that temperature, the mixture was stirred overnight. After the completion of the reaction, a 1 N ammonium chloride solution (200 ml) was added, and the organic layer was extracted with diethyl ether, was dried over sodium sulfate, and was applied to column chromatography (CH2Cl2:hexane=1:1) to give an objective compound 5-decyl-5′-formyl-2,2′-bithiophene as a yellow solid (37.2 g, yield 87.60%). An NMR spectrum of the compound thus obtained was measured at room temperature with an NMR spectrometer (model JNM-LA400W, manufactured by Japan Electric Optical Laboratory). 1H-NMR (CDCl3, TMS/ppm): 0.88 (t, 3H, J=6.83 Hz), 1.26 (m, 14H), 1.69 (m, 2H), 2.81 (t, 2H, J=7.32 Hz), 6.74 (d, 1H, J=3.90 Hz), 7.16 (d, 1H, J=3.90 Hz), 7.18 (d, 1H, J=3.90 Hz), 7.64 (d, 1H, J=3.90 Hz), 9.84 (s, 1H).
Reaction SMILES: O[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([OH:12])[C:8](=[CH:10][CH:11]=1)[OH:9])=O.[CH3:13][O:14]C(C)(C)C>>[CH:11]1[C:5]([CH2:3][CH2:2][CH2:13][OH:14])=[CH:6][C:7]([OH:12])=[C:8]([OH:9])[CH:10]=1
Reactant: O=C(CO)c1ccc(O)c(O)c1
Reactant: COC(C)(C)C
Product: OCCCc1ccc(O)c(O)c1
Temperature: 40 °C

Procedure:
A special house made pressure reactor, a 50 ml 10 bar glass reactor with steel mantle and a magnetic stirring bar, was charged with catalyst, 4-hydroxyacetyl-catechol (produced according to Example 2) and t-butyl methyl ether. The reactor was evacuated and filled with hydrogen. Hydrogenation was started by stirring at 5 bar hydrogen pressure while heating to 40° C. By the end of the reaction the hydrogen was replaced by air, the slurry was filtered, the catalyst was washed with ethyl acetate. After evaporation of the solvents and drying at 1 mbar the product was analyzed quantitatively. The details of some reactions and the results are shown in Table 1.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[F:19][C:20]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:27][C:28](O)=[O:29]>>[F:19][C:20]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:27][C:28]([NH:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18])=[O:29]
Reactant: O=C(O)Cc1cccc(F)c1F
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Product: O=C(Cc1cccc(F)c1F)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-(2,3-difluorophenyl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.31 (dd, J=7.9, 1.3 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.97-8.01 (m, 1H), 7.91 (td, J=7.5, 1.3 Hz, 1H), 7.35 (dtd, J=10.2, 8.1, 1.9 Hz, 1H), 7.27-7.31 (m, 1H), 7.19-7.25 (m, 1H), 3.81-3.84 (m, 4H), 3.80 (s, 2H), 3.07-3.12 (m, 4H); MS (ESI+) M/Z 401 (M+H)+.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[OH:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]1>>[OH:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:13]1
Reactant: OCC1CCCNC1
Reactant: N#Cc1ccccc1F
Product: N#Cc1ccccc1N1CCCC(CO)C1

Procedure:
According to a similar manner to that in Reference Example 12, the title compound was synthesized from 2-fluorobenzonitrile and 3-(hydroxymethyl)piperidine.
Reaction SMILES: OC(C(F)(F)F)=O.[OH:8][C:9]([CH3:31])([CH3:30])[CH2:10][C@@:11]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:16][C:15](=[O:17])[N:14]([C@H:18]2[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]2)[CH2:13][CH2:12]1.F[C:33]1[C:38]([F:39])=[CH:37][CH:36]=[CH:35][N:34]=1.CCN(C(C)C)C(C)C.Cl>CO.C(O)CC>[F:39][C:38]1[C:33]([N:20]2[CH2:21][CH2:22][CH2:23][C@H:18]([N:14]3[CH2:13][CH2:12][C@:11]([CH2:10][C:9]([OH:8])([CH3:31])[CH3:30])([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[O:16][C:15]3=[O:17])[CH2:19]2)=[N:34][CH:35]=[CH:36][CH:37]=1
Reactant: Fc1cccnc1F
Reactant: CC(C)(O)C[C@]1(c2ccccc2)CCN([C@H]2CCCNC2)C(=O)O1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)C[C@]1(c2ccccc2)CCN([C@H]2CCCN(c3ncccc3F)C2)C(=O)O1
Temperature: 25 °C
Yield: 37.7 %

Procedure:
A solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-piperidin-3-yl)-1,3-oxazinan-2-one TFA salt (12 mg, 0.036 mmol), 2,3-difluoropyridine (6 mg, 2equiv), and i-Pr2NEt (30 μL, 5 equiv) in 1:6 MeOH/n-Propanol (2 mL) was heated in the microwave oven for 15 min. at 150° C. After being cooled to rt, the mixture was acidified with 5% aq HCl solution and purified by prep HPLC to afford (S)-3-((S)-1-(3-fluoropyridin-2-yl)piperidin-3-yl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one (5.8 mg, 50% yield). LC-MS Method 1 tR=1.51 min, m/z=428(M+1); 1H NMR (CD3OD) 7.92(dd, 1H), 7.51-7.28(m, 6H), 6.88(m, 1H), 4.10(m, 1H), 3.91(m, 2H), 3.06(td, 1H), 2.51(m, 2H), 2.19(s, 2H), 1.24(s, 3H), 0.94(s, 3H).
Reaction SMILES: [C:1]([C:4]1[N:9]=[CH:8][C:7]([NH:10][C:11]2[N:16]=[C:15]([C:17]#[C:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:25][C:26]([NH2:28])=[O:27])[C:14]([C:29]([F:32])([F:31])[F:30])=[CH:13][N:12]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2]>CN(C=O)C.CCO.CCN(CC)CC.[Pd]>[C:1]([C:4]1[N:9]=[CH:8][C:7]([NH:10][C:11]2[N:16]=[C:15]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:25][C:26]([NH2:28])=[O:27])[C:14]([C:29]([F:30])([F:31])[F:32])=[CH:13][N:12]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(Nc2ncc(C(F)(F)F)c(C#Cc3ccccc3CC(N)=O)n2)cn1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)c1ccc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3CC(N)=O)n2)cn1
Reaction time: 20 h
Yield: 57.1 %

Procedure:
A solution of 2-(2-((2-((6-acetylpyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethynyl)phenyl)acetamide (A142) (0.347 g, 0.790 mmol) in DMF (20 mL), EtOH (3 mL) and Et3N (1 mL) containing 10% palladium on carbon (0.110 g) was stirred under a hydrogen atmosphere for 20 hours. The reaction mixture was filtered through a pad of Celite and the solvent was concentrated in vacuo. The crude material was adsorbed onto silica gel and purified by silica gel column chromatography (CombiFlash Rf, 24 g SiO2 Cartridge, 0-10% MeOH in DCM) to give the title compound (A143) as a white solid (0.200 g, 57%). LCMS-B: 6.80 min; m/z 444 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:13](Br)[C:14]#[CH:15].[Br-].[Na+]>>[CH3:1][C:2]([CH2:15][C:14]#[CH:13])([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: C#CCBr
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: [Br-]
Agent: [Na+]
Product: C#CCC(C)(C(=O)OCC)C(=O)OCC

Procedure:
At 35° to 40° to C., with stirring, 174 g (1.0 ml) of diethyl methylmalonate are added dropwise to an alkoxide solution (prepared from 23 g of sodium and 800 ml of absolute ethanol), the mixture is stirred for a further hour and then at 45° C. 130.8 g (1.1 mol) of propargyl bromide are added dropwise. The mixture is refluxed for a further 2 hours. After cooling the precipitated sodium bromide is separated by suction filtering and the filtrate is substantially evaporated in vacuo. The residue is stirred into ice water and the aqueous solution is extracted several times with ether. The combined organic phases are dried and evaporated to dryness in vacuo. The resulting oil is used in the next stage without any further purification.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:14][CH2:15][C:16](OC)=[O:17])(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=O)C.[BH4-].[Na+].C(O)(C)(C)C.Cl>CO>[NH2:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH2:14][CH2:15][CH2:16][OH:17])(=[O:13])=[O:12])=[CH:9][CH:10]=1
Reactant: COC(=O)CCS(=O)(=O)c1ccc(NC(C)=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)(C)O
Product: Nc1ccc(S(=O)(=O)CCCO)cc1
Yield: 20 %

Procedure:
A mixture of methyl 3-(4-acetamidophenylsulfonyl)propionate (54.2 g, 190 mmol), sodium borohydride (22.3 g, 590 mmol), and 400 mL of t-butanol was stirred mechanically and heated to reflux. Methanol (11 mL) was added dropwise over 20 minutes, and the resulting solution was stirred at reflux for 2 hours. The reaction mixture was cooled, and 250 mL of 3M aqueous HCl was added slowly with vigorous gas evolution occurring. The resulting mixture was partially concentrated at reduced pressure to remove t-butanol, and the residue was heated at reflux for 2 hours. The mixture was cooled, and solid sodium bicarbonate was added slowly until the pH of the mixture was 6-7. The mixture was allowed to stand several hours at 23° C. and then the precipitated product was filtered. After recrystallization from methanol containing a small amount of ether, 8.2 g (20%) of cream-colored powder was obtained, mp 99°-102° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][N:10]=[C:9]([NH2:12])[C:8]=2[CH:13]=1)([O-:3])=[O:2].[N:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[C:15]=[O:16]>C1COCC1>[CH2:17]([NH:14][C:15]([NH:12][C:9]1[C:8]2[CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=2[S:11][N:10]=1)=[O:16])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCN=C=O
Reactant: Nc1nsc2ccc([N+](=O)[O-])cc12
Solvent: C1CCOC1
Product: CCCCCCNC(=O)Nc1nsc2ccc([N+](=O)[O-])cc12
Temperature: 70 °C
Reaction time: 2 h

Procedure:
100 mg (0.513 mmol) of 5-nitrobenzo[d]isothiazol-3-ylamine were suspended in 5 ml of THF. Addition of 78.1 mg (0.61 mmol) of 1-isocyanatohexane was followed by stirring at RT for 2 h and at 70° C. for 2 h. Then a further 0.3 mmol of 1-isocyanatohexane was added, and stirring was continued at 70° C. for 6 h. The reaction mixture was concentrated, and the residue was dissolved in water and extracted with ethyl acetate. The organic phase was concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 18 mg (11%), M+H+: 323.15.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:13](=[O:14])[C:12]3[CH:15]=C(C#N)[CH:17]=[CH:18][C:11]=3[CH2:10][O:9][C:8]=2[CH:21]=1)([CH3:3])[CH3:2].[C:22]([OH:25])(=[O:24])[CH3:23].Cl>O>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:13](=[O:14])[C:12]3[CH:15]=[C:23]([C:22]([OH:25])=[O:24])[CH:17]=[CH:18][C:11]=3[CH2:10][O:9][C:8]=2[CH:21]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CC(C)c1ccc2c(c1)OCc1ccc(C#N)cc1C2=O
Agent: Cl
Solvent: O
Product: CC(C)c1ccc2c(c1)OCc1ccc(C(=O)O)cc1C2=O

Procedure:
Reflux a mixture of 2.8 gm. (0.010 mole) of 6,11-dihydro-3-isopropyl-11-oxodibenz[b.e]oxepin-9-carbonitrile, 50 ml. of acetic acid, 5 ml. of water and 5 ml. of concentrated hydrochloric acid for 140 hours. Cool the reaction mixture, separate the solids by filtration and dry. (yield 2.07 gm., m.p. 202°-204° C.). Recrystallize from toluene to obtain the title product (m.p. 203°-204.5° C.).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17](Cl)[N:16]=2)[CH2:10][C:9]1([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=[NH:37])(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[N:16]=[C:17]([NH2:37])[CH:18]=[CH:19][CH:20]=2)[CH2:10][C:9]1([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)CC(Oc2cccc(Cl)n2)CCN1Cc1ccccc1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC1(C)CC(Oc2cccc(N)n2)CCN1Cc1ccccc1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
Combine 2-(1-benzyl-2,2-dimethyl-piperidin-4-yloxy)-6-chloro-pyridine (preparation 54, 0.57 g, 1.72 mmol), benzhydrylideneamine (0.31 g, 1.72 mmol) and toluene (20 mL), add sodium-t-butoxide (0.22 g, 2.24 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.043 g, 0.69 mmol), stir and heat at 80° C. After 10 min., add tris(dibenzylideneacetone)-dipalladium(0) (0.032 g, 0.345 mmol), stir and heat at 80° C. After 16 hr., add tris(dibenzylideneacetone)-dipalladium(0) (0.032 g, 0.345 mmol) and continue heating. After additional 24 hr., cool to ambient temperature. Partition between water (50 mL) and ethyl acetate (50 mL). Separate the organic layer, wash with aqueous NaCl solution (50 mL), dry over sodium sulfate, filter and concentrate. Dissolve residue in tetrahydrofuran (80 mL) and treat with 1M aqueous hydrochloric acid (30 mL) with stirring. After 1 hr., make the reaction mixture basic by adding 2M aqueous sodium hydroxide solution; extract with ethyl acetate. Separate the organic layer, dry over sodium sulfate, filter and concentrate. Purify residue by silica gel flash chromatography eluting with 5% (2M ammonia/methanol)/dichloromethane to of impure title compound (0.50 g). Mass spectrum (electrospray): m/z=312.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1I)[C:5]([NH:7][C:8]1[C:13]([Cl:14])=[CH:12][C:11]([C:15]([F:24])([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[Cl:25])=[O:6].[CH3:30][N:31](C)C=O>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[C:30]#[N:31])[C:5]([NH:7][C:8]1[C:13]([Cl:14])=[CH:12][C:11]([C:15]([F:24])([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[Cl:25])=[O:6]
Reactant: CN(C)C=O
Reactant: O=C(Nc1c(Cl)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1Cl)c1ccc(I)c(Cl)c1
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: N#Cc1ccc(C(=O)Nc2c(Cl)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2Cl)cc1Cl
Temperature: 80 °C
Reaction time: 7 h
Yield: 68.2 %

Procedure:
3-Chloro-N-[2,6-dichloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)phenyl]-4-iodobenzamide (1.59 g) was dissolved in N,N-dimethylformamide (20 ml). The resulting solution was deaerated under argon atmosphere, and then zinc cyanide (0.38 g) and tetrakis(triphenyl phosphine) palladium (0) (0.37 g) were added thereto. The mixture was heated and stirred for 7 hours at 80° C. under argon atmosphere. The reaction mixture was cooled, diluted with ethyl acetate, and then washed twice with water. The organic phase was dried over magnesium sulfate. The drying agent was removed by filtration, and the solvent was distilled off under reduced pressure to obtain a crude product, which was then purified by column chromatography to give 3-chloro-4-cyano-N-[2,6-dichloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-phenyl]-benzamide (0.90 g, yield 68.2%).