Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:18])[C:5]([F:17])=[C:6]([CH:16]=1)[O:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].[Cu][C:20]#[N:21]>CN(C=O)C>[C:20]([C:2]1[CH:3]=[C:4]([F:18])[C:5]([F:17])=[C:6]([CH:16]=1)[O:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])#[N:21]
Reactant: CCOC(=O)CCCOc1cc(Br)cc(F)c1F
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1cc(C#N)cc(F)c1F
Temperature: 120 °C
Reaction time: 24 h
Yield: 94.5 %

Procedure:
To a solution of ethyl 4-(5-bromo-2,3-difluorophenoxy)butanoate (2.9 g, 9.0 mmol) in anhydrous DMF (30 mL) was added copper(I) cyanide (1.6 g, 18.0 mmol) under nitrogen atmosphere. The resulting mixture was heated to 120° C. for 16 hours. Additional amount of copper(I) cyanide (0.8 g, 9.0 mmol) was added and the reaction mixture was stirred at 120° C. for 24 hours. A second additional amount of copper(I) cyanide (0.8 g, 9.0 mmol) was added. After 24 additional hours at 120° C., the reaction mixture was cooled down and filtered through a pad of Celite, which was rinsed with EtOAc. The organic layer was washed many times with an aqueous solution of NH4OH and brine, dried (MgSO4) and concentrated under vacuum affording the title compound as a beige solid (2.29 g, 95%). HPLC (Method A) Rt 4.73 min (Purity: 84.4%).
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[N:6]=1.[F:19][C:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[CH:22][C:21]=1[C:35]1[CH:36]=[N:37][C:38]([NH2:41])=[N:39][CH:40]=1>>[F:19][C:20]1[CH:25]=[C:24]([C:2]2[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=2[O:4][C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[N:6]=2)[CH:23]=[CH:22][C:21]=1[C:35]1[CH:40]=[N:39][C:38]([NH2:41])=[N:37][CH:36]=1
Reactant: FC(F)(F)c1cccc(Oc2ccccc2Br)n1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: Nc1ncc(-c2ccc(-c3ccccc3Oc3cccc(C(F)(F)F)n3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 2-(2-bromophenoxy)-6-(trifluoromethyl)pyridine and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C22H14F4N4O, 426.11; m/z found, 427.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 2H), 8.04 (m, 1H), 7.59-7.48 (m, 4H), 7.41 (m, 1H), 7.35-7.24 (m, 4H), 6.89 (s, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[OH:11])([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20]Br.O>CN(C=O)C>[N+:1]([C:4]1[C:5]2[O:11][CH2:20][CH2:19][O:10][C:6]=2[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(O)c1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc2c1OCCO2
Temperature: 110 °C
Yield: 62.2 %

Procedure:
To a solution of 3-nitrobenzene-1,2-diol (11 g, 0.071 mol) in N,N′-dimethylformamide (500 mL) was added potassium carbonate (29 g, 0.0.213 mol) followed by 1,2-dibromoethane (14.7 g, 0.078 mol). The mixture was heated at 110° C. for 2 hours. After cooled to room temperature, the mixture was poured into water and then extracted with ether. The organic phases were combined and dried over anhydrous sodium sulfate, filtrated and concentrated to give a crude product, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate 20/1) to afford the product 5-nitro-2,3-dihydrobenzo[b][1,4]dioxine (8 g, yield 62%). 1H NMR (400 MHz, CDCl3) δ ppm 7.48-7.50 (dd, 1H, J=1.6 Hz, 8.4 Hz), 7.09-7.12 (dd, 1H, J=1.6 Hz, 8.4 Hz), 6.88-6.92 (t, 1H, J=8.4 Hz), 4.40-4.42 (m, 2H), 4.34-4.36 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([NH2:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[S:13][C:14]([CH3:22])=[CH:15][C:16]=1[C:17](OCC)=[O:18]>C(Cl)(Cl)Cl>[CH3:22][C:14]1[S:13][C:12]2[N:11]=[C:2]3[CH:3]=[CH:4][C:5]([C:8]([NH2:10])=[O:9])=[CH:6][N:7]3[C:17](=[O:18])[C:16]=2[CH:15]=1
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: CCOC(=O)c1cc(C)sc1N
Solvent: ClC(Cl)Cl
Product: Cc1cc2c(=O)n3cc(C(N)=O)ccc3nc2s1
Temperature: 185 °C
Reaction time: 6 h
Yield: 6.1 %

Procedure:
A mixture of 6.0 g (0.038 mol) of 6-chloro-3-pyridinecarboxamide (Aldrich Chemical Company) and 10.0 g (0.054 mol) of 2-amino-5-methyl-3-thiophenecarboxylic acid, ethyl ester (Chemische Berichte, Vol. 99, pages 94-100, 1966) is heated in an oil bath at 185° C. for one hour then at 135°-140° C. for sixteen hours and finally at 195° C. for six hours. The mixture is cooled and then suspended in hot chloroform and filtered to give 0.6 g of 2-methyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxamide; mp 350°-354° C. after recrystallization from pyridine.
Reaction SMILES: [C:1]([C:5]1[CH:29]=[CH:28][C:8]([CH2:9][N:10]2[CH2:14][CH:13]([CH2:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[N:12]([CH3:26])[C:11]2=[O:27])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[I:30]I>C(O)C.S([O-])([O-])(=O)=O.[Ag+2]>[C:1]([C:5]1[CH:29]=[CH:28][C:8]([CH2:9][N:10]2[CH2:14][CH:13]([CH2:15][CH2:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[C:22]([I:30])[CH:23]=3)[N:12]([CH3:26])[C:11]2=[O:27])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: II
Reactant: COc1ccc(CCCC2CN(Cc3ccc(C(C)(C)C)cc3)C(=O)N2C)cc1
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: COc1ccc(CCCC2CN(Cc3ccc(C(C)(C)C)cc3)C(=O)N2C)cc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
To a solution of 1-(4-tert-Butyl-benzyl)-4-[3-(4-methoxy-phenyl)-propyl]-3-methyl-imidazolidin-2-one (0.630 g, 1.60 mmole) in ethanol (15 mL), is added iodine (0.810 g, 3.20 mmole) followed by silver sulfate (0.998 g, 3.20 mmole). The reaction mixture is stirred at room temperature overnight. The precipitate is removed through filtration, and the solution is concentrated in vacuo. The residue is purified by column chromatography (silica gel, gradient elution 0-20% acetone in hexane) to provide a white foamy solid (0.584 g, 70%). Mass [EI+] 521 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([C:13]2[NH:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=3)[N:17]=2)[N:10]([C:25](=[O:35])[CH:26]([NH:30][C:31]([O:33][CH3:34])=[O:32])[CH:27]([CH3:29])[CH3:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:36][O:37][C:38](=[O:64])[NH:39][CH:40]([C:44]([N:46]1[CH2:50][CH2:49][CH2:48][CH:47]1[C:51]1[NH:52][CH:53]=[C:54]([C:56]2[CH:61]=[CH:60][C:59]([C:62]#[CH:63])=[CH:58][CH:57]=2)[N:55]=1)=[O:45])[CH:41]([CH3:43])[CH3:42].C(N(CC)CC)C>[Cu]I.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>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([C:13]2[NH:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([C:63]#[C:62][C:59]4[CH:60]=[CH:61][C:56]([C:54]5[N:55]=[C:51]([CH:47]6[CH2:48][CH2:49][CH2:50][N:46]6[C:44](=[O:45])[CH:40]([NH:39][C:38]([O:37][CH3:36])=[O:64])[CH:41]([CH3:43])[CH3:42])[NH:52][CH:53]=5)=[CH:57][CH:58]=4)=[CH:20][CH:19]=3)[N:17]=2)[N:10]([C:25](=[O:35])[CH:26]([NH:30][C:31]([O:33][CH3:34])=[O:32])[CH:27]([CH3:29])[CH3:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1ccc(-c2c[nH]c(C3CCCN3C(=O)C(NC(=O)OC)C(C)C)n2)cc1
Reactant: COC(=O)NC(C(=O)N1CN(C(=O)OC(C)(C)C)CC1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)NC(C(=O)N1CCCC1c1nc(-c2ccc(C#Cc3ccc(-c4c[nH]c(C5CN(C(=O)OC(C)(C)C)CN5C(=O)C(NC(=O)OC)C(C)C)n4)cc3)cc2)c[nH]1)C(C)C
Temperature: 80 °C
Reaction time: 1 h
Yield: 34.5 %

Procedure:
A mixture of 4-(4-bromo-phenyl)-3′-(2-methoxycarbonylamino-3-methyl-butyryl)-2′,3′,4′,5′-tetrahydro-1H-[2,4′]biimidazolyl-1′-carboxylic acid tert-butyl ester (686 mg, 1.74 mmol), (1-{2-[4-(4-ethynyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (800 mg, 1.45 mmol), copper(I) iodide (28 mg, 0.14 mmol), tetrakis(triphenylphosphine)palladium(0) (167 mg, 0.14 mmol), triethylamine (2.0 mL, 14.5 mmol) and degassed dimethylformamide (10 mL) was stirred at 80° C. for 1 hour. (1-{2-[4-(4-Ethynyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (200 mg, 0.57 mmol) was added. After 1 hour the solvent was removed under reduced pressure. The residue was taken up in dichloromethane (50 mL) and washed with water (10 mL), saturated ammonium chloride (2×10 mL), dried over sodium sulfate and filtered. The solvent was removed under reduced pressure. The residue was subjected to flash chromatography with eluent of (10% methanol in ethyl acetate) and hexane. The product-containing fractions were combined and the solvent was removed under reduced pressure to yield 3′-(2-methoxycarbonylamino-3-methyl-butyryl)-4-[4-(4-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-phenylethynyl)-phenyl]-2′,3′,4′,5′-tetrahydro-1H-[2,4′]biimidazolyl-1′-carboxylic acid tert-butyl ester (439 mg, 0.50 mmol, 35%).
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Cl:2].[S:6](=[O:9])([OH:8])[O-:7].[Na+:10]>>[Na+:10].[Cl:2][CH2:1][CH:3]([OH:5])[CH2:4][S:6]([O-:9])(=[O:8])=[O:7]
Reactant: ClCC1CO1
Reactant: O=S([O-])O
Agent: [Na+]
Product: O=S(=O)([O-])CC(O)CCl
Temperature: 80 °C

Procedure:
Epichlorohydrin (one mole, 93 g) is slowly added to an aqueous solution of one mole sodium bisulfite (104 g in about 120 ml water) while maintaining the temperature at about 80° C. The epichlorohydrin is added dropwise over about three hours, and after addition is complete, the mixture is stirred for an additional hour. After the mixture cools to about 20° C., the solids of 3-chloro-2-hydroxypropylsulfonic acid sodium salt formed from the reaction are filtered and analyzed by Nuclear Magnetic Resonance (NMR). The ISC spectra shows peaks at 69.99 ppm, 56.97 ppm, and 51.18 ppm from TMS (tetramethyl silane) and the proton spectrum shows, three groups of peaks centering at 2.95, 3.58 and 4.17 ppm (from TMS), in a 2:2:1 ratio respectively, consistent with the structure of CHPS.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[CH:11][CH:10]=[N:9]1.C([Li])CCC.[S:18](Cl)([Cl:21])(=[O:20])=[O:19]>C(OCC)C.CCCCCC>[N:8]1([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[S:18]([Cl:21])(=[O:20])=[O:19])[CH:12]=[CH:11][CH:10]=[N:9]1
Reactant: O=S(=O)(Cl)Cl
Reactant: Brc1ccccc1-n1cccn1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: O=S(=O)(Cl)c1ccccc1-n1cccn1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 52 g of 1-(2-bromophenyl)pyrazole in 230 ml of diethyl ether under a nitrogen atmosphere and cooled at -70° C. was added dropwise 175 ml of a 1.6M solution of n-butyl lithium in hexane. The suspension was allowed to warm from -70° C. to -25° C. on its own, then a solution of 37 ml of sulfuryl chloride in 69 ml of hexane was added dropwise at -25° to -20° C. After allowing the suspension to warm to room temperature, the suspension was stirred for 5 hours, then filtered to yield 38 g of crude 2-(1H-pyrazol-1-yl)benzenesulfonyl chloride which was contaminated with inorganic salts.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:5]=[CH:6][C:7]=1[OH:8].Cl[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH:5]=[CH:6][C:7]=1[O:8][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc([N+](=O)[O-])cn2)c(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.1 %

Procedure:
To a solution of tert-butyl (3-fluoro-4-hydroxyphenyl)carbamate (17.2 g, 75.7 mmol) in dimethyl sulfoxide (100 mL) were added 2-chloro-5-nitropyridine (10 g, 63.1 mmol) and cesium carbonate (30.8 g, 94.6 mmol), and the mixture was stirred at room temperature for 4 hr. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was washed with hexane/ethyl acetate (=5/1) and collected by filtration to give the title compound (17.0 g, 77%).
Reaction SMILES: [CH3:1][C:2]1([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:20]1(C2(C(Cl)=O)CCCCC2)[CH:25]=[CH:24]C=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[C:1]1([C:2]2([C:8]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N+:17]([O-:19])=[O:18])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH:24]=[CH:25][CH:20]=[CH:21][CH:22]=1
Reactant: CC1(C(=O)Nc2ccccc2[N+](=O)[O-])CCCCC1
Reactant: O=C(Cl)C1(c2ccccc2)CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: O=C(Nc1ccccc1[N+](=O)[O-])C1(c2ccccc2)CCCCC1
Yield: 91 %

Procedure:
This compound was prepared following the procedure described for compound 39A in example 39, except that 1-phenylcyclohexanecarbonyl chloride (J. Am. Chem. Soc. 68, 2345-7 (1946)) was used in place of 1-methylcyclohexanecarbonyl chloride, toluene in place of CH2Cl2, DIPEA in place of triethylamine and reaction mixture was refluxed for 15 h. The crude was purified by flash chromatography (petroleum ether-EtOAc 98:2). Yield 91%.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[N:4][CH:3]=1.[Cu](C#N)[C:14]#[N:15].[C-]#N.[Na+]>>[C:14]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[N:4][CH:3]=1)#[N:15]
Reactant: Oc1ncc(Br)c2ccccc12
Reactant: N#C[Cu]C#N
Agent: [C-]#N
Agent: [Na+]
Product: N#Cc1cnc(O)c2ccccc12
Temperature: 180 °C
Reaction time: 4 h
Yield: 52.3 %

Procedure:
4-Bromo-1-hydroxyisoquinoline (1.56 g) was dissolved in N-methyl-2-pyrrolidine (25 mL), and copper cyanide (1.56 g) was added thereto. The mixture was stirred at 180° C. for 4 hr with heating. The reaction mixture was added to cool to 100° C. and added to an aqueous solution (125 mL) of sodium cyanide (31.25 g). The mixture was extracted with dichloromethane and the extract was dried and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 4-cyano-1-hydroxyisoquinoline (0.62 g) as a pale-yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](I)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH:11]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)=[CH2:12]>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:11][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(I)c1
Reactant: C=Cc1ccncc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: O=[N+]([O-])c1cccc(C=Cc2ccncc2)c1
Temperature: 100 °C
Yield: 66.3 %

Procedure:
A mixture of 3.0 g (20 mmol) of 3-nitroiodobenzene, 3.5 mL (25 mmol) of TEA, 0.045 g (0.20 mmol) of palladium(II) acetate and 2.77 g (25.0 mmol) of 4-vinylpyridine was suspended in 4 mL of dry acetonitrile in a pyrex sealed tube and heated to 100° C. for 48 h. The mixture was cooled to rt and was quenched with 200 mL of 10% hydrochloric acid. The resulting yellow solid was isolated by filtration and partitioned between 250 mL of EtOAc and 250 mL of 1 N aqueous sodium hydroxide. The organic phase was dried over MgSO4 and concentrated to give 3.0 g (66%) of 4-[2-(3-nitrophenyl)ethenyl]-pyridine as a yellow solid: 1H NMR (DMSO-d6): δ 3.0-4.6 (br s, 1H), 7.71-7.78 (m, 2H), 8.07 (d, J=15.8 Hz, 1H), 8.13-8.16 (m, 3H), 8.24 (d, J=8.0 Hz, 1H), 8.56 (s, 1H), 8,84 (d, J=5.7 Hz, 2H); ESI−MS m/z 227 (M+1)+. A portion (1.3 g, 7.1 mmol) of this solid was dissolved in 100 mL of EtOAc, and 0.5 g of 10% palladium on charcoal was added. The mixture was hydrogenated on a Parr apparatus at 40 psi for 1.5 h. Another 0.5 g batch of 10% palladium on charcoal was added and the mixture was subjected to further hydrogenation for 1 h. The palladium catalyst was removed by filtration through a pad of celite, and the filtrate was concentrated to give 1.13 g (100%) of 3-(4-pyridinyl)ethylaniline: 1H NMR (DMSO-d6): δ 2.69 (m, 2H), 2.80 (m, 2H), 4.9 (bs, 2H), 6.33 (d, J=7.7 Hz, 2H), 6.38 (s, 1H), 6.86 (t, J=7.7 Hz, 1H), 7.20 (d, J=5.8 Hz, 2H), 8.41 (d, J=5.8 Hz, 2H). Conversion of 3-[2-(4-pyridinyl)ethyl]-aniline to 4-(2-pyridin-4-yl-ethyl)-1H-indole-2,3-dione was accomplished according to Procedure A in 24% overall yield: 1H NMR (DMSO-d6): δ 2.80 (m, 2H), 3.10 (m, 2H), 6.70 (d, J=8.0 Hz, 1H), 6.81 (d, J=8.0 Hz, 1H), 7.24 (m, 2H), 7.40 (t, J=8.0 Hz, 1H), 8.42 (bs, 2H), 11.00 (s, 1H). Conversion of 4-(2-pyridin-4-ylethyl)-1H-indole-2,3-dione to the title compound was accomplished according to Procedure G in 40% overall yield: 1H NMR (DMSO-d6): δ 2.98 (t, J=7.9 Hz, 2H), 3.30 (m, 2H, underneath water peak), 6.78 (d, J=7.7 Hz, 1H), 6.88 (d, J=7.6 Hz, 1H), 7.17 (t, J=7.6 Hz, 1H), 7.25 (s, 2H), 7.29 (d, J=6.0 Hz, 2H), 7.37 (d, J=8.8 Hz, 2H), 7.66 (d, J=8.8 Hz, 2H), 8.47 (d, J=6.0 Hz, 2H), 11.13 (s, 1H), 12.98 (s, 1H); APCI−MS m/z 420 (M−1)−. Anal. Calcd for C21H19N5O3S.0.15 HCl: C, 55.93, H, 4.43; N, 15.53; S, 7.11. Found C, 56.05, H, 4.36; N, 15.38; S, 7.18.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4].C([O-])([O-])=O.[Na+].[Na+].Cl[C:21]([O:23][CH3:24])=[O:22]>C1COCC1>[CH3:24][O:23][C:21]([NH:1][C@@H:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4])=[O:22]
Reactant: N[C@@H](CCc1ccccc1)C(=O)O
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)N[C@@H](CCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.3 %

Procedure:
(S)-2-amino-4-phenylbutanoic acid (0.50 g, 2.8 mmol) was suspended in 1M Na2CO3 (8.4 mL, 8.4 mmol) and then a solution of methyl chloroformate (0.32 mL, 4.2 mmol) in THF (4.0 mL) was added and the mixture was stirred vigorously at room temperature for 4 hours. The mixture was then concentrated under reduced pressure and the residue was dissolved in water and made acidic with 0.1N HCl. The mixture was extracted with ethyl acetate, dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound (0.64 g, 97% yield).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]=[C:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:19]1[C:24]([Br:25])=[CH:23][CH:22]=[CH:21][N:20]=1>C1COCC1.O>[CH2:1]([N:8]1[CH2:9][CH:10]=[C:11]([CH2:14][O:15][C:19]2[C:24]([Br:25])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncccc1Br
Reactant: OCC1=CCN(Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Brc1cccnc1OCC1=CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-methanol (0.675 g, 3.019 mmol) [C.A.S. 158984-76-0] in dry THF (40 ml) cooled at 0° C., was added NaH (0.138 g, 3.622 mmol; 60% mineral oil). The resulting reaction mixture was stirred at 0° C. for 30 min. Then, a solution of 2-chloro-3-bromopyridine (0.58 g, 3.019 mmol) in dry THF (10 ml) was added and the mixture was heated in a sealed tube at 85° C. for 2 h. After cooling, additional (1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-methanol (0.675 g, 3.019 mmol), NaH (0.138 g, 3.622 mmol; 60% mineral oil) were added to the reaction mixture, which was then heated at 85° C. overnight. Then, after cooling, the mixture was diluted with water and extracted with EtOAc. The organic phase was separated, dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography (silica gel; DCM/7M solution of NH3 in MeOH up to 2% as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate D58 (0.55 g, 50%).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[C:7]([OH:12])(=O)[C:8]([CH3:10])=[CH2:9].CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O>ClCCl>[CH3:1][C:2]1[S:3][C:4]2[C:7](=[O:12])[CH:8]([CH3:10])[CH2:9][C:5]=2[CH:6]=1
Reactant: C=C(C)C(=O)O
Reactant: Cc1cccs1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Solvent: ClCCl
Product: Cc1cc2c(s1)C(=O)C(C)C2
Reaction time: 0.08 h
Yield: 22.7 %

Procedure:
A mixture of 150 g of 2-methylthiophene (1.5 mol) and 157.5 g of methacrylic acid (1.8 mol) was added within 30 minutes at about 80° C. to 1500 ml of Eaton's reagent, and the temperature was between 78° C. and 83° C. On completion of addition, the reaction mixture was stirred for a further 5 minutes and then gradually poured into a vigorously stirred mixture of 3000 ml of water and 500 ml of dichloromethane. The organic phase was removed and dried over magnesium sulfate. The solvent was distilled off on a rotary evaporator and 263.5 g of crude product were obtained in a purity of 88.2% according to GC-MS analysis. A portion of the crude product (79 g) was distilled (92° C., 0.02 torr). 56.5 g (76%) of product were obtained as a mixture of two isomers in a ratio of approx. 9:1 (thiophen-6-one: thiophen-4-one).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][C:7]1=[O:14].[CH2:25]([NH:28][C:29]1[CH2:33][S:32][C:31](=[O:34])[N:30]=1)[C:26]#[CH:27].C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:33]2/[C:29]([NH:28][CH2:25][C:26]#[CH:27])=[N:30][C:31](=[O:34])[S:32]/2)[CH2:8][C:7]1=[O:14]
Reactant: C#CCNC1=NC(=O)SC1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)C(=O)C1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)C(=O)C1
Temperature: 80 °C
Reaction time: 4 h
Yield: 34.6 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]-2-oxopiperidine-4-carbaldehyde (1.00 g) and 4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one (0.66 g) in 2-propanol (10 mL) was added piperidinium acetate (0.41 g). The reaction mixture was stirred at 80° C. for 4 hr and concentrated. Ethyl acetate was added to the residue, and the precipitate was removed. Water was added to the filtrate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethanol/heptane to give the title compound (0.48 g).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH3:17])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:5]2=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].Cl.[CH3:29][O:30][C:31](=[O:34])[CH2:32][NH2:33]>CN(C=O)C>[CH3:17][N:8]1[C:6]2=[N:7][C:2]([NH:33][CH2:32][C:31]([O:30][CH3:29])=[O:34])=[CH:3][C:4]([C:18]([F:21])([F:20])[F:19])=[C:5]2[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:9]1
Reactant: Cn1nc(-c2ccccc2)c2c(C(F)(F)F)cc(Br)nc21
Reactant: COC(=O)CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CNc1cc(C(F)(F)F)c2c(-c3ccccc3)nn(C)c2n1
Temperature: 100 °C
Yield: 32 %

Procedure:
To a stirred mixture of 6-bromo-1-methyl-3-phenyl-4-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine (0.15 g, 0.422 mmol) and Na2CO3 (0.135 g, 1.267 mmol) in dry DMF (6.0 mL), glycine methylester×HCl (0.08 g, 0.633 mmol) was added at it and heated to 100° C. for 6 h. The reaction mixture was cooled to it and poured into rapidly stirred ice cold water. The crude compound was extracted with EtOAc and purified by column chromatography (eluent: 10% EtOAc in hexane) to yield the title compound as a colorless solid (0.05 g, 32%). [1H-NMR (CDCl3, 300 MHz) δ 7.55-7.38 (m, 5H), 6.68 (s, 1H), 5.42 (t, 1H), 4.32 (d, 2H), 4.05 (s, 3H), 3.75 (s, 3H); LCMS RtC=0.469 min; [M+H]+=364.8]