Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][CH:4]=1.[CH3:12][N:13]([CH3:22])[CH2:14][CH2:15][O:16][CH:17]1[CH2:21][CH2:20][NH:19][CH2:18]1>C1C=CC=CC=1>[CH3:12][N:13]([CH3:22])[CH2:14][CH2:15][O:16][CH:17]1[CH2:21][CH2:20][N:19]([C:10]([NH:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[O:11])[CH2:18]1
Reactant: CN(C)CCOC1CCNC1
Reactant: COc1ccc(N=C=O)cc1
Solvent: c1ccccc1
Product: COc1ccc(NC(=O)N2CCC(OCCN(C)C)C2)cc1
Reaction time: 2 h

Procedure:
A solution of 3.0 g. (0.02 mole) of p-methoxyphenyl isocyanate in 10 ml. of dry benzene was added dropwise to a stirring solution of 3.2 g. (0.02 mole) of 3-(2-dimethylaminoethoxy)pyrrolidine in 100 ml. of dry benzene under anhydrous conditions. When the addition was complete, the reaction mixture was allowed to stir for two hours. The mixture was concentrated under reduced pressure to give 4.9 g. (80%) of product which crystallized upon standing. Recrystallization from benzeneisooctane gave 4.8 g. of solid melting at 92°-94° C.
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].I[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C(#N)C>[CH3:17][C:3]1([C:1]#[C:2][C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reactant: Ic1cccs1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#Cc1cccs1)O2
Reaction time: 4 h
Yield: 56 %

Procedure:
A mixture of 4.6 g (20 mmol) of rac-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran -6ol, 6.3 g (30 mmol) of 2-iodothiophene, 0.8 g of triphenylphosphine, 0.19 g of cuprous iodide, 6 ml of triethylamine and 200 ml of acetonitrile was stirred and degassed with argon for 15 minutes. Palladium acetate, 220 mg, was then added and stirring under argon was continued for 4 hours. The solvent was removed under reduced pressure and the residue was partitioned between methylene chloride and saturated aqueous sodium bicarbonate solution. The organic phase was separated, dried and evaporated. The residue was chromato graphed over 200 g of silica gel (Merck 70-230 mesh) using methylene chloride. Crystallization of the combined clean fractions from ether/hexane yielded 3.5 g (56 %) of rac-3,4-dihydro-2,5,7,8-tetramethyl-2-[(2-thienyl) ethynyl]-2H-1-benzopyran-6ol with m.p. 112-114° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:19][C:20]#[N:21])([C:14](OCC)=[O:15])[C:10](=[O:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>[Pt]=O.C(O)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:14](=[O:15])[NH:21][CH2:20][CH2:19]2)[CH:10]([OH:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1(CC#N)CCN(Cc2ccccc2)CC1=O
Agent: O=[Pt]
Solvent: CC(=O)O
Solvent: CO
Product: O=C1NCCC12CCN(Cc1ccccc1)CC2O
Temperature: 90 °C
Reaction time: 24 h

Procedure:
To a flask charged with ethyl 1-benzyl-4-(cyanomethyl)-3-oxopiperidine-4-carboxylate (900 mg, 3.0 mmol) and a stir bar was added platinum oxide (100 mg, 0.44 mmol), MeOH (20 mL) and acetic acid (20 mL). The mixture was allowed to stir vigorously under an atmosphere of hydrogen for 24 hours. LC indicated complete reaction at that point. The catalyst was removed by filtration through a pad of CELITE®, and the filtrate was concentrated under reduced pressure. The residue was dissolved in EtOH (100 mL), and K2CO3 was added (2.1 g, 15 mmol). The mixture was heated to 90° C. for 4 hours. The reaction was cooled, and DCM was added (200 mL) to precipitate the solids. The solids were then removed by filtration, and the crude reaction was adsorbed onto silica gel, and flushed out with DCM and 10% MeOH (mixed with 10% NH4OH) to give the title compound. LCMS: m/z 261 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[C:6]([CH3:20])=[N:7][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18]O)=[CH:14][CH:13]=2)[C:9]=1[CH3:10].C(N(CC)CC)C.CS([Cl:33])(=O)=O>ClCCl>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[C:6]([CH3:20])=[N:7][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][Cl:33])=[CH:14][CH:13]=2)[C:9]=1[CH3:10]
Reactant: COC(=O)Cc1c(C)nn(Cc2ccc(CO)cc2)c1C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Cc1c(C)nn(Cc2ccc(CCl)cc2)c1C
Reaction time: 12 h

Procedure:
[1-(4-Hydroxymethyl-benzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-acetic acid methyl ester (intermediate 16.1.1, 4.8 g, 16.7 mmol) was dissolved in 60 ml dichloromethane. Triethylamine (3.5 ml, 25 mmol) was added, followed by dropwise addition of methanesulfonyl chloride (1.29 ml, 16.7 mmol). After 12 h at room temperature, the mixture was washed with water, aqueous KHSO4 solution, water, aqueous NaHCO3 solution and with water. The organic layer was dried over MgSO4 and the solvent was evaporated under reduced pressure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6]([C:12]1[CH:13]=[CH:14][C:15]([O:19][CH3:20])=[C:16]([NH2:18])[CH:17]=1)=[CH:5]2.[C:21](Cl)(Cl)=[S:22]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6]([C:12]1[CH:13]=[CH:14][C:15]([O:19][CH3:20])=[C:16]([N:18]=[C:21]=[S:22])[CH:17]=1)=[CH:5]2
Reactant: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1N
Reactant: S=C(Cl)Cl
Product: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1N=C=S

Procedure:
The product from Example 3, 5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine (5.48 g, 20 mmol) was reacted with thiophosgene (1.9 mL, 25 mmol) according to the procedure for Example 26, Step A to give the product as a greenish tan solid (5.40 g).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[O:12])[CH2:4][CH2:3]1.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25]([N:27]=[C:28]=[O:29])=[O:26]>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:11](=[O:12])[CH2:10][CH2:9][CH2:8][N:5]2[CH2:6][CH2:7][CH:2]([NH:1][C:28]([NH:27][C:25]([C:21]3[O:20][CH:24]=[CH:23][CH:22]=3)=[O:26])=[O:29])[CH2:3][CH2:4]2)=[CH:14][CH:15]=1
Reactant: NC1CCN(CCCC(=O)c2ccc(F)cc2)CC1
Reactant: O=C=NC(=O)c1ccco1
Product: O=C(NC(=O)c1ccco1)NC1CCN(CCCC(=O)c2ccc(F)cc2)CC1

Procedure:
Using a procedure analogous to Example 1, 4-amino-1-(4-[4-fluorophenyl]-4-oxobutyl)piperidine is reacted with 2-furoyl isocyanate to give the title compound.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH2:13][C:14]#[N:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].O>C1COCC1>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:4]=[C:5]([CH:13]([C:14]#[N:15])[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: N#CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCOC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC(C#N)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 44.94 %

Procedure:
3,5-Bis(trifluoromethyl)-phenylacetonitrile (1.4 mL, 1.0 eq.) was dissolved in THF (20 mL). The reaction mixture was cooled to −78° C. where a solution of NaHMDS (35% in THF) (4.34 mL, 1.05 eq.) was added dropwise. The reaction mixture was allowed to warm to 10° C. and stirred for 15 min. Then it was cooled to −78° C. where ethyl bromoacetate (0.87 mL, 1.0 eq.) was added. The reaction mixture was then allowed to warm to room temperature where it was stirred for 16 h. Reaction mixture was poured into water (50 mL) and was extracted with EtOAc (3×20 mL) The combined organic layers were washed with brine solution (3×50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 3.5 g of crude product, which was purified by chromatography (4% ethyl acetate in hexane) to give 1.2 g of ethyl 3-(3,5-bis(trifluoromethyl)phenyl)-3-cyanopropanoate (Yield 44.94%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH:17]([OH:22])[C:18]([F:21])([F:20])[F:19])[C:13]([O:15]C)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:23]1[CH:28]=[CH:27][CH2:26][CH2:25][CH2:24]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH:17]([O:22][CH:24]1[CH2:25][CH2:26][CH2:27][CH2:28][O:23]1)[C:18]([F:21])([F:20])[F:19])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)C(O)C(F)(F)F
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C(NC(C(=O)O)C(OC1CCCCO1)C(F)(F)F)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 2-(N-benzyloxycarbonylamino)3-hydroxy-4,4,4-trifluorobutyrate (3.3 g) in methylene chloride (33 ml) was added dihydropyran (1.1 ml) and pyridinium p-toluenesulfonate (251 mg) at room temperature. After stirring for 2 hours at room temperature, the solvent was distilled off and the residue was diluted with ethyl acetate, washed successively with aqueous sodium hydrogen carbonate and brine. After drying over sodium sulfate, the ethyl acetate was evaporated and the residue was diluted with methanol (20 ml). To the methanol solution was added 1N sodium hydroxide (10 ml) and the mixture was stirred for 2 hours at room temperature. The solvent distilled off and the residue was washed with ethyl acetate. The aqueous layer was acidified with citric acid to pH 4 and extracted with ethyl acetate (2 times). The combined ethyl acetate extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was crystallized with a mixture of diisopropylether and hexane to give 2-(N-benzyloxycarbonylamino)-3-(2-tetrahydropyranyloxy)- 4,4,4,-trifluorobutyric acid (1 g).
Reaction SMILES: [CH:1]1([S:4][C:5]2[CH:10]=[CH:9][C:8](/[C:11](/[C:28]3[CH:33]=[CH:32][C:31](I)=[CH:30][CH:29]=3)=[CH:12]/[CH2:13][O:14][C:15]3[CH:26]=[CH:25][C:18]([O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[C:17]([CH3:27])[CH:16]=3)=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.[CH3:35][N:36]([CH2:38][C:39]#[CH:40])[CH3:37].C(NC(C)C)(C)C>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH:1]1([S:4][C:5]2[CH:10]=[CH:9][C:8](/[C:11](/[C:28]3[CH:33]=[CH:32][C:31]([C:40]#[C:39][CH2:38][N:36]([CH3:37])[CH3:35])=[CH:30][CH:29]=3)=[CH:12]/[CH2:13][O:14][C:15]3[CH:26]=[CH:25][C:18]([O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[C:17]([CH3:27])[CH:16]=3)=[CH:7][CH:6]=2)[CH2:3][CH2:2]1
Reactant: C#CCN(C)C
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2ccc(SC3CC3)cc2)cc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCN(C)C)cc2)c2ccc(SC3CC3)cc2)cc1C
Temperature: 25 °C

Procedure:
To a degassed solution of methyl (Z)-[4-[3-(4-cyclopropylsulfanylphenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetate (480 mg, 0.818 mmol; prepared as described in example 53), N,N-dimethylpropargylamine (0.175 mL, 1.64 mmol) and diisopropylamine (0.539 mL, 3.85 mmol) in anhydrous tetrahydrofuran (10 mL), bis(triphenylphosphine)-palladium(II) dichloride (29 mg, 0.041 mmol) and copper(I) iodide (13 mg, 0.068 mmol) were added. The reaction mixture was stirred at ambient temperature over night under nitrogen. The solvents were evaporated in vacuo and the residue was purified by flash column chromatography (silica gel Fluka 60, dichloromethane/methanol 99:1-98:2) yielding methyl (E)-[4-[3-(4-cyclopropylsulfanylphenyl)-3-[4-[3-(N,N-dimethylamino)propynyl]phenyl]allyloxy]-2-methylphenoxy]acetate as yellow oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([CH2:24][CH3:25])[C:13]3[C:18]([C:19]=2[C:20]#[N:21])=[CH:17][CH:16]=[C:15]([O:22][CH3:23])[CH:14]=3)=[CH:7][CH:6]=1.CCN(CC)CC.[C:33](Cl)(=[O:35])[CH3:34]>C1COCC1>[C:20]([C:19]1[C:18]2[C:13](=[CH:14][C:15]([O:22][CH3:23])=[CH:16][CH:17]=2)[N:12]([CH2:24][CH3:25])[C:11]=1[C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:1][C:33](=[O:35])[CH3:34])=[CH:6][CH:7]=1)#[N:21]
Reactant: CCn1c(-c2ccc(OCCN)cc2)c(C#N)c2ccc(OC)cc21
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCn1c(-c2ccc(OCCNC(C)=O)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
2-[4-(2-Aminoethoxy)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (30 mg, 0.09 mmol), prepared as in example 1BB, step B, was dissolved in THF (400 μL), and Et3N (24 μL, 0.17 mmol). Acetyl chloride (10 μL, 0.14 mmol) was added, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was partitioned between EtOAc and H2O. The organic layer was dried and concentrated. Purification by silica gel chromatography (EtOAc) yielded N-{2-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)phenoxy]ethyl} acetamide (33 mg, 97%) as a white solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1B(O)O.[N:14]1([CH2:19][C:20]2[CH:21]=[CH:22][C:23](Br)=[N:24][CH:25]=2)[CH:18]=[CH:17][N:16]=[CH:15]1>>[N:14]1([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)=[N:24][CH:25]=2)[CH:18]=[CH:17][N:16]=[CH:15]1
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: Brc1ccc(Cn2ccnc2)cn1
Product: c1ccc2cc(-c3ccc(Cn4ccnc4)cn3)ccc2c1

Procedure:
Synthesized using 2-naphthylboronic acid (217 g, 1.26 mmol) and 1a (150 mg, 0.63 mmol) according to Method C. Yellow solid. Yield: 118 mg, 0.41 mmol, 66%. 1H NMR (CDCl3, 500 MHz): δH (ppm): 5.23 (s, 2H), 6.97 (s, 1H), 7.17 (s, 1H), 7.50-7.53 (m, 2H), 7.57 (dd, J=8.2, 2.4 Hz, 1H), 7.85-7.88 (m, 3H), 7.95 (d, J=8.8 Hz, 2H), 8.11 (dd, J=8.5, J=1.8 Hz, 1H), 8.47 (d, J=0.9 Hz, 1H), 8.65 (d, J=1.8 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=48.4, 119.2, 120.9, 124.3, 126.4, 126.5, 126.8, 127.7, 128.6, 128.7, 129.3, 129.8, 133.4, 133.8, 135.7, 136.0, 137.2, 148.7; MS (ESI): m/z=285.92 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([CH2:17][OH:18])[CH2:15][OH:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:19].O1CCOCC1>CO>[ClH:19].[NH:8]1[CH2:13][CH2:12][CH:11]([CH:14]([CH2:17][OH:18])[CH2:15][OH:16])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(CO)CO)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: OCC(CO)C1CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1-tert-butoxycarbonylpiperidine-4-ol, triethylamine, benzenesulfonyl chloride and methylene chloride was stirred for two days at room temperature to give 1-tert-butoxycarbonylpiperidine-4-ylbenzenesulfonate. A mixture of the obtained 1-tert-butoxycarbonylpiperidine-4-ylbenzenesulfonate, diethyl malonate, 20% sodium ethoxide-EtOH solution and EtOH was stirred for 22 hours heated to reflux to give diethyl[1-(tert-butoxycarbonyl)piperidine-4-yl]malonate. A mixture of the obtained diethyl[1-(tert-butoxycarbonyl)piperidine-4-yl]malonate, lithium borohydride, toluene and THF was stirred for 18 hours at 60° C. to give 2-(1-tert-butoxycarbonylpiperidine-4-yl)propane-1,3-diol. A mixture of the obtained 2-(1-tert-butoxycarbonylpiperidine-4-yl)propane-1,3-diol, 4M HCl-dioxane solution and MeOH was stirred for one hour at room temperature to give 2-piperidine-4-ylpropane-1,3-diol hydrochloride.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][NH:6][C:7]([C:9]1[C:10](=[O:22])[S:11][C:12]2[C:17]([C:18]=1[OH:19])=[CH:16][C:15]([Cl:20])=[CH:14][C:13]=2Br)=[O:8])[CH3:2].[CH3:24][Sn](C)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][NH:6][C:7]([C:9]1[C:10](=[O:22])[S:11][C:12]2[C:17]([C:18]=1[OH:19])=[CH:16][C:15]([Cl:20])=[CH:14][C:13]=2[CH3:24])=[O:8])[CH3:2]
Reactant: CCOC(=O)CNC(=O)c1c(O)c2cc(Cl)cc(Br)c2sc1=O
Reactant: C[Sn](C)(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)c1c(O)c2cc(Cl)cc(C)c2sc1=O
Temperature: 120 °C
Yield: 94.5 %

Procedure:
[(8-Bromo-6-chloro-4-hydroxy-2-oxo-2H-thiochromene-3-carbonyl)-amino]-acetic acid ethyl ester (500 mg, 1.19 mmol) was dissolved in anhydrous N,N-dimethylformamide (4 mL). Tetramethyl tin (247 μL, 1.783 mmol), dichloro(bis-triphenylphosphino) palladium (125 mg, 0.18 mmol), and 4 angstrom molecular sieves were added sequentially to the reaction. The reaction was sealed and heated to 120° C. in an oil bath for 45 min. The reaction was cooled, diluted with ethyl acetate, and partitioned with water. The organic phase was washed with water, brine, and dried over sodium sulfate. The crude material was purified by silica gel chromatography (15%-45% ethyl acetate in hexanes) to provide [(6-chloro-4-hydroxy-8-methyl-2-oxo-2H-thiochromene-3-carbonyl)-amino]-acetic acid ethyl ester (400 mg, 95%). MS ESI(−) m/e: 354.223 (M−1).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH:14]=[C:13]([C:27]([F:30])([F:29])[F:28])[N:12]=2)[CH:10]=1)CCC.[C:39]([NH:43][S:44]([C:47]1[S:48][C:49](Br)=[CH:50][CH:51]=1)(=[O:46])=[O:45])([CH3:42])([CH3:41])[CH3:40].CCCCCCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:39]([NH:43][S:44]([C:47]1[S:48][C:49]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:16]=[C:15]([C:17]4[CH:18]=[CH:19][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:21][CH:22]=4)[CH:14]=[C:13]([C:27]([F:28])([F:29])[F:30])[N:12]=3)[CH:10]=2)=[CH:50][CH:51]=1)(=[O:45])=[O:46])([CH3:42])([CH3:40])[CH3:41]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2cc(-c3ccc(C(F)(F)F)cc3)cc(C(F)(F)F)n2)cn1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cn(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)s1
Temperature: 25 °C
Yield: 57.4 %

Procedure:
A stirred mixture of 2-(4-tributylstannanyl-imidazol-1-yl)-6-trifluoromethyl-4-(4-trifluoromethyl-phenyl)-pyridine (Example G.12) (0.570 g, 0.88 mmol), commercially available 5-bromo-thiophene-2-sulfonic acid tert-butylamide (0.295 g, 0.99 mmol), tetrakis(triphenylphosphine)palladium (0.061 g, 0.046 mmol) in toluene (6 mL) was heated under reflux conditions for 16 h. Cooled to rt, some precipitate occurred, diluted with toluene (˜5 mL), added heptane, filtered the precipitate off, washed with toluene/heptane, dried in HV to give the title compound as a white solid (290 mg, 57%). MS (ISP) 575.2 [(M+H)+]; mp>250° C.
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([C:9]2(O)[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[C:1]([C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(C#N)nc2)CC1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(C#N)nc2)CC1
Reaction time: 8 h
Yield: 46 %

Procedure:
To solution of tert-butyl 4-(6-cyanopyridin-3-yl)-4-hydroxypiperidine-1-carboxylate (compound 51.2, 600 mg, 1.98 mmol, 1.00 equiv) in pyridine (15 mL) under nitrogen at 10-15° C. was carefully added POCl3 (3 g, 19.74 mmol, 9.97 equiv). After stirring overnight under nitrogen in a water/ice bath, the mixture was concentrated and the residue was dissolved in 50 mL of ethyl acetate. The organic phase was washed with 1×50 mL of hydrogen chloride (aq. 1M) followed by 1×50 mL of sodium bicarbonate (aq.sat.). The organic layer was then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:10) as the eluent to yield 0.26 g (46%) of the title compound as a white solid.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:25][S:26][C:27]1[CH:28]=[C:29]([N:33]=[C:34]=[O:35])[CH:30]=[CH:31][CH:32]=1>O1CCCC1>[CH3:25][S:26][C:27]1[CH:28]=[C:29]([NH:33][C:34]([N:15]2[CH2:16][CH2:17][N:12]([C:10]3[S:9][N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:11]=3)[CH2:13][CH2:14]2)=[O:35])[CH:30]=[CH:31][CH:32]=1
Reactant: CSc1cccc(N=C=O)c1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CSc1cccc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.3 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 3-methylthiophenyl isocyanate (0.168 ml, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and ethyl acetate to give 168 mg (50.3%) of the desired product as a solid.
Reaction SMILES: [SH:1][CH:2]([CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)[C:3]([OH:5])=[O:4].[OH-].[K+].O.Cl[C:15]1[N:20]=[C:19]([O:21][CH3:22])[N:18]=[C:17]([O:23][CH3:24])[N:16]=1>CC(C)=O>[CH3:24][O:23][C:17]1[N:18]=[C:19]([O:21][CH3:22])[N:20]=[C:15]([S:1][CH:2]([CH:6]2[CH2:10][CH2:9][CH2:8][CH2:7]2)[C:3]([OH:5])=[O:4])[N:16]=1
Reactant: COc1nc(Cl)nc(OC)n1
Reactant: O=C(O)C(S)C1CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: COc1nc(OC)nc(SC(C(=O)O)C2CCCC2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 40.1 %

Procedure:
To a mixture solution of 6.0 g of 2-mercapto-2-cyclopentyl acetic acid, 4.2 g of potassium hydroxide and 50 ml of water, a solution of 30 ml of acetone and 6.6 g of 2-chloro-4,6-dimethoxy S-triazine was added at a temperature of from 0° to 5° C. for 20 mimutes. Then, the reaction mixture was stirred at room temperature for 1.5 hours. Acetone was removed by distillation under reduced pressure, and the residue was extracted with ethyl ether. The ethyl ether layer was removed, and the aqueous layer was adjsuted to pH 2 to 3 with a 5% hydrochloric acid aqueous solution and extracted with ethyl acetate. The ethyl acetate extract was washed with water and dried. Then, ethyl acetate was removed by distillation under reduced pressure to obtain a white solid. The solid was recrystallized from isopropyl ether and n-hexane to obtain 4.5 g of the desired product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC(OS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
To a stirred solution of the title compound of Example 1 (44.3 g, 220 mmol) and Et3N (61.4 mL, 440 mmol, 2 eq) in THF (250 mL) was added dropwise at rt (maintained by cooling from an ice bath), methanesulfonyl chloride (27.77 g, 242 mmol, 1.1 eq). The reaction mixture was stirred for 1 h at rt when TLC (solvent system C) indicated completion. The precipitated Et3NHCl was removed by filtration and the filter cake was washed with 50 mL of THF. The combined flitrate and washings were evaporated in vacuo to give the crude product as a yellow oil. This was dissolved in EtOAc/hexanes (1:2) and passed through a pad of silica gel eluting with ethyl acetate/hexanes (1:3). Evaporation of the flitrate afforded the product as a pale yellow oil (59.1 g, 96%) which crystallized on standing. Recrystallization from EtOAc/hexane (1:10) afforded an analytically pure sample of the title compound: mp 69°-70° C.; 1H-NMR (CDCl3) ∂ 4.72 (m,1H), 3.63 (m, 2H), 3.46 (m, 1H), 3.32 (m, 1H), 3.05 (s, 3H), 1.75-2.06 (complex m, 4H), 1.46 (s, 9H); CIMS (MH+ calcd for C11H21NO5S): 280. Found (MH+): 280; Anal. (calcd for C11H21NO5S): C, H, N.