Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C:13]([F:21])([F:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Na+].[I-].[NH3:24].C1(S(O)(=O)=O)C=CC=CC=1>C(OC(C)C)(=O)C.CS(C)=O>[C:5]1([S:8]([OH:11])(=[O:10])=[O:9])[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1.[F:20][C:13]([F:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[CH2:12][NH2:24]
Reactant: N
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)c2ccccn2)cc1
Agent: O=S(=O)(O)c1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)OC(C)C
Solvent: CS(C)=O
Product: NCC(F)(F)c1ccccn1
Temperature: 80 °C

Procedure:
10 g of 2,2-Difluoro-2-pyridin-2-ylethyl 4-methylbenzenesulfonate (J) obtained in step 3, 5 g of NaI, 20 mL of DMSO and 90 mL of aqueous ammonia were taken in a 500 mL autoclave vessel. The reaction mixture was heated to 80° C. and a pressure of 15 to 17 kg of ammonia maintained for 30-40 hours. The volume of the reaction mass was reduced by vacuum distillation. The RM was washed with 60 mL of IPE. The pH of the RM was adjusted to 10-14 by adding a 50% NaOH solution and extracted three times with 60 mL of MDC. The combined MDC layers were washed with brine, dried over sodium sulphate and distilled under vacuum (crude weight=8 g). The crude mass obtained was dissolved with 10 mL of MDC, and to this 4.5 g benzene sulphonic acid (BSA) dissolved in 30 mL isopropyl acetate (IPAc) was added dropwise over a period of 30 minutes with stirring at RT. The RM was stirred for 30 minutes at RT. The solid obtained was filtered and washed with IPAc and dried under vacuum, resulting in 5 g of the titled compound (Yield=49.5%).
Reaction SMILES: [OH:1][C@H:2]([CH3:22])[CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1([CH3:21])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.[H-].[Na+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>CN(C=O)C>[CH2:25]([O:1][C@H:2]([CH3:22])[CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1([CH3:21])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C[C@@H](O)CCCCOC1(C)CCN(C(=O)OC(C)(C)C)CC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](CCCCOC1(C)CCN(C(=O)OC(C)(C)C)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
To a solution of (R)-tert-butyl 4-((5-hydroxyhexyl)oxy)-4-methylpiperidine-1-carboxylate (4.5 g, 14.27 mmol) in DMF (50 mL) at 0° C. was added 60% NaH (0.685 g, 17.12 mmol) and the resulting mixture was stirred at room temp for 1 h. Benzyl bromide (2.55 mL, 21.40 mmol) was then added and the mixture was stirred for 16 h. Water (20 mL) was then added and the mixture was extracted with ether (100 mL), washed with brine (25 ml), dried (Na2SO4), filtered and concentrated. The residue was then purified by Biotage (0-20% EtOAc/hexane) to afford (R)-tert-butyl 4-((5-(benzyloxy)hexyl)oxy)-4-methylpiperidine-1-carboxylate (3.5 g, 8.63 mmol, 60.5% yield) as light yellow oil. 1H NMR (500 MHz, CDCl3) δ 7.38-7.35 (m, 4H), 7.31-7.25 (m, 1H), 4.60 (d, J=11.8 Hz, 1H), 4.48 (d, J=11.8 Hz, 1H), 3.86-3.62 (m, 3H), 3.58-3.50 (m, 1H), 3.31 (t, J=6.3 Hz, 2H), 3.14 (br. s., 2H), 1.74 (d, J=12.9 Hz, 2H), 1.59-1.51 (m, 3H), 1.47 (s, 9H), 1.46-1.37 (m, 4H), 1.22 (d, J=6.1 Hz, 3H), 1.17 (s, 3H). LCMS (M+H)=406.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[N:10]1[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]1)[NH2:6].Cl[C:17]1[N:22]=[C:21]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])[C:20]([CH3:29])=[C:19]([CH2:30][O:31][CH2:32][C:33]([F:36])([F:35])[F:34])[N:18]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:6][C:17]2[N:22]=[C:21]([O:23][CH2:24][C:25]([F:28])([F:26])[F:27])[C:20]([CH3:29])=[C:19]([CH2:30][O:31][CH2:32][C:33]([F:36])([F:34])[F:35])[N:18]=2)[CH:7]=[CH:8][C:9]=1[N:10]1[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]1
Reactant: Cc1c(COCC(F)(F)F)nc(Cl)nc1OCC(F)(F)F
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1cc(Nc2nc(COCC(F)(F)F)c(C)c(OCC(F)(F)F)n2)ccc1-n1cnc(C)c1
Temperature: 120 °C
Yield: 83.5 %

Procedure:
3-Methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (0.066 g, 0.32 mmol), 2-chloro-5-methyl-4-(2,2,2-trifluoroethoxy)-6-((2,2,2-trifluoroethoxy)methyl)pyrimidine (0.11 g, 0.32 mmol), palladium(II) acetate (11 mg, 0.05 mmol), 2-(dicyclohexylphosphino)biphenyl (0.017 g, 0.05 mmol) and cesium carbonate (0.212 g, 0.65 mmol) were mixed in dioxane (3 mL). The vial was capped, evacuated and flushed with nitrogen. The mixture was heated by microwave irradiation at 120° C. for 1.5 h. The mixture was filtered and the residue was purified by column chromatography on silica eluting with a gradient of methanol in DCM to give the title compound 135 mg (82%).
Reaction SMILES: [C:1]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[CH2:9][C:10]([OH:12])=O)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C(OCCC)(=O)C.C(OC(=O)C)(=O)C.[O-2].[Mg+2]>C(O)(=O)C>[C:1]([NH:7][C@@H:8]1[C:13](=[O:14])[O:15][C:10](=[O:12])[CH2:9]1)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]
Reactant: CC(=O)CC(=O)N[C@@H](CC(=O)O)C(=O)O
Agent: [Mg+2]
Agent: [O-2]
Solvent: CC(=O)OC(C)=O
Solvent: CCCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)CC(=O)N[C@H]1CC(=O)OC1=O
Temperature: 10 °C
Reaction time: 1.25 h

Procedure:
N-acetoacetyl-L-aspartic acid, 80.4 parts, was mixed with 111 parts by volume of dry n-propyl acetate and 39.6 parts of acetic anhydride. A solution of 0.207 parts magnesium oxide in 7.4 parts by volume glacial acetic acid was added and the mixture was stirred at 45°-50° C. for 75 minutes. The resulting slurry was cooled to 10° C. and the solid was collected on a filter under nitrogen. The solid was rinsed with n-propyl acetate and dried at 0.1 mm to afford 70.3 parts of N-acetoacetyl-L-aspartic anhydride.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([NH2:7])=[N:4][CH:3]=1.[C:8]1([CH:14]([C:20](OCC)=[O:21])[C:15](OCC)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.N12CCCN=C1CCCCC2>CN(C=O)C>[CH3:1][C:2]1[N:6]=[C:5]2[N:7]=[C:20]([OH:21])[C:14]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[C:15]([OH:16])[N:4]2[CH:3]=1
Reactant: Cc1cnc(N)[nH]1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cn2c(O)c(-c3ccccc3)c(O)nc2n1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
18 g (135 mmol) 5-Methyl-1H-imidazol-2-ylamine are dissolved in 155 mL DMF and 31.8 g (135 mmol) diethyl phenylmalonate are added. After dropwise addition of 61.5 g (404 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene the reaction mixture is stirred at 100° C. for 16 h. The DMF has been removed and the darkbrown oily residue treated with 150 mL water (complete dissolution). 2M HCl (250 mL) is added at room temperature until a pH of 1. After stirring for 1 h at ice bath cooling the formed crystals are collected by filtration to yield the product (10.2 g=31%), which is used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]2[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[C:10]3[S:16][CH:17]=[CH:18][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:28][C:29]1[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:30]=1[C:31](Cl)=[O:32]>C(Cl)Cl>[O:15]=[C:11]1[CH2:12][CH2:13][CH2:14][N:8]([C:6]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:31](=[O:32])[C:30]3[CH:34]=[CH:35][CH:36]=[C:37]([F:38])[C:29]=3[CH3:28])=[CH:20][CH:19]=2)=[O:7])[C:9]2[CH:18]=[CH:17][S:16][C:10]1=2
Reactant: Cc1c(F)cccc1C(=O)Cl
Reactant: Nc1ccc(C(=O)N2CCCC(=O)c3sccc32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(F)cccc1C(=O)Nc1ccc(C(=O)N2CCCC(=O)c3sccc32)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 72 %

Procedure:
To a mixture of 287 mg of 4,5,6,7-tetrahydro-4-(4-aminobenzoyl)-8H-thieno[3,2-b]azepin-8-one in 3 ml of methylene chloride is added 209 μl of triethylamine which is cooled to 0° C. is added 207.1 mg of 2-methyl-3-fluorobenzoyl chloride. The cooling bath is removed and the reaction mixture stirred at room temperature under argon for 18 hours. An additional 50 ml of methylene chloride and 20 ml of water is added and the separated organic layer washed with 2N citric acid, 1M NaHCO3 and brine. The organic layer is dried with Na2SO4 and passed through a short pad of hydrous magnesium silicate and the filtrate evaporated in vacuo to a white foam which is crystallized from ethyl acetate-hexane to give 305 mg of the desired product as a white solid, 200°-202° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.COB(OC)OC>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11]([N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: C1CCNC1
Agent: COB(OC)OC
Solvent: CC#N
Product: COc1c(N2CCCC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 25 °C
Yield: 88.1 %

Procedure:
A mixture of 2.95 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (10 mmol), 1.42 g of pyrrolidine (20 mmol), 1.04 g of trimethoxyborane (10 mmol) and 20 ml of acetonitrile was refluxed with heating for 3.5 hours. The reaction solution was cooled to room temperature, acetonitrile was distilled under vacuum and 15 ml of ethanol was added into the resultant product. Separated crystals were filtered and dried to obtain 3.05 g of the objective compound (88.2%).
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1)([CH3:5])[CH2:3][OH:4].O.[CH3:14][N:15](C=O)C>>[CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([C:14]#[N:15])=[CH:8][CH:7]=1)([CH3:5])[CH2:3][OH:4]
Reactant: CN(C)C=O
Reactant: CC(C)(CO)c1ccc(Br)cc1
Solvent: O
Product: CC(C)(CO)c1ccc(C#N)cc1
Temperature: 25 °C

Procedure:
p-(1,1-Dimethyl-2-hydroxyethyl)bromobenzene, 148 g, 0.646 mole, was added to a 1 L flask fitted with a reflux condenser, magnetic stirrer and oil bath. Dimethylformamide, 350 mL, and cuprous cyanide, 69.4 g, 0.775 mole were then added to the flask. The heterogeneous mixture was heated to gentle reflux whereupon it became somewhat more homogeneous and would then easily stir. The mixture was heated at reflux for five hours. While still hot the mixture was cast into 1 L of water using 100 mL of hot DMF for washing out the flask. The precipitated residue was stirred by hand as well as possible, allowed to settle and the greater portion of the water decanted and discarded. A freshly prepared solution of ferric chloride, 340 g; conc. HCl, 85 mL; water, 510 mL was added to the residue to destroy copper complexes. The mixture was heated with good stirring at 60° to 70° C. for 20 to 30 minutes. The crude nitrile was then extracted with three 200 mL portions of benzene. The benzene extracts were combined and dried over anhydrous K2CO3 for 1/2 hour. Benzene was removed in a rotoevaporator to give a yellowish oil which crystallized easily when cooled to room temperature and scratched. The yield was about 102 g (90%), mp=70°-82° C.
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[O:17][CH2:16][C:15]3[N:18]=[CH:19][CH:20]=[CH:21][C:14]=3[C:13](=[CH:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][C:28]([C:32]4[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=4)([OH:31])[CH2:27][CH2:26]3)[C:12]=2[CH:39]=1)(=O)C.[OH-].O.C(OCC)(=O)C>C(O)C>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([C:28]2([OH:31])[CH2:27][CH2:26][N:25]([CH2:24][CH2:23][CH:22]=[C:13]3[C:12]4[CH:39]=[C:8]([O:7][CH2:6][CH2:5][OH:4])[CH:9]=[CH:10][C:11]=4[O:17][CH2:16][C:15]4[N:18]=[CH:19][CH:20]=[CH:21][C:14]3=4)[CH2:30][CH2:29]2)=[CH:33][CH:34]=1
Reactant: CC(=O)OCCOc1ccc2c(c1)C(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1CO2
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: OCCOc1ccc2c(c1)C(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1CO2
Yield: 92.8 %

Procedure:
To a solution of 1-[3-(7-(2-acetoxyethyl)oxy-5,11-pyrido[2,3-c][1]benzoxepin-5-ylidene)propyl]-4-(4-chlorophenyl)piperidin-4-ol (Example 50) (140 mg) in ethanol (5 ml) were added 15% sodiun hydroxide aqueous solution (2 ml) and the mixture was heated to reflux for 1 hour. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with methylene chloride-methanol (10:1) to give the titled compound (120 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:15])[CH3:14])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].CC(C)([O-])C.[K+].[C:22](OCC)(=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24].[Cl-].[NH4+]>C1COCC1>[OH:15][C:13]([C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)=[CH:14][C:22](=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Reactant: CCOC(=O)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)C=C(O)c1cc(OC)c(OC)c(OC)c1

Procedure:
3′,4′,5′-Trimethoxyacetophenone (12.0 g) was dissolved in THF (50 mL), and potassium tert-butoxide (8.16 g) was added to the solution at 0° C. A THF solution (20 mL) of diethyl oxalate (11.4 g) was then added dropwise to the mixture, and the resultant mixture was stirred for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the resultant mixture was extracted with ethyl acetate. The resultant organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant crude crystals were recrystallized from chloroform-hexane to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[N+:7]([O-])=[CH:6][C:5]([CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:18]([CH3:19])=[CH:17][C:16]([C:20]3[N:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[O:22][N:21]=3)=[CH:15][C:14]=2[CH3:29])=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:32].C(N(CC)CC)C>C(Cl)Cl>[Cl:32][CH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:18]([CH3:19])=[CH:17][C:16]([C:20]3[N:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[O:22][N:21]=3)=[CH:15][C:14]=2[CH3:29])=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(-c2noc(C(F)(F)F)n2)cc(C)c1OCCCc1ccc(C)[n+]([O-])c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(-c2noc(C(F)(F)F)n2)cc(C)c1OCCCc1ccc(CCl)nc1
Reaction time: 0.5 h
Yield: 31 %

Procedure:
To a solution of 1.8 g (4.4 mmol) of 6-methyl-3-[3-[4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]-propyl]-pyridine-N-oxide in 18 ml of methylene chloride was added dropwise a solution of 0.41 ml (1.13 eq) POCl3 in 4 ml of methylene chloride. After addition of 10% of POCl3 solution, triethylamine (0.54 ml; 1.1 eq) in 4 ml of methylene chloride was added portions. The exothermic mixture was stirred for 30 min, washed with saturated ammonium chloride solution, and the organic layer was separated and dried over sodium sulfate. The organic layer was concentrated in vacuo and purified by flash filtration through silica gel (hexane/ether, 2:1) to afford 0.59 g (31%) of 6-chloromethyl-3-[3-[4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethyl-phenoxy]-propyl]-pyridine (BIL-1991-187), as a pale yellow oil which solidified upon standing, m.p. 79°-81° C.
Reaction SMILES: Br[C:2]1[N:6]=[CH:5][N:4]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1.[CH2:21]([SH:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C([O-])([O-])=O.[K+].[K+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C(OCC)(=O)C.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(C)=CC=CC=1>[CH2:21]([S:27][C:2]1[N:6]=[CH:5][N:4]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCS
Reactant: C[Si](C)(C)CCOCn1cnc(Br)c1-c1cccnc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: CCCCCCSc1ncn(COCC[Si](C)(C)C)c1-c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 18 %

Procedure:
To a degassed solution of xylene (30 ml) containing compound 73 (0.6 g, 1.70 mmol), were added 1.25 eq (0.30 ml) of hexane-1-thiol and 1.25 eq of K2CO3 (0.29 g). The resulting mixture was stirred for another 2 hours under N2. Successively were added 10 mol % of Pd2(dba)3 (160 mg) and 20 mol % of Xantphos (200 mg). After the addition, the resulting solution was stirred for 18 hours at 130° C. under N2. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with a saturated NaHCO3 solution, dried (Na2SO4), filtered and concentrated. The resulting residue was purified by flash chromatography (diethyl ether) to afford 3-[5-hexylsulfanyl-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazol-4-yl]-pyridine (74B) as an oil (120 mg, 18%) and starting material (73, 380 mg), 1H-NMR (400 MHz, CDCl3): δ 9.38 (d, J=2 Hz, 1H), 8.53 (dd, J=5 Hz, 2 Hz, 1H), 8.42 (dt, J=8 Hz, 2 Hz, 1H), 7.82 (s, 1H), 7.35-7.30 (m, 1H), 5.43 (s, 2H), 3.59-3.54 (m, 2H), 2.66 (t, J=7 Hz, 2H), 1.46-1.37 (m, 2H), 1.28-1.06 (m, 8H), 0.96-0.89 (m, 2H), 0.80 (t, J=7 Hz, 3H), 0.0 (s, 9H).
Reaction SMILES: Br[N:2]1[C:6]2=[N:7][C:8]([CH3:11])=[CH:9][CH:10]=[C:5]2[NH:4][CH:3]1[CH2:12][CH2:13][CH2:14][CH3:15].[CH:16](OB(O)O)=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:12]([C:3]1[NH:4][C:5]2[C:6]([N:2]=1)=[N:7][C:8]([CH3:11])=[C:9]([CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:10]=2)[CH2:13][CH2:14][CH3:15]
Reactant: OB(O)OC=Cc1ccccc1
Reactant: CCCCC1Nc2ccc(C)nc2N1Br
Product: CCCCc1nc2nc(C)c(C=Cc3ccccc3)cc2[nH]1
Yield: 103.2 %

Procedure:
The same procedure as in step 8 of Example 1 was repeated using 4.0 g(0.0133 mole) of the compound obtained in step 4 of Example 1 and 3.0 g(0.0203 mole) of styrylboric acid to obtain 4.0 g of the title compound(yield 93%).
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]([CH3:10])[CH3:9])=[O:7])=[CH:4][N:3]=1.CN(C=O)C.[N-:18]=[N+:19]=[N-:20].[Na+]>O>[N:18]([C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]([CH3:10])[CH3:9])=[O:7])=[CH:4][N:3]=1)=[N+:19]=[N-:20]
Reactant: CN(C)C(=O)c1ccc(Cl)nc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc(N=[N+]=[N-])nc1
Temperature: 120 °C
Reaction time: 60 h
Yield: 26.4 %

Procedure:
In a 500 mL round-bottomed flask, 6-chloro-N,N-dimethylnicotinamide (8.15 g, 44.1 mmol) was combined with DMF (50.0 ml) to give a brown solution. Sodium azide (3.44 g, 53.0 mmol) was added and the reaction mixture was heated to 120° C. and stirred for 60 h. The reaction mixture was diluted with 100 mL H2O and extracted with EtOAc (2×200 mL). The organic layers were combined, washed with H2O (1×50 mL), sat NaCl (1×100 mL), dried over Na2SO4 and concentrated in vacuo to a yellow oil. MeOH was added and the entire mixture solidified upon concentration. The crude product was dried under vacuum overnight. The pasty solid was recrystallized from EtOAc/Hex. The solid was filtered and washed with a minimal amount of hexane. The white powder was dried under vacuum at 45° C. for 3 hrs to give 2.23 g (26%) of the title compound. 1H NMR (300 MHz, CHLOROFORM-d) δ: 8.95 (s, 1H), 8.09 (d, J=9.1 Hz, 1H), 7.75 (dd, J=9.1, 1.5 Hz, 1H), 3.15 (br. s., 6H).
Reaction SMILES: [Li]CCCC.[CH3:6][C:7]1[C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][C:11]=2[CH:10]=[CH:9][CH:8]=1.Br[CH2:21][CH2:22][CH:23]1[O:27][CH2:26][CH2:25][O:24]1.CCOC(C)=O>C1COCC1.CCCCCC>[CH3:6][C:7]1[C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]([CH2:21][CH2:22][CH:23]3[O:27][CH2:26][CH2:25][O:24]3)[C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: Cc1cccc2c1-c1ccccc1C2
Reactant: BrCCC1OCCO1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cccc2c1-c1ccccc1C2CCC1OCCO1
Temperature: 25 °C
Yield: 80.2 %

Procedure:
A solution of BuLi (2.5 M in hexane, 20.4 mL, 51.0 mmol) was slowly added into a cooled (-78° C.) solution of 4-methylfluorene (prepared according to Example 10; 9.0 g, 49.8 mmol) in 100 mL of THF. After 30 minutes 2-(2-bromoethyl)-1,3-dioxolane (18.9 g, 105.0 mmol) was added to the cold solution and the solution was warmed up to room temperature. The reaction mixture was stirred for weekend at room temperature. TLC (silica, 25% EtOAc in hexane) was used to monitor the reaction. The reaction was quenched with water and the product was extracted into EtOAc. The organic layer was washed with water (×3), dried over magnesium sulfate and evaporated. Short path chromatography (5% ethyl acetate/hexane) afforded 11.2 g(82.8%) of the product.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:22])=[CH:8][C:9]=2[NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)(=[O:14])=[O:13])[S:4][C:3]=1[CH3:23].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[N:27]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O1CCOCC1.O.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>[Cl:21][C:17]1[CH:16]=[C:15]([S:12]([NH:11][C:9]2[CH:8]=[C:7]([CH3:22])[N:6]=[C:5]3[S:4][C:3]([CH3:23])=[C:2]([C:28]4[CH:29]=[CH:30][CH:31]=[C:26]([O:25][CH3:24])[N:27]=4)[C:10]=23)(=[O:14])=[O:13])[CH:20]=[CH:19][CH:18]=1
Reactant: COc1cccc(B2OC(C)(C)C(C)(C)O2)n1
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(Br)c(C)sc2n1
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: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cccc(-c2c(C)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)n1
Temperature: 120 °C
Yield: 12.8 %

Procedure:
Under nitrogen, N-(3-bromo-2,6-dimethylthieno[2,3-b]pyridin-4-yl)-3-chlorobenzenesulfonamide (Example 61) (65 mg, 0.151 mmol) was dissolved in 1,4-dioxane (1.5 mL) and water (0.7 mL). 2-(Methyloxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (53.1 mg, 0.226 mmol), tetrakis(triphenylphosphine)palladium(0) (17.40 mg, 0.015 mmol) and potassium carbonate (62.4 mg, 0.452 mmol) were then added and the mixture heated in a microwave at 120° C. for 15 min (×2). Ethyl acetate (10 mL) was added and the mixture washed with water (2×5 mL). The organic layer was dried over MgSO4, filtered and the solvent removed in vacuo. The residue was purified by normal phase chromatography, eluting with a gradient of 0-30% ethyl acetate in cyclohexane, and then further purified by MDAP (acidic conditions), to give the title compound (8.9 mg). LCMS (A) m/z: 460 [M+1]+, Rt 1.45 min (acidic).
Reaction SMILES: [NH2:1][C:2]([CH3:9])([CH:6]([CH3:8])[CH3:7])[C:3]([NH2:5])=[O:4].[Cl:10][C:11]1[C:15]2=[N:16][C:17]3[C:23](=[O:24])[O:22][C:20](=[O:21])[C:18]=3[CH:19]=[C:14]2[S:13][CH:12]=1>C1COCC1>[C:3]([C:2]([NH:1][C:23]([C:17]1[N:16]=[C:15]2[C:11]([Cl:10])=[CH:12][S:13][C:14]2=[CH:19][C:18]=1[C:20]([OH:22])=[O:21])=[O:24])([CH3:9])[CH:6]([CH3:8])[CH3:7])(=[O:4])[NH2:5]
Reactant: O=C1OC(=O)c2nc3c(Cl)csc3cc21
Reactant: CC(C)C(C)(N)C(N)=O
Solvent: C1CCOC1
Product: CC(C)C(C)(NC(=O)c1nc2c(Cl)csc2cc1C(=O)O)C(N)=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 75.6 %

Procedure:
2-Amino-2,3-dimethylbutyramide (0.71 g) all in one portion is added to a stirred solution of 3-chlorothieno[3,2-b]pyridine-5,6-dicarboxylic acid anhydride, (1.2 g) in THF (1.0 mL). After standing for five minutes, the ice bath is removed and the reaction stirred at room temperature for 28 hours. THF (5 mL) is added and the mixture heated at reflux for two hours and then set aside overnight. The cooled mixture is filtered and the collected solid washed with ether to give 1.4 g of the desired 5-[(1-carbamoyl-1,2-dimethylpropyl)carbamoyl]3-chlorothieno[3,2-b]pyridine-6-carboxylic acid.