Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.I[CH2:10][C:11](=[CH2:21])[CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].C([O-])([O-])=O.[K+].[K+]>>[C:17]([Si:14]([O:13][CH2:12][C:11]([CH2:21][O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1)=[CH2:10])([CH3:15])[CH3:16])([CH3:19])([CH3:20])[CH3:18]
Reactant: Oc1ccc(I)cc1
Reactant: C=C(CI)CO[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=C(COc1ccc(I)cc1)CO[Si](C)(C)C(C)(C)C
Yield: 94 %

Procedure:
Alkylation of 4-iodophenol with iodide 165 (see Example 2GGG) and K2CO3 as in Example 2GGG above for 6 h, followed by chromatography of the product on silica gel, eluting with petroleum ether (foreruns) and then with 5% CH2Cl2/petroleum ether, gave tert-butyl({2-[(4-iodophenoxy)methyl]-2-propenyl}oxy)dimethylsilane (167) (94%) as an oil; 1H NMR (CDCl3) δ 7.54 (dt, J=8.9, 2.7 Hz, 2H), 6.70 (dt, J=8.9, 2.7 Hz, 2H), 5.25 (d, J=1.0 Hz, 1H), 5.19 (d, J=1.2 Hz, 1H), 4.51 (s, 2H), 4.23 (s, 2H), 0.91 (s, 9H), 0.07 (2 s, 6H); HRFABMS calcd for C16H26H26Si m/z [M+H]+ 405.0747. found 405.0739.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([O:16][CH2:17][CH3:18])[CH2:5][C:6]1[C:14]2[CH:13]=[CH:12][S:11][C:10]=2[C:9]([OH:15])=[CH:8][CH:7]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:28][C:29]([CH3:35])=[C:30]([CH2:32][CH2:33]O)[N:31]=2)=[CH:23][CH:22]=1.ClC1C=CC(C=O)=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([O:16][CH2:17][CH3:18])[CH2:5][C:6]1[C:14]2[CH:13]=[CH:12][S:11][C:10]=2[C:9]([O:15][CH2:33][CH2:32][C:30]2[N:31]=[C:27]([C:24]3[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=3)[O:28][C:29]=2[CH3:35])=[CH:8][CH:7]=1
Reactant: Cc1oc(-c2ccc(Cl)cc2)nc1CCO
Reactant: CCOC(Cc1ccc(O)c2sccc12)C(=O)OC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=Cc1ccc(Cl)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(Cc1ccc(OCCc2nc(-c3ccc(Cl)cc3)oc2C)c2sccc12)C(=O)OC

Procedure:
In analogy to the procedure described in example 17 a], [rac]-2-ethoxy-3-(7-hydroxy-benzo[b]thiophen-4-yl)-propionic acid methyl ester (example 151 a]) was reacted with 2-[2-(4-chloro-phenyl)-5-methyl-oxazol-4-yl]-ethanol (prepared by conversion of the 4-chloro-benzaldehyde into 2-[2-(4-chloro-phenyl)-5-methyl-oxazol-4-yl]-ethanol in analogy to the sequence described in examples 21 a] to 21 e]) in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-3-(7-{2-[2-(4-chloro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-benzo[b]thiophen-4-yl)-2-ethoxy-propionic acid methyl ester, which was further saponified in analogy to the procedure described in example 91 e] to yield [rac]-3-(7-{2-[2-(4-chloro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-benzo[b]thiophen-4-yl)-2-ethoxy-propionic acid as colorless oil.
Reaction SMILES: Cl[C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[N+:9]([C:3]1[C:2]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5])([O-:11])=[O:10]
Reactant: Nc1cccc(Cl)c1[N+](=O)[O-]
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1cccc(N2CCCCC2)c1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
To a solution of 3-chloro-2-nitroaniline (CXXI) (2.00 g, 11.6 mmol, 1 eq) and piperidine (2.95 g, 34.7 mmol, 3 eq) in DMF (60 ml) was added K2CO3 (4.78 g, 34.4 mmol, 3 eq) in one portion and the mixture was stirred at 120° C. under nitrogen overnight. The reaction mixture was diluted with ethyl acetate (60 ml) and washed with saturated NaHCO3 solution (50 mL). The organic phases were dried over Na2SO4 and concentrated in vacuo, the resultant residue was purified by silica gel column chromatography (PE:EtOAc=5:1→1:1) to give 2-nitro-3-(piperidin-1-yl)aniline (CXXII) (1.8 g, 8.14 mmol, 70.3% yield) as a black solid. ESIMS found for C11H15N3O2 m/z 222 (M+H).
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[H-].[Na+].[F:8][C:9]1[CH:10]=[C:11]([CH:24]2[C:33]([CH3:35])([CH3:34])[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[C:29]([C:36](O)=[O:37])[CH:30]=3)[NH:25]2)[CH:12]=[C:13]([N:15]2[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]2)[CH:14]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[F:8][C:9]1[CH:10]=[C:11]([CH:24]2[C:33]([CH3:35])([CH3:34])[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[C:29]([C:36]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:37])[CH:30]=3)[NH:25]2)[CH:12]=[C:13]([N:15]2[CH2:16][CH2:17][N:18]([CH:21]([CH3:22])[CH3:23])[CH2:19][CH2:20]2)[CH:14]=1
Reactant: CC(C)N1CCN(c2cc(F)cc(C3Nc4ccc(C(=O)O)cc4CC3(C)C)c2)CC1
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1CCN(c2cc(F)cc(C3Nc4ccc(C(=O)NS(C)(=O)=O)cc4CC3(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.2 %

Procedure:
To a suspension of methanesulfonic acid amide (266 mg, 2.8 mmol) in N,N-dimethylformamide (3 mL) was added sodium hydride (112 mg, 2.8 mmol). The resulting mixture was stirred at 25° C. for 1 h. A solution of 2-[3-fluoro-5-(4-isopropyl-piperazin-1-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (120 mg, 0.28 mmol), and 1,1′-carbonyldiimidazole (91.5 mg, 0.56 mmol) in N,N-dimethylformamide (2 mL) was stirred at 70° C. for 1 h. The above suspension of methanesulfonic acid amide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-{2-[3-Fluoro-5-(4-isopropyl-piperazin-1-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl}methanesulfonamide (20 mg, 14%) as a white solid: LC/MS m/e calcd for C26H35FN4O3S (M+H)+: 503.7, observed: 503.3.
Reaction SMILES: C([C:4]1[CH:5]=[C:6]([O:12][CH3:13])[C:7]([F:11])=[C:8]([F:10])[CH:9]=1)C=C.[C:14]([OH:17])(=[O:16])[CH3:15].O=[O+][O-].O=O>C(OCC)(=O)C.O>[F:10][C:8]1[CH:9]=[C:4]([CH2:15][C:14]([OH:17])=[O:16])[CH:5]=[C:6]([O:12][CH3:13])[C:7]=1[F:11]
Reactant: CC(=O)O
Reactant: C=CCc1cc(F)c(F)c(OC)c1
Agent: O=O
Agent: O=[O+][O-]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(CC(=O)O)cc(F)c1F
Temperature: 50 °C

Procedure:
1.59 g of 5-allyl-1,2-difluoro-3-methoxybenzene (C2) are dissolved in 5.25 ml of ethyl acetate and 19.75 ml of glacial acetic acid and cooled to 0° C. in an ice bath. The solution is subsequently treated with ozone for 15 min (ozone generator: oxygen flow rate 40 l/h—corresponds to 5 g/h of O3). The mixture is subsequently diluted with 12 ml of water and warmed at 50° C. for a further 15 min. The reaction solution is then evaporated in vacuo, and the residue remaining is dissolved in 50 ml of tetrahydrofuran. 420 μl of H2O2 (30% solution) and 163 mg of phenylselenic acid are added. The reaction solution is subsequently heated under reflux for 2 h and, when the reaction is complete, evaporated to dryness in vacuo. The residue is purified by flash column chromatography on silica gel (solvent gradient: dichloromethane/0-40% by vol. of methanol), giving 806 mg of the title compound as a colourless oil; MS: 203.1 (MH+); TLC: Rf=0.40 (cyclohexane/ethyl acetate 9:1).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=2)[C:24](=[O:38])[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:33]([C:32]2[CH:31]=[CH:30][C:29]([CH2:28][N:25]3[CH2:26][CH2:27][N:22]([C:20]([O:19][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:21])[CH2:23][C:24]3=[O:38])=[CH:37][CH:36]=2)=[O:34])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C(=O)O)cc2)C(=O)C1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)cc2)C(=O)C1

Procedure:
500 mg of methyl 4-(bromomethyl)benzoate was reacted with 480 mg of tert-butyl 3-oxopiperazine-1-carboxylate and 1 g of Cesium Carbonate in 9 mL of DMF at 45° C. Upon completion, the reaction was extracted in Ethyl Acetate 2 times saturated bicarbonate, dried over Magnesium Sulfate, filtered and concentrated to give tert-butyl 4-(4-(methoxycarbonyl)benzyl)-3-oxopiperazine-1-carboxylate. 613 mg of tert-butyl 4-(4-(methoxycarbonyl)benzyl)-3-oxopiperazine-1-carboxylate was hydrolyzed via Procedure M to give 4-((4-(tert-butoxycarbonyl)-2-oxopiperazin-1-yl)methyl)benzoic acid. 200 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-((4-(tert-butoxycarbonyl)-2-oxopiperazin-1-yl)methyl)benzoic acid via Procedure G. The crude product was extracted twice with saturated bicarbonate in Ethyl Acetate, dried over Magnesium Sulfate, filtered and concentrated to give crude tert-butyl 4-(4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzyl)-3-oxopiperazine-1-carboxylate. 4N HCl was subsequently added to crude tert-butyl 4-(4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzyl)-3-oxopiperazine-1-carboxylate and concentrated to give the HCl salt of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((2-oxopiperazin-1-yl)methyl)benzamide. The reaction was purified by reverse phase HPLC to give pure N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((2-oxopiperazin-1-yl)methyl)benzamide. MS (Q1) 421.3 (M)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]#[C:7][CH2:8][S:9][CH2:10][CH2:11][OH:12].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(OCC)C>[CH3:20][S:21]([O:12][CH2:11][CH2:10][S:9][CH2:8][C:7]#[C:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: OCCSCC#Cc1cccs1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCSCC#Cc1cccs1
Reaction time: 0.5 h

Procedure:
A solution of 1.28 g of 9c and 1.5 ml of triethyl amine in 10 ml of diethyl ether was treated at 0° C. with 0.78 g of methanesulphonyl chloride in 5 ml of diethyl ether. The reaction mixture was stirred for ½ h and then quenched by addition of 20 ml of water. The product was extracted into ethyl acetate and the combined extracts were washed once with 1M K2CO3 and once with water, dried and concentrated, to provide 1.7 g as essentially pure 9d and was used without further purification in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH2:9][S:10][CH3:11])[CH:6]=[CH:5][C:3]=1[NH2:4].O[CH2:13][CH:14]([CH2:16]O)O>>[CH3:11][S:10][CH2:9][C:7]1[CH:6]=[C:5]2[C:3](=[C:2]([Br:1])[CH:8]=1)[N:4]=[CH:16][CH:14]=[CH:13]2
Reactant: OCC(O)CO
Reactant: CSCc1ccc(N)c(Br)c1
Product: CSCc1cc(Br)c2ncccc2c1

Procedure:
2-bromo-4-(methylthiomethyl)aniline and glycerol can be combined to form 6-(methylthiomethyl)-8-bromoquinoline, and
Reaction SMILES: [CH:1]1([N:7]([C@@H:19]2[CH2:23][CH2:22][N:21]([C:24]([C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[O:25])[CH2:20]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16][C:17]#N)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.SC[C@@H]([C@@H](CS)O)O.CI>>[CH:1]1([N:7]([C@@H:19]2[CH2:23][CH2:22][N:21]([C:24]([C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[O:25])[CH2:20]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16][CH3:17])=[CH:14][N:15]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: N#CSc1cnc(NC(=O)N(C2CCCCC2)[C@@H]2CCN(C(=O)c3cccs3)C2)s1
Agent: O[C@H](CS)[C@@H](O)CS
Solvent: CI
Product: CSc1cnc(NC(=O)N(C2CCCCC2)[C@@H]2CCN(C(=O)c3cccs3)C2)s1

Procedure:
Prepared as described in general procedure (H) using 1-cyclohexyl-3-(5-thiocyanato-thiazol-2-yl)-1-[1-(thiophene-2-carbonyl)-pyrrolidin-3 (R)-yl]-urea, dithioerythritol and methyliodide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19]=[CH:20][S:21](Cl)(=[O:23])=[O:22]>N1C=CC=CC=1>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19]=[CH:20][S:21]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:9])=[O:10])(=[O:23])=[O:22]
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: O=S(=O)(Cl)C=Cc1ccccc1Cl
Solvent: c1ccncc1
Product: NS(=O)(=O)c1ccccc1NS(=O)(=O)C=Cc1ccccc1Cl
Reaction time: 0.5 h
Yield: 36.2 %

Procedure:
2-Aminobenzene sulfonamide (153 mg, 0.89 mmol) was added in one portion to a solution of 2-(2-chloro-phenyl)-ethenesulfonyl chloride (150 mg, 0.63 mmol) in pyridine (2 mL) at RT. After 30 minutes of stirring, no more starting material was detected by tlc. The reaction mixture was concentrated under reduced pressure and the residue was taken up in ethyl acetate and a small amount of methanol. The organic phase was washed with 1N HCl, saturated sodium bicarbonate, dried over MgSO4, and concentrated under reduced pressure. Purification by preparative tlc afforded the target compound, which was then recrystallized from ethyl acetate/pentane/diethyl ether to afford the title compound (85 mg, 36%) as a white solid.
Reaction SMILES: [C:1]([CH:4]([NH2:12])[CH2:5][CH2:6][S:7]([CH2:10][CH3:11])(=O)=O)([OH:3])=[O:2].C(C(N)CCCSC)(O)=O>>[C:1]([CH:4]([NH2:12])[CH2:5][CH2:6][S:7][CH2:10][CH3:11])([OH:3])=[O:2]
Reactant: CCS(=O)(=O)CCC(N)C(=O)O
Agent: CSCCCC(N)C(=O)O
Product: CCSCCC(N)C(=O)O

Procedure:
1-carboxy-3-ethylsulfonyl-propylamine; 1-carboxy-4-methylthiobutyl amine;
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1.[CH2:12]1[C:16]2([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:15][CH2:14][N:13]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].CCN(C(C)C)C(C)C>C(O)(C)C>[F:9][C:8]([F:11])([F:10])[C:4]1[N:3]=[C:2]([N:19]2[CH2:20][CH2:21][C:16]3([CH2:12][N:13]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:14][CH2:15]3)[CH2:17][CH2:18]2)[CH:7]=[CH:6][N:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Reactant: FC(F)(F)c1nccc(Cl)n1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC2(CCN(c3ccnc(C(F)(F)F)n3)CC2)C1
Yield: 47 %

Procedure:
4-Chloro-2-(trifluoromethyl)pyrimidine (2.72 mmol, 1 eq.) and isopropanol (4 ml) were introduced into a microwave vessel. tert-Butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (2.72 mmol, 1 eq.) and DIPEA (0.6 ml, 6.8 mmol), 2.5 eq.) were added in succession and the reaction mixture was introduced into a microwave oven at 75° C. for 45 min. After TLC control, the reaction mixture was concentrated on a rotary evaporator. A reddish liquid remained and was diluted with methylene chloride (200 ml). The organic phase was washed with water (2×100 ml) and sat. NaCl solution (50 ml), dried over sodium sulfate and concentrated. The brown liquid residue was purified by column chromatography (silica gel, ethyl acetate). Yield: 47%
Reaction SMILES: [N+:1](=[C:3]([C:14]([CH3:16])=[O:15])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5])=[N-:2].C(N(CC)CC)C.[Si:24](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25].[I-].[Na+]>C(#N)C.C(Cl)Cl>[N+:1](=[C:3]([C:14]([O:15][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])=[CH2:16])[C:4]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:5])=[N-:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(=O)C(=[N+]=[N-])C(=O)OCc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: ClCCl
Product: C=C(O[Si](C)(C)C(C)(C)C)C(=[N+]=[N-])C(=O)OCc1ccccc1
Temperature: 40 °C
Reaction time: 4 h
Yield: 93.4 %

Procedure:
To 1.5 ml of dry acetonitrile were added 83 mg (0.380 millimole) of benzyl 2-diazoacetoacetate, 130 μl (0.933 millimole) of triethylamine and 140 mg (0.929 millimole) of tert-butyldimethylsilyl chloride. A solution obtained by dissolving 70 mg (0.467 millimole) of sodium iodide in 0.5 ml of dry acetonitrile was added dropwise thereto at a room temperature. After the conclusion of the dropwise addition, the reaction mixture was further agitated at 40° C. for 4 hours. To the reaction mixture was added 30 ml of methylene chloride, and the resultant was washed twice with 10 ml portions of water. The organic layer was dried over anhydrous sodium sulfate and concentrated under a reduced pressure to give 118 mg (yield 93.7 %) of the desired compound in a yellow solid. 1H NMR (90 MHz, CDCl3) 4 (ppm): 0.28 (6H, s), 0.97 (9H, s), 4.24 (1H, d), 5.03 (1H, d), 5.21 (2H, s), 7.31 (5H, s).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH:25]=O>[OH-].[K+].CCO>[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH:25]=[C:14]1[CH2:13][CH2:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([O:8][CH2:7][CH2:6][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)[CH:10]=2)[C:15]1=[O:19]
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Reactant: O=Cc1ccco1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C(=Cc2ccco2)CCc2cc(OCCn3ccnc3)ccc21
Yield: 67.1 %

Procedure:
According to the method of Example 6, 6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.250 g, 0.98 mmol) was reacted with 2-furaldehyde (0.151 g, 1.57 mmol) in 3.0 mL of 4% KOH in EtOH for 15 hours at room temperature to afford 0.220 g (67%) of the title compound as a light tan solid, mp 109-110° C.: CI-MS m/e 334 (M+), 335 (M+ +1);
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11]O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[BrH:13].C(OCC)C>C(O)(=O)C>[BrH:13].[Br:13][CH2:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[CH:1]=[N:2][CH:3]=[CH:4]2
Reactant: OCc1ccc2cnccc2c1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: BrCc1ccc2cnccc2c1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
A solution of 190 mg (1.19 mmol) of 6-isoquinoline-methanol in 1 ml of glacial acetic acid was treated with 2 ml of 30% HBr in glacial acetic acid and the mixture was heated at 70° C. for 45 minutes. The reaction mixture was cooled, treated with 20 ml of diethyl ether and stirred at 0° C. for 30 min. The resulting solid was filtered off, washed with diethyl ether and dried in a high vacuum. There was obtained 6-bromomethyl-isoquinoline hydrobromide (73% of theory) as a light brown solid; MS: 221, 223 (M)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH3:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([CH:18]=[C:19]([C:21]3[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=3)[N:20]=2)[CH:17]=1.C(N(C(C)C)CC)(C)C.CCOC(C)=O>S(Cl)(Cl)=O.C1COCC1>[F:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:25][C:24]2[CH:23]=[CH:22][C:21]([C:19]3[N:20]=[C:15]4[CH:14]=[CH:13][C:12]([CH3:11])=[CH:17][N:16]4[CH:18]=3)=[CH:27][CH:26]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: Cc1ccc2nc(-c3ccc(N)cc3)cn2c1
Reactant: O=C(O)c1ccc(F)nc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2nc(-c3ccc(NC(=O)c4ccc(F)nc4)cc3)cn2c1
Yield: 60 %

Procedure:
A stirred suspension of 6-fluoronicotinic acid (80 mg, 0.414 mmol) in thionyl chloride (2 ml) was heated under reflux for 4 h. The excess reagent was then removed under reduced pressure to give a crude solid. The amide was prepared as described in the Amide Coupling section using the crude solid and 4-(6-methylimidazo[1,2-a]pyridin-2-yl)aniline (92 mg, 0.414 mmol) in dry THF (13 ml) and diisopropylethylamine (106 μl, 0.608 mmol) to give the title compound (86 mg, 60%) as a colourless solid after work-up and flash chromatography (EtOAc).
Reaction SMILES: [ClH:1].N1C=CC=CC=1.[CH3:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:28]C)[CH:24]=3)[C:19]=2[C:30]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][N:41]3[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]3)=[CH:34][CH:33]=2)=[O:31])=[CH:14][CH:13]=1)(=[O:11])=[O:10]>>[ClH:1].[OH:28][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[C:19]([C:30]([C:32]1[CH:33]=[CH:34][C:35]([O:38][CH2:39][CH2:40][N:41]3[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]3)=[CH:36][CH:37]=1)=[O:31])=[C:18]([C:15]1[CH:14]=[CH:13][C:12]([S:9]([CH3:8])(=[O:11])=[O:10])=[CH:17][CH:16]=1)[CH:27]=[CH:26]2
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(S(C)(=O)=O)cc3)ccc2c1
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(-c2ccc3cc(O)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)cc2)cc1
Temperature: 200 °C
Yield: 69 %

Procedure:
Add pyridine hydrochloride (4.0 g) to the compound of Example 74 (100 mg, 0.18 mmol). Purge the vessel with nitrogen, cap it, and heat to 200° C. for 4 hours. Cool to room temperature and dilute with saturated aqueous NaHCO3. Extract with 25% isopropanol (i-PrOH) in CHCl3, dry over Na2SO4 and concentrate in vacuo. Purify using an SCX column (eluting with 2M NH3/MeOH) followed by flash chromatography (0-10% MeOH/CHCl3). Dissolve the product in 1:1 CH3CN/1M aqueous HCl and lyophilize to yield 70.3 mg of the title compound (68%). LCMS: m/z=530 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](=[NH:5])[NH2:4].O=[C:9]([CH3:15])[CH2:10][C:11](OC)=[O:12].C[O-].[Na+]>CO>[CH3:15][C:9]1[N:4]=[C:3]([C:2]([F:7])([F:6])[F:1])[NH:5][C:11](=[O:12])[CH:10]=1
Reactant: N=C(N)C(F)(F)F
Reactant: COC(=O)CC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(=O)[nH]c(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,2,2-trifluoroethanimidamide (3.02 g, 22.9 mmol) and 3-oxobutanoic acid, methyl ester (2.60 mL, 24.0 mmol) in methanol (25 mL) was added 25 wt % sodium methoxide (10.5 mL, 45.8 mmol). The reaction solution was stirred at room temperature overnight. The solvent was removed in vacuo and diluted with ethyl acetate and 5M HCl. The aqueous layer was extracted with ethyl acetate once. The organic solutions were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on a silica gel column to give the desired product as white solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[OH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][N:7]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O>[OH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:14])([F:13])[F:15])=[CH:8][N:7]=1.[Cl:3][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][N:7]=1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])[O-]
Agent: Oc1ccc(C(F)(F)F)cn1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(Cl)nc1
Temperature: 60 °C

Procedure:
30 g of thionyl chloride was added to 12 g of 2-hydroxy-5-trifluoromethylpyridine dissolved in 20 g of dimethylformamide. The 2-hydroxy-5-trifluoromethylpyridine was prepared as disclosed in Examples 4 and 5 of applicant's copending application earlier referred to and incorporated herein by reference. The solution was then heated to 60° C. for 24 hours, cooled to 20° C. and diluted with 200 cc of water and the pH adjusted to 5.5 with sodium carbonate. The acid solution was extracted three times with 100 cc of chloroform each time and the extracts washed three times with 20 cc of water each time. The chloroform solution was evaporated at reduced pressure to give 2-chloro-5-trifluoromethylpyridine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]([NH:11][C:12]2[CH:20]=[C:19]([C:21]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:22]=3[CH:23]=[CH:24][NH:25]4)[CH:18]=[C:17]3[C:13]=2[CH:14]=[N:15][NH:16]3)=[O:10])=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.CCN(C(C)C)C(C)C>CS(C)=O.CS(C)=O.CO>[Cl:1][C:2]1[C:3]([C:9]([NH:11][C:12]2[CH:20]=[C:19]([C:21]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:22]=3[CH:23]=[CH:24][NH:25]4)[CH:18]=[C:17]3[C:13]=2[CH:14]=[N:15][NH:16]3)=[O:10])=[N:4][C:5]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:6][CH:7]=1
Reactant: C1CCNCC1
Reactant: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1nc(Cl)ccc1Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1nc(N2CCCCC2)ccc1Cl
Temperature: 160 °C
Yield: 18.7 %

Procedure:
To a microwave vial was added 2 ml of a solution of 3,6-dichloro-N-[6-(1H-indol-4-yl)-1H-indazol-4-yl]-2-pyridinecarboxamide (306 mg, 0.71 mmol) in DMSO (6 ml). Piperidine (0.024 ml, 0.25 mmol) and DIPEA (0.129 ml) were added and the mixture was heated at 160° C. for 2 h under microwave irradiation. The crude reaction mixture was dissolved in DMSO/MeOH (1:1) and purified by Mass Directed Automated Preparative HPLC (Method E). The sample was further purified by Mass Directed Automated Preparative HPLC (Method E) and product-containing fractions were dried under a stream of nitrogen to afford the title compound (22 mg).