Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([N:11]=[N+]=[N-])[CH:10]=1>C1(C)C=CC=CC=1.C1C=CC=CC=1>[Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]2=[N+:14]([O-:16])[O:15][N:11]=[C:9]2[CH:10]=1
Reactant: [N-]=[N+]=Nc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: [O-][n+]1onc2cc(Oc3ccc(C(F)(F)F)cc3Cl)ccc21

Procedure:
5-(2-Chloro-4-trifluoromethylphenoxy)-2-nitrophenyl azide (1.2 g) is cautiously heated to reflux temperature in toluene (10 ml) and is heated under reflux for 3 hours. The reaction is cooled, and diluted with benzene, washed with water (3X) and with brine, dried, stripped and purified by prep. TLC (6.5% ethyl acetate/hexane) to give 5-(2-chloro-4-trifluoromethylphenoxy)-benzo-2,1,3-oxadiazole N-oxide, m.p. 60°-61°. (C; X=H, Y=Cl, Y'=H, Z=CF3).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1)[CH3:2].Br[CH2:11][CH:12]([O:15][CH3:16])[O:13][CH3:14].CO.C[O-].[Na+]>>[CH3:14][O:13][CH:12]([O:15][CH3:16])[CH2:11][S:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=1
Reactant: COC(CBr)OC
Reactant: CCc1ccc(S)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCc1ccc(SCC(OC)OC)cc1
Reaction time: 0.17 h
Yield: 92.4 %

Procedure:
Under a nitrogen atmosphere, 4-ethylbenzenethiol (3.50 ml, 25.4 mmol) and 2-bromo-1,1-dimethoxyethane (3.3 ml, 27.9 mmol) were added to a sodium methoxide methanol solution (0.5 M, 81.4 ml, 40.7 mmol) under cooling with ice. The reaction mixture was stirred at the same temperature for 10 minutes, and then heated to reflux for five hours. The reaction mixture was concentrated under reduced pressure, and cold water was added. The resulting mixture was extracted with ether and the organic layer was washed with a saturated sodium chloride aqueous solution and dried with sodium sulfate. After filtration, the solvent was distilled under reduced pressure and the obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:20)] to obtain the title compound (5.31 g, 93%).
Reaction SMILES: [C:1]([NH:7][C:8](=[O:30])[NH:9][C:10]1[N:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=O)[O:25]C(C)=C)[CH:18]=2)=[CH:12][CH:11]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:31]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)[CH3:32].CN1CCCC1>O1CCOCC1.CC#N.O>[CH2:31]([N:33]1[CH2:38][CH2:37][N:36]([C:24]([NH:23][C:19]2[CH:18]=[C:17]([O:16][C:13]3[CH:14]=[N:15][C:10]([NH:9][C:8]([NH:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[O:30])=[CH:11][CH:12]=3)[CH:22]=[CH:21][N:20]=2)=[O:25])[CH2:35][CH2:34]1)[CH3:32]
Reactant: CCN1CCNCC1
Reactant: C=C(C)OC(=O)Nc1cc(Oc2ccc(NC(=O)NC(=O)C(C)(C)C)nc2)ccn1
Agent: CN1CCCC1
Solvent: CC#N
Solvent: O
Solvent: C1COCCO1
Product: CCN1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)NC(=O)C(C)(C)C)nc3)ccn2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32.1 %

Procedure:
A mixture of Example C2 (0.203 g, 0.491 mmol), N-ethyl piperazine (0.1 mL, 0.79 mmol) and N-methylpyrrolidine (0.021 g, 0.25 mmol) in dioxane (5 mL) was heated at 80° C. for 3 h, cooled to RT, and concentrated to dryness. The residue was dissolved in DCM and stirred with sat'd NaHCO3 for ˜15 min. The aqueous layer was back-extracted with DCM (3×) and the organic phases combined, dried (Na2SO4) and concentrated to afford a light brown oil. The crude residue was purified via silica gel chromatography (MeOH/DCM) to afford a colorless oil, which was suspended in MeCN/H2O, sonicated, frozen and lypholized overnight to afford 4-ethyl-N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)piperazine-1-carboxamide as a white solid (74 mg, 32%). 1H NMR (400 MHz, DMSO-d6): δ 11.22 (s, 1H), 10.44 (s, 1H), 9.25 (s, 1H), 8.23 (d, J=2.9 Hz, 1H), 8.12 (d, J=5.7 Hz, 1H), 8.08 (d, J=9.0 Hz, 1H), 7.71 (dd, J=9.0, 2.9 Hz, 1H), 7.37 (d, J=2.4 Hz, 1H), 6.61 (dd, J=5.7, 2.4 Hz, 1H), 3.44-3.35 (m, 4H), 2.35-2.23 (m, 6H), 1.21 (s, 9H), 0.98 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 470.3 (M+H+).
Reaction SMILES: [CH2:1]([N:3]1[C:15]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:14]2[C:5]([C:6]([NH2:26])=[N:7][C:8]3[CH:9]=[C:10]([O:24]C)[CH:11]=[CH:12][C:13]=32)=[N:4]1)[CH3:2].[Cl-:27].[NH+]1C=CC=CC=1>>[ClH:27].[NH2:26][C:6]1[C:5]2=[N:4][N:3]([CH2:1][CH3:2])[C:15]([CH2:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[C:14]2[C:13]2[CH:12]=[CH:11][C:10]([OH:24])=[CH:9][C:8]=2[N:7]=1
Reactant: [Cl-]
Reactant: CCn1nc2c(N)nc3cc(OC)ccc3c2c1CCc1ccccc1
Agent: c1cc[nH+]cc1
Product: CCn1nc2c(N)nc3cc(O)ccc3c2c1CCc1ccccc1
Product: Cl
Temperature: 25 °C
Yield: 96.3 %

Procedure:
2-Ethyl-7-methoxy-1-(2-phenylethyl)-2H-pyrazolo[3,4-c]quinolin-4-amine (0.37 g, 1.07 mmol) was added in one portion to boiling pyridinium chloride (3.70 g, 32.0 mmol). The mixture was heated at reflux for 4 hours, and then was allowed to cool to room temperature. The mixture was triturated with ice water and the precipitate was isolated by filtration, washed with water, and dried to yield 0.38 g of 4-amino-2-ethyl-1-(2-phenylethyl)-2H-pyrazolo[3,4-c]quinolin-7-ol hydrochloride as a light grey solid, mp>300° C.
Reaction SMILES: N[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][C:5]([C:18]2([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:4][C:3]=1[O:28][CH2:29][CH:30]1[CH2:32][CH2:31]1.N([O-])=O.[Na+].CC#N.O.[ClH:41]>O.Cl[Cu]>[Cl:41][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][C:5]([C:18]2([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:4][C:3]=1[O:28][CH2:29][CH:30]1[CH2:32][CH2:31]1
Reactant: CCOC(=O)C1(c2cc(OCC3CC3)c(N)c(-c3ccc(C(F)(F)F)cc3)c2)CCCC1
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)C1(c2cc(OCC3CC3)c(Cl)c(-c3ccc(C(F)(F)F)cc3)c2)CCCC1
Temperature: 90 °C
Reaction time: 0.67 h

Procedure:
Ethyl 1-(6-amino-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylate (1 g, 2.2 mmol) was dissolved in a mixture of MeCN/H2O/HCl 30 mL/30 mL/2 mL at 0° C. A solution of NaNO2 (0.200 g, 2.9 mmol) in water (10 mL) was added drop wise at 0° C., and the reaction mixture was stirred for 40 min, at the same temperature. A solution of CuCl (1.1 g, 11.1 mmol) in water (10 mL) was added drop wise at 0° C. The reaction mixture was heated to 90° C. for 2.0 h and the solvent was evaporated. The reaction mixture was extracted with EtOAc (3×50 mL), and the combined organic layers were washed with water (50 mL) followed by brine (50 mL). The solution was dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude black oil. The oil was purified by chromatography over silica gel (hexane/EtOAc) to give ethyl 1-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylate as yellow oil (1.1 g).
Reaction SMILES: C1(OC(=O)[N:9]([CH2:13][CH2:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:10]([CH3:12])[CH3:11])C=CC=CC=1.[OH-].[Na+].C(Cl)[Cl:29]>Br.CO>[ClH:29].[F:24][C:21]1[CH:20]=[CH:19][C:18]([S:15]([CH2:14][CH2:13][NH:9][CH:10]([CH3:12])[CH3:11])(=[O:16])=[O:17])=[CH:23][CH:22]=1
Reactant: CC(C)N(CCS(=O)(=O)c1ccc(F)cc1)C(=O)Oc1ccccc1
Reactant: ClCCl
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)NCCS(=O)(=O)c1ccc(F)cc1
Product: Cl

Procedure:
A solution of 60.25 g (0.165 mole) of N-[2-[(4-fluorophenyl)sulfonyl]ethyl]-N-(1-methylethyl)carbamic acid phenyl ester in 400 ml of 48% HBr was heated at reflux for 8 hr. The reaction mixture was cooled with ice and made alkaline with 50% sodium hydroxide. The aqueous phase was extracted with chloroform. The chloroform layer was extracted with sodium hydroxide. Evaporation of the chloroform layer gave an oil residue. The oil was dissolved in methylene chloride and the solution extracted with 1N sulfuric acid. The acidic layer was made alkaline with a mixture of ice and 50% sodium hydroxide solution and extracted with chloroform. Removal of chloroform gave an oil, the free base of the title compound, which was dissolved in methanol and reacted with ethereal hydrogen chloride to give the hydrochloride salt. On recrystallization from methanol-diethyl ether a white crystalline product; m.p. 168°-169° C. in 31.1% yield was obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].CN(C=O)C.[CH3:19][N:20]1[C:29]2[C:24](=[CH:25][C:26]([O:30][CH2:31][CH2:32][CH2:33][NH:34][CH2:35][C:36]3[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=3)=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]1=[O:42]>C(OCC)(=O)C>[CH2:12]([O:11][C:9](=[O:10])[CH2:8][N:34]([CH2:33][CH2:32][CH2:31][O:30][C:26]1[CH:25]=[C:24]2[C:29](=[CH:28][CH:27]=1)[N:20]([CH3:19])[C:21](=[O:42])[CH:22]=[CH:23]2)[CH2:35][C:36]1[CH:37]=[CH:38][N:39]=[CH:40][CH:41]=1)[CH3:13]
Reactant: CCOC(=O)CBr
Reactant: Cn1c(=O)ccc2cc(OCCCNCc3ccncc3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CN(CCCOc1ccc2c(ccc(=O)n2C)c1)Cc1ccncc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Potassium carbonate (1.66 g) and ethyl bromoacetate (1.16 ml) were added to a DMF solution (50 ml) of 1-methyl-6-{3-[(pyridin-4-ylmethyl)amino]propoxy}-1H-quinolin-2-one (1.5 g), and stirred at room temperature overnight. The reaction mixture was added to ice water, and extraction with ethyl acetate was performed. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=100:0→85:15). The purified product was condensed under reduced pressure to give the title compound (1.28 g) as a orange oil.
Reaction SMILES: [Cl:1][CH:2]1[CH2:6][N:5]([CH3:7])[C:4](=S)[N:3]1[CH3:9].CI.ClC1N(C)C=NC=1>C(Cl)Cl>[Cl-:1].[CH3:9][N+:3]1[C:2]([Cl:1])=[CH:6][N:5]([CH3:7])[CH:4]=1
Reactant: CN1CC(Cl)N(C)C1=S
Agent: Cn1cncc1Cl
Solvent: ClCCl
Solvent: CI
Product: Cn1cc(Cl)[n+](C)c1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The starting material, 4-chloro-1,3-dimethylimidazoline-2-thione was first prepared by adding dropwise and intimately admixing 5.68 grams (0.04 mol) of methyl iodide to a solution of 4.0 grams (0.0343 mol) of 5-chloro-1-methylimidazole in 25 milliliters of methylene chloride. The resulting mixture was stirred overnight at room temperature whereupon a crystalline product was found to have formed. The latter was recovered with cold methylene chloride to obtain 1,3-dimethyl-5-chloroimidazolium chloride.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([S:14](Cl)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH2:18][C:19]1[CH:45]=[CH:44][C:22]([CH2:23][N:24]2[C:28]3[CH:29]=[C:30]([C:33](=[O:42])[NH:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=4)[CH:31]=[CH:32][C:27]=3[N:26]=[C:25]2[CH3:43])=[CH:21][CH:20]=1.O>C(Cl)(Cl)Cl>[C:8]1([S:14]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:23][N:24]3[C:28]4[CH:29]=[C:30]([C:33](=[O:42])[NH:34][CH2:35][C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=5)[CH:31]=[CH:32][C:27]=4[N:26]=[C:25]3[CH3:43])=[CH:44][CH:45]=2)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1nc2ccc(C(=O)NCc3ccccn3)cc2n1Cc1ccc(N)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1nc2ccc(C(=O)NCc3ccccn3)cc2n1Cc1ccc(NS(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.1 %

Procedure:
Triethylamine (0.185 g) and benzenesulfonyl chloride (0.210 g) were added to a solution of 0.340 g of 1-(4-aminobenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]-benzimidazole in 10 ml of chloroform, and the mixture was stirred at room temperature for 8 hours. Water was added thereto to stop the reaction, and the reaction mixture was extracted with chloroform. The organic layer was washed three times with water, dried, and concentrated. The residue was then purified through silica-gel column chromatography (eluent: a mixture of ethyl acetate and methanol at a ratio of 100:1 to 4:1) to give 0.300 g of 1-[4-(benzenesulfonylamino)benzyl]-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole (263).
Reaction SMILES: [C:1]([N:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]([O:18]CC)=[O:17])=[C:11]([CH3:21])[C:10]1=[O:22])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[CH3:25]O.O>>[CH3:21][C:11]1[C:10](=[O:22])[N:9]([CH:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH3:25])[CH:14]=[C:13]([CH3:15])[C:12]=1[C:16]([OH:18])=[O:17]
Reactant: CCOC(=O)c1c(C)cn(C(=O)c2ccccc2)c(=O)c1C
Reactant: CO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1cn(C(C)c2ccccc2)c(=O)c(C)c1C(=O)O
Yield: 7.3 %

Procedure:
To the solution of ethyl 1-benzoyl-3,5-dimethyl-2-oxo-1,2-dihydropyridine-4-carboxylate (1.06 g, 3.54 mmol) in methanol/H2O (40 mL, 1:1) was added KOH (0.79 g, 14.16 mmol). The mixture was refluxed overnight. Then the mixture was concentrated under vacuum, diluted with water (5 mL) and acidified with 1 N HCl to pH=2. The mixture was extracted with ethyl acetate. The extractions were combined, dried over Na2SO4, and concentrated to give a residue 3,5-dimethyl-2-oxo-1-(1-phenylethyl)-1,2-dihydropyridine-4-carboxylic acid as a white solid. (70 mg, yield 7.3%) LRMS (M+H+) m/z: calcd 271.31. found 272.1. The residue was used in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][N:9]=[CH:10][C:11]=3[N:12]2[N+:15]([O-])=O)=[CH:4][CH:3]=1.O.O.[Sn](Cl)(Cl)(Cl)Cl.Cl>CCO>[NH2:15][N:12]1[C:11]2[CH:10]=[N:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:14][C:2]([Cl:1])=[CH:3][CH:4]=2
Reactant: O=[N+]([O-])n1c2cnccc2c2ccc(Cl)cc21
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: CCO
Product: Nn1c2cnccc2c2ccc(Cl)cc21
Reaction time: 3.5 h
Yield: 100.2 %

Procedure:
To a suspension of 7-chloro-9-nitro-β-carboline (548 mg, 2.22 mmol) in EtOH (14 mL) at 65° C. to 70° C. was added tin chloride dihydrate (2.5 g, 11.1 mmol). Thereafter, 6M aqueous HCl (14 mL) was added dropwise. The mixture was stirred at 70° C. to 80° C. for 3.5 h and then partitioned slowly into saturated aqueous NaHCO3 (150 mL) and EtOAc (100 mL). The aqueous phase was extracted (2 times) and the combined organic solutions dried (brine; NaSO4) and concentrated to give 484 mg of 9-amino-7-chloro-β-carboline.
Reaction SMILES: [C:1](Cl)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[F:19][C@@H:20]1[C@@H:24]([CH2:25][OH:26])[O:23][C@@H:22]([N:27]2[CH:35]=[C:33]([CH3:34])[C:31](=[O:32])[NH:30][C:28]2=[O:29])[CH2:21]1.C(Cl)(Cl)Cl.CO>N1C=CC=CC=1>[F:19][C@@H:20]1[C@@H:24]([CH2:25][O:26][C:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[O:23][C@@H:22]([N:27]2[CH:35]=[C:33]([CH3:34])[C:31](=[O:32])[NH:30][C:28]2=[O:29])[CH2:21]1
Reactant: Cc1cn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCC(=O)OC[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1F
Temperature: 25 °C

Procedure:
At 0° C., 1.2 equivalents of palmitoyl chloride were added to a solution of 3'-deoxy-3'-fluorothymidine in pyridine. The solution was warmed slowly to room temperature. As soon as a thin layer chromatographic control (CHCl3 /methanol=95/5 on silica gel) showed a complete reaction, the solution was poured into ice water. The aqueous phase was decanted, the resulting oil was chromatographed on silica gel with chloroform eluent. The title compound was recovered from the suitable fractions by evaporation of the solvent. M.P. 65°-66° C. (cyclohexane).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=2)=[O:14])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(N(CC)CC)C.[CH:29]1([C:35]#[CH:36])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>CN(C=O)C.C(OCC)(=O)C.[Cu](I)I.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>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:36]#[C:35][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[CH:16]=2)=[O:14])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)c1cccc(I)c1
Reactant: C#CC1CCCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)ccc1NC(=O)c1cccc(C#CC2CCCCC2)c1
Yield: 35.6 %

Procedure:
0.5 g (1.2 mmol) of methyl 5-chloro-2-{[(3-iodophenyl)carbonyl]amino}benzoate obtained in Example 63-(i), 146 mg (1.4 mmol) of triethylamine, 11.5 mg (0.06 mmol) of copper iodide, 25 mg (0.036 mmol) of bis(triphenylphosphine)palladium(II) dichloride (PdCl2(PPh3)2), and 208 mg (1.92 mmol) of cyclohexylacetylene were stirred in DMF (10 mL) at room temperature for 21 hours. The reaction mixture was diluted with ethyl acetate, and washed with H2O, diluted hydrochloric acid, aqueous saturated sodium hydrogen carbonate solution, and saturated saline in this order. Thereafter, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography, thereby giving 169 mg of methyl 5-chloro-2-({[3-(cyclohexylethynyl)phenyl]carbonyl}amino)benzoate (yield: 36%).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH:15]([CH3:18])[C:16]#[N:17].[I-].[K+]>CC(CC)=O.O>[O:7]([CH:15]([CH3:18])[C:16]#[N:17])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(Cl)C#N
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CC(C#N)Oc1ccccc1
Reaction time: 0.33 h

Procedure:
A mixture of phenol (18.8 g.) and anhydrous potassium carbonate (25 g.) in dry ethyl methyl ketone (35 ml.) was stirred and heated to reflux, during the dropwise addition of a solution of 2-chloropropionitrile (19.7 g.) in dry ethyl methyl ketone (15 ml.) containing finely-powdered potassium iodide (0.5 g.). The addition took 20 minutes. Stirring and heating were continued for a total of 2 hours after which the mixture was cooled, poured into water (200 ml.) and extracted with ether (200, 75 and 75 ml.). The combined ether extract was washed several times with 2N-sodium hydroxide to remove phenol, dried over anhydrous sodium sulphate, and evaporated. The residue was distilled under water-pump vacuum to give pure 2-phenoxypropionitrile, b.p. 117°-118°/13 mm.
Reaction SMILES: I[C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[O:13])[NH:11][C:9](=[O:10])[C:8]2=[CH:14][C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1I.[Cu][C:29]#[N:30].[CH3:31][N:32](C=O)C>C(OCC)(=O)C.O.Cl.[Fe](Cl)(Cl)Cl>[C:31]([C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[O:13])[NH:11][C:9](=[O:10])[C:8]2=[CH:14][C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:29]#[N:30])#[N:32]
Reactant: N#C[Cu]
Reactant: CN(C)C=O
Reactant: O=C1NC(=O)c2cc(Nc3ccccc3I)c(Nc3ccccc3I)cc21
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1ccccc1Nc1cc2c(cc1Nc1ccccc1C#N)C(=O)NC2=O
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A solution of 581 mg (1 mmol) of 4,5-bis(2-iodoanilino)phthalimide and 197 mg (2.2 mmol) of copper(I) cyanide in DMF is stirred for 6 hours at 130°-140° C., the dark-brown solution changing into a dark-yellow suspension. The reaction mixture is cooled to 80° C. and diluted with 8 ml ethyl acetate. After further cooling to 60°-70° C., a solution of 467 mg (2.88 mmol) of iron(III) chloride in 1.6 ml of water and 300 μl of concentrated hydrochloric acid is added dropwise and the mixture is stirred for 30 minutes. 2 ml of water and Hyflo Super Cel® (kieselguhr from Fluka, Buchs, Switzerland) are added to the reaction mixture which is then filtered through Hyflo Super Gel® and the phases are separated. The aqueous phase is extracted once with ethyl acetate and the combined organic phases are washed twice with water, once with saturated sodium hydrogen carbonate solution and twice more with water, dried over magnesium sulfate and concentrated by evaporation. The resulting oily brown crystal mixture is chromatographed on silica gel with ethyl acetate/hexane 2:3. The product fractions are concentrated by evaporation and crystallized from boiling dichloromethane, yielding the title compound in the form of pale-yellow crystals: FAB-MS: 380 (M+ +H), m.p.: 279°-280° C.
Reaction SMILES: C([O:5][C:6](=[O:30])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][S:12](=[O:15])[CH:11]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])=[CH:18][CH:17]=2)[CH2:10]1)(C)(C)C.[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32].C1(C)C=CC=CC=1>C(Cl)Cl>[F:34][C:33]([F:36])([F:35])[C:31]([OH:37])=[O:32].[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[O:22][C:19]1[CH:20]=[CH:21][C:16]([CH:11]2[S:12](=[O:15])[CH2:13][CH2:14][N:9]([CH2:8][CH2:7][C:6]([OH:30])=[O:5])[CH2:10]2)=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)CCN1CCS(=O)C(c2ccc(Oc3ccccc3Cl)cc2)C1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCN1CCS(=O)C(c2ccc(Oc3ccccc3Cl)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-{2-[4-(2-Chloro-phenoxy)-phenyl]-1-oxo-thiomorpholin-4-yl}-propionic acid tert-butyl ester (0.19 g; 0.42 mmol) in CH2Cl2 (10 mL) was added TFA (2 mL). The resulting mixture was stirred, at RT, overnight, treated with toluene, and concentrated in vacuo. The residue was dissolved in CH2Cl2 and concentrated in vacuo to afford 3-{2-[4-(2-Chloro-phenoxy)-phenyl]-1-oxo-thiomorpholin-4-yl}-propionic acid trifluoroacetic acid salt as an oil (0.17 g). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.83 (t, J=8 Hz, 2H), 2.92-3.13 (m, 1H), 3.21-3.34 (m, 2H), 3.34-3.44 (m, 2H), 3.44-3.61 (m, 2H), 3.86 (t, J=12 Hz, 1H), 4.44 (d, J=12 Hz, 1H), 7.04 (m, 2H), 7.23 (d, J=8 Hz, 1H), 7.33 (m, 1H), 7.40 (dd, J=8 and 2 Hz, 1H), 7.47 (m, 2H), 7.69 (dd, J=8 and 2 Hz, 1H), 11.00-13.00 (bs, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:25]2[CH2:30][CH2:29][CH2:28][C@H:27]([NH:31]C(=O)OC(C)(C)C)[CH2:26]2)=[N:4][C:5]([N:8]2[C:16]3[CH:15]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[C:21]([CH2:23][CH3:24])[CH:22]=4)[N:13]=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:6][CH:7]=1.Cl>CO.O1CCOCC1>[Cl:1][C:2]1[C:3]([N:25]2[CH2:30][CH2:29][CH2:28][C@H:27]([NH2:31])[CH2:26]2)=[N:4][C:5]([N:8]2[C:16]3[CH:15]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[C:21]([CH2:23][CH3:24])[CH:22]=4)[N:13]=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCc1cncc(-c2cc3c(cn2)cnn3-c2ccc(Cl)c(N3CCC[C@H](NC(=O)OC(C)(C)C)C3)n2)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCc1cncc(-c2cc3c(cn2)cnn3-c2ccc(Cl)c(N3CCC[C@H](N)C3)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.2 %

Procedure:
To a solution of tert-butyl N-[(3S)-1-[3-chloro-6-[6-(5-ethyl-3-pyridyl)pyrazolo[4,3-c]pyridin-1-yl]-2-pyridyl]-3-piperidyl]carbamate (0.0446 mmol; 23.8 mg) in Methanol (10 mL) was added hydrochloric acid, 4.0 M in 1,4-Dioxane (5 mL). The resulting mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by reverse phase HPLC to afford 117 (7.0 mg, 33%). 1H NMR (400 MHz, DMSO) δ 9.36-9.31 (s, 1H), 9.18-9.11 (m, 2H), 8.74-8.65 (s, 1H), 8.58-8.52 (d, J=1.9 Hz, 1H), 8.34-8.30 (s, 1H), 8.02-7.97 (d, J=8.4 Hz, 1H), 7.60-7.55 (d, J=8.4 Hz, 1H), 3.95-3.81 (dd, J=27.5, 10.2 Hz, 2H), 3.06-2.97 (t, J=10.2 Hz, 1H), 2.93-2.84 (t, J=9.5 Hz, 1H), 2.81-2.72 (m, 3H), 1.98-1.90 (d, J=12.6 Hz, 1H), 1.89-1.80 (d, J=13.3 Hz, 1H), 1.79-1.68 (d, J=12.9 Hz, 1H), 1.68-1.48 (s, 2H), 1.31-1.26 (t, J=7.6 Hz, 3H), 1.26-1.20 (m, 1H); MS (ESI) m/z: 434.2 [M+H]+