Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.[C:12]1(/[C:18](/[C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[I-:32].[Na+].O>CC(C)=O>[I:32][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]/[CH:19]=[C:18](\[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)/[C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1
Reactant: OCCCCC/C=C(\c1ccccc1)c1cccnc1
Reactant: [I-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: ICCCCC/C=C(\c1ccccc1)c1cccnc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.7 %

Procedure:
p-Toluenesulfonate of (E)-7-phenyl-7-(3-pyridyl)-6-hepten-1-ol (15 g, 36 mmoles) and sodium iodide (18 g, 120 mmoles) were dissolved in acetone (100 ml) and the solution was stirred at room temperature for 3 hours. Water (200 ml) was added to the mixture and the product was extracted twice with ethyl ether. The organic layer was washed with water, dried (magnesium sulfate) and concentrated under reduced pressure to give (E)-1-iodo-7-phenyl-7-(3-pyridyl)-6-heptene (13 g, 96%) as an oil.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH2:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:16][C:17]1[N:22]=[C:21]([Cl:23])[C:20]([Cl:24])=[C:19](Cl)[C:18]=1[Cl:26].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:19]2[C:18]([Cl:26])=[C:17]([Cl:16])[N:22]=[C:21]([Cl:23])[C:20]=2[Cl:24])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: Clc1nc(Cl)c(Cl)c(Cl)c1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CNc2c(Cl)c(Cl)nc(Cl)c2Cl)CC1
Yield: 62.4 %

Procedure:
A mixture of 1-Boc-4-(aminomethyl)piperidine (2.0 g, 9.33 mmol), pentachloropyridine (2.58 g, 10.3 mmol) and potassium carbonate (2.58 g, 18.7 mmol) was heated at 60° C. in DMF (22 mL) for 2 h. Excess DMF was removed in vacuo and the residue taken in to water/ethyl acetate. The aqueous solution was extracted with ethyl acetate (×3) and the combined organic solution dried (MgSO4) and concentrated in vacuo. Flash chromatography (SiO2, hexane/diethyl ether 30% to 60% gave the product as a white solid (2.5 g, 62%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][C:12]([C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[C:20]([N+:28]([O-:30])=[O:29])[CH:19]=3)([C:14]([F:17])([F:16])[F:15])[O:11][N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[Li+]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][C:12]([C:18]3[CH:27]=[CH:26][C:21]([C:22]([OH:24])=[O:23])=[C:20]([N+:28]([O-:30])=[O:29])[CH:19]=3)([C:14]([F:15])([F:17])[F:16])[O:11][N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(=O)c1ccc(C2(C(F)(F)F)CC(c3cc(Cl)cc(Cl)c3)=NO2)cc1[N+](=O)[O-]
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(C2(C(F)(F)F)CC(c3cc(Cl)cc(Cl)c3)=NO2)cc1[N+](=O)[O-]
Yield: 388.3 %

Procedure:
A solution of methyl 4-[3-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-5-yl]-2-nitrobenzoate (1 g, 0.43 mmol) and lithium hydroxide (73 mg) in tetrahydrofuran (20 ml) and water (10 ml) was stirred for 1 hour at room temperature. Tetrahydrofuran was then removed and the residue was extracted with ethyl acetate (2×25 ml). The combined organic layers were dried over sodium sulfate and concentrated to give 4-[3-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-5-yl]-2-nitrobenzoic acid (0.75 g), 1H-NMR (400 MHz, DMSO): 7.85-7.87 (2H, m), 7.82 (1H, m), 7.66-7.69 (1H, m), 7.61-7.62 (2H, m), 4.22-4.46 (2H, m) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[O:15][C:14]([NH:17][C:18]4[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=4)=[N:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>N1C=CC=CC=1>[CH3:29][O:28][C:20]1[CH:19]=[C:18]([NH:17][C:14]2[O:15][C:16]3[C:8]([C:5]4[CH:6]=[CH:7][C:2]([NH:1][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:3][CH:4]=4)=[CH:9][CH:10]=[CH:11][C:12]=3[N:13]=2)[CH:23]=[C:22]([O:24][CH3:25])[C:21]=1[O:26][CH3:27]
Reactant: COc1cc(Nc2nc3cccc(-c4ccc(N)cc4)c3o2)cc(OC)c1OC
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COc1cc(Nc2nc3cccc(-c4ccc(NS(C)(=O)=O)cc4)c3o2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 0.12 g (0.307 mmol) [7-(4-amino-phenyl)-benzooxazol-2-yl]-(3,4,5-trimethoxy-phenyl)-amine (example 11) and 0.041 g (0.36 mmol) methanesulfonyl chloride in 6 ml pyridine is stirred for 1.5 h at room temperature. Then the reaction mixture is poured on water and extracted 3× with EtOAc. The combined organic layers are washed with 0.1N NaOH solution and water, dried over MgSO4, filtered and the filtrate is concentrated in vacuo. The residue is purified by crystallisation from dichloromethane/diethyl ether to afford the title compound as off-white crystals. Rt=2.22 min (Waters Symmetry C8, 2.1×50 mm, detection 210-250 nM, 5% to 100% CH3CN in H2O in 2 min+0.05% TFA, flow rate 1.0 ml/min); MS: 470 (M+1)+; m.p. 222-225° C.
Reaction SMILES: C(O[C:4](=[O:22])[CH2:5][N:6]1[CH2:10][C@H:9]([O:11][CH3:12])[C@@H:8]([NH:13][C:14]([C:16]2[S:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[O:15])[CH2:7]1)C.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH:35]=[CH:34][N:33]=[CH:32][C:31]2=[O:36])=[CH:26][C:25]=1[F:37]>>[F:37][C:25]1[CH:26]=[C:27]([N:30]2[CH:35]=[CH:34][N:33]=[CH:32][C:31]2=[O:36])[CH:28]=[CH:29][C:24]=1[NH:23][C:4]([CH2:5][N:6]1[CH2:10][C@H:9]([O:11][CH3:12])[C@@H:8]([NH:13][C:14]([C:16]2[S:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[O:15])[CH2:7]1)=[O:22]
Reactant: Nc1ccc(-n2ccncc2=O)cc1F
Reactant: CCOC(=O)CN1C[C@H](NC(=O)c2ccc(Cl)s2)[C@@H](OC)C1
Product: CO[C@H]1CN(CC(=O)Nc2ccc(-n3ccncc3=O)cc2F)C[C@@H]1NC(=O)c1ccc(Cl)s1

Procedure:
Using general procedure F {(3S,4S)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-methoxy-pyrrolidin-1-yl}-acetic acid ethyl ester (example 25.2) was reacted with 1-(4-amino-3-fluoro-phenyl)-1H-pyrazin-2-one (prepared from 2-fluoro-4-iodoaniline by reaction with 1H-pyrazin-2-one, Cu(I)I, N,N′-dimethylethylenediamine and cesium carbonate in dioxane at 120° C.) to give 5-chloro-thiophene-2-carboxylic acid ((3S,4S)-1-{[2-fluoro-4-(2-oxo-pyrazin-1-yl)-phenylcarbamoyl]-methyl}-4-methoxy-pyrrolidin-3-yl)-amide. Yellow solid. MS 506.3 ([M+H]+)
Reaction SMILES: Br.[F:2][CH:3]([F:20])[O:4][C:5]1[N:9]([CH3:10])[N:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[C:6]=1[CH2:15][S:16]C(=N)N.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:20][CH:3]([F:2])[O:4][C:5]1[N:9]([CH3:10])[N:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[C:6]=1[CH2:15][SH:16]
Reactant: Cn1nc(C(F)(F)F)c(CSC(=N)N)c1OC(F)F
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc(C(F)(F)F)c(CS)c1OC(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
To a solution of 1.00 g (2.60 mmol) of 2-(5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole-4-ylmethyl)-isothiourea hydrobromide in 2 ml of N,N-dimethylformamide were added 0.43 g (3.12 mmol) of anhydrous potassium carbonate and 1 ml of water, followed by 1 hour of stirring at room temperature. After the completion of the reaction was confirmed, the reaction solution was poured into water and extracted with diethyl ether. The resulting organic layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure to obtain 0.66 g (purity: 84.9%, yield: 82.4%) of (5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole-4-yl)-methanethiol.
Reaction SMILES: [Cl:1][CH:2]([CH3:16])[CH2:3][CH:4]([CH3:15])[O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1.[C:17]([C:19]1[CH:24]=[CH:23][C:22](O)=[CH:21][CH:20]=1)#[N:18].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[C:17]([C:19]1[CH:24]=[CH:23][C:22]([O:11][C:10](=[O:12])[C:9]2[CH:13]=[CH:14][C:6]([O:5][C@@H:4]([CH3:15])[CH2:3][C@@H:2]([Cl:1])[CH3:16])=[CH:7][CH:8]=2)=[CH:21][CH:20]=1)#[N:18]
Reactant: N#Cc1ccc(O)cc1
Reactant: CC(Cl)CC(C)Oc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: C[C@H](Cl)C[C@H](C)Oc1ccc(C(=O)Oc2ccc(C#N)cc2)cc1

Procedure:
1.00 g of 4-(3'-chloro-1'-methylbutoxy)benzoic acid, 0.50 g of 4-cyanophenol, 0.93 g of dicyclohexylcarbodiimide, 0.10 g of 4-pyrrolydinopyridine and 10 ml of methylene chloride were stirred together at room temperature for five hours. The dicyclohexyl urea thus precipitated was filtered and the filtrate was desolvated. The crude product thus obtained was purified by silica gel column chromatography with the use of a mixture of ethyl acetate and n-hexane (1:4) as a developing solvent to thereby give the title compound.
Reaction SMILES: [NH:1]([C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[CH:5][N:4]=1)[NH2:2].[CH3:14][C:15](OC(C)=O)=[O:16]>O1CCOCC1>[CH3:10][O:9][C:8]1[C:3]([NH:1][NH:2][C:15](=[O:16])[CH3:14])=[N:4][CH:5]=[C:6]([N+:11]([O-:13])=[O:12])[CH:7]=1
Reactant: COc1cc([N+](=O)[O-])cnc1NN
Reactant: CC(=O)OC(C)=O
Solvent: C1COCCO1
Product: COc1cc([N+](=O)[O-])cnc1NNC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
To a suspension of 2-hydrazinyl-3-methoxy-5-nitropyridine (Step 84.1) (20 g, 106 mmol) in dioxane (170 mL) was added at RT Ac2O (13.1 mL, 138 mmol) and the reaction mixture was stirred for 1 hr at RT. The reaction mixture was poured onto ice-water (700 mL) and stirred for 1 hr at 0° C. The precipitate was collected by filtration, washed with H2O and Et2O, and dried under reduced pressure at 50° C. to afford the title product (23.3 g, 101 mmol, 95% yield) as a yellow solid. tR: 0.45 min (LC-MS 2); ESI-MS: 227 [M+H]+ (LC-MS 2); ESI-MS: 225 [M−H]− (LC-MS 2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:24][CH2:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[NH:14][C:15]([CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:16][C:9]=12.[C:32](O)(=[O:34])[CH3:33].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:24][CH2:25][CH:26]2[CH2:27][CH2:28][N:29]([C:32](=[O:34])[CH3:33])[CH2:30][CH2:31]2)=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[NH:14][C:15]([CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:16][C:9]=12
Reactant: CN1CCC(c2cc3c(-c4nc(NCC5CCNCC5)ccc4Cl)ccnc3[nH]2)CC1
Reactant: CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(CNc2ccc(Cl)c(-c3ccnc4[nH]c(C5CCN(C)CC5)cc34)n2)CC1
Reaction time: 8 h

Procedure:
To a solution of Example 165 (20 mg, 0.05 mmol) in N,N-dimethylformamide (1 mL) was added acetic acid (4 mg, 0.07 mmol) and triethylamine (0.1 mL) at room temperature. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (11 mg, 0.07 mmol) and N-hydroxybenzotriazole (10 mg, 0.07 mmol) were added and the mixture was stirred overnight. Purification by HPLC (Zorbax XDB C-18 (32) using a gradient of 5-40% acetonitrile/water (containing 0.1% trifluoroacetic acid) afforded the title compound. 1H NMR (400 MHz, DMSO-d6): δ 1.57-1.93 (m, 5H), 1.96 (s, 3H), 2.28 (d, J=13.73 Hz, 2H), 2.80 (d, J=3.97 Hz, 3H), 2.87-3.01 (m, 2H), 3.02-3.22 (m, 5H), 3.52 (d, J=11.60 Hz, 2H), 3.77 (d, J=13.12 Hz, 2H), 4.34 (d, J=12.82 Hz, 2H), 6.10 (s, 1H), 6.61 (d, J=9.16 Hz, 1H), 7.11-7.18 (m, 1H), 7.56 (d, J=9.16 Hz, 1H), 8.23 (d, J=5.19 Hz, 1H). LCMS: 481 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[Cl:20])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[Cl:21])[N:4]=1.I([O-])(=O)(=O)=[O:23].[Na+].CN(C=O)C>CCOC(C)=O>[Cl:21][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:11]=[C:12]([C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[Cl:20])[C:3]([CH:2]=[O:23])=[N:4]2
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: Fc1ccc(Cl)c(-c2nc3c(Cl)cccc3nc2CBr)c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1nc2cccc(Cl)c2nc1-c1cc(F)ccc1Cl
Temperature: 150 °C
Reaction time: 3 h

Procedure:
A mixture of 2-(bromomethyl)-5-chloro-3-(2-chloro-5-fluorophenyl)quinoxaline (Prepared in Example 100, 0.5625 g, 1.457 mmol) and sodium metaperiodate (0.1613 mL, 2.914 mmol) in DMF (9.714 mL, 1.457 mmol) was heated at 150° C. with stirring. After 3 h, the mixture was cooled to room temperature, diluted with EtOAc (100 mL), washed with brine (50 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 80 g of Redi-Seplivi column using 0 to 10% gradient of EtOAc in hexane over 10 min, then 10% isocratic of EtOAc for 20 min, then 10 to 20% gradient of EtOAc in hexane over 20 min, then 20% isocratic of EtOAc for 3 min as eluent to give 5-chloro-3-(2-chloro-5-fluorophenyl)quinoxaline-2-carbaldehyde as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 10.16 (1 H, s), 8.35-8.41 (1 H, m), 8.29-8.34 (1 H, m), 8.07 (1 H, dd, J=8.4, 7.6 Hz), 7.68 (1 H, dd, J=8.8, 4.9 Hz), 7.44-7.58 (2 H, m); LC-MS (ESI) m/z 321.0 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:10]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH:17]=2)[N:8]=[C:7]([NH:27][C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=2)[CH:6]=1)=O.[NH3:34].CO>>[C:3]([C:5]1[N:10]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH:17]=2)[N:8]=[C:7]([NH:27][C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=2)[CH:6]=1)(=[O:2])[NH2:34]
Reactant: N
Reactant: COC(=O)c1cc(Nc2cc(C)[nH]n2)nc(N2CCCC2c2cc(-c3ccccn3)no2)n1
Solvent: CO
Product: Cc1cc(Nc2cc(C(N)=O)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)n[nH]1
Yield: 93 %

Procedure:
A mixture of 6-methoxycarbonyl-2-{2-[3-(pyrid-2-yl)isoxazol-5-yl]pyrrolidin-1-yl}-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine (Example 56) (200 mg, 0.45 mmol) and a solution of 7N ammonia in methanol (7 ml, 49 mmol) was heated at 65° C. in a sealed vessel under microwave irradiation for 1 hour. The reaction mixture was evaporated, dissolved in methanol and passed through a 50 g isolute SCX-2 ion exchange column. The column was eluted with methanol to elute any neutrals, followed by 7M methanolic ammonia to elute the product. The solvent was removed by evaporation and the residue triturated with diethylether. The resulting solid was collected by filtration to give the title compound (180.0 mg, 93%).
Reaction SMILES: O1CC1CO[C:6]1[CH:23]=[CH:22][CH:21]=[CH:20][C:7]=1[C:8]([NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[CH:14][NH:15]2)=[O:9].C(N)(CC)(C)C>C(O)C>[NH:15]1[C:16]2[C:12](=[C:11]([NH:10][C:8](=[O:9])[C:7]3[CH:6]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:19]=[CH:18][CH:17]=2)[CH:13]=[CH:14]1
Reactant: O=C(Nc1cccc2[nH]ccc12)c1ccccc1OCC1CO1
Agent: CCC(C)(C)N
Solvent: CCO
Product: O=C(Nc1cccc2[nH]ccc12)c1ccccc1

Procedure:
3.5 g of the product of Step B dissolved in 35 ml of ethanol was refluxed with stirring and under an inert atmosphere for 5 hours with 3 ml of tert-pentyl-amine and the solvent was evaporated off. The residue was purified by chromatography over silica (eluant:methylene chloride/methanol 9:1) to obtain 3.5 g of 2-[3-[1,1-dimethylpropyl)amino]-2-hydroxypropoxy]-N-(1H-indol-4-yl)benzamide.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]2[S:23][CH:24]=[CH:25][C:18]=12>CN(C)C=O>[S:23]1[C:19]2=[N:20][CH:21]=[CH:22][C:17]([O:13][CH:10]3[CH2:9][CH2:8][CH:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[CH2:12][CH2:11]3)=[C:18]2[CH:25]=[CH:24]1
Reactant: Clc1ccnc2sccc12
Reactant: OC1CCC(N2CCOCC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1cc(OC2CCC(N3CCOCC3)CC2)c2ccsc2n1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 4-(morpholin-4-yl)cyclohexan-1-ol (164 mg, 0.89 mmol, 1.50 equiv) in N,N-dimethylformamide (15 mL), sodium hydride (47 mg, 1.96 mmol, 2.00 equiv). The resulting mixture was stirred at 80° C. for 30 minutes. Then 4-chlorothieno[2,3-b]pyridine (100 mg, 0.59 mmol, 1.00 equiv) was added to the mixture. The resulting solution was stirred for 4 h at 120° C. in an oil bath. The reaction was then quenched by the addition of 5 mL of water. The resulting solution was extracted with 3×30 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×15 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (10:1). The crude product (120 mg) was purified by Prep-HPLC with the following conditions: Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, CH3CN and water with 0.05% HCOOH (10.0% water with 0.05% HCOOH up to 50.0% in 10 min, up to 100.0% in 2 min, down to 10.0% in 2 min); Detector, uv 254/220 nm. This resulted in 72.2 mg (32%) of 4-(4-[thieno[2,3-b]pyridin-4-yloxy]cyclohexyl)morpholine as a white semi-solid. MS: (ES, m/z): 319.10 [M+H]+ 1H NMR (400 MHz, D2O, ppm): δ1.53-1.71 (m, 4H), 2.19-2.33 (dd, J1=29.7 Hz, J2=9.3 Hz, 4H), 3.24-3.30 (m, 3H), 3.51 (m, 2H), 4.07 (s, 2H), 4.60 (m, 1H), 6.98 (d, J=4.5 Hz, 1H), 7.37 (d, J=4.5 Hz, 1H), 7.52 (d, J=4.5 Hz, 1H), 8.33 (d, J=4.5 Hz, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[CH3:25][S:26](Cl)(=[O:28])=[O:27]>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:26]([CH3:25])(=[O:28])=[O:27])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CCCCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: CS(=O)(=O)Cl
Product: CCCCCc1nc2c(N)nc3ccccc3c2n1CCCCNS(C)(=O)=O
Yield: 34.3 %

Procedure:
Using the general method of Example 245, 1-(4-aminobutyl)-2-pentyl-1H-imidazo[4,5-c]quinolin-4-amine (1.50 g, 4.6 mmol) was reacted with methanesulfonyl chloride (0.57 mL, 7.4 mmol) to provide 636 mg of N-[4-(4-amino-2-pentyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide as an off white solid, m.p. 136.8-138.1° C. Analysis: Calculated for C20H29N5O2S: % C, 59.53; % H, 7.24; % N, 17.35;
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](OCCCNC2C(=O)N(C(C)(C)C)S(=O)(=O)C=2C2C=CC=CC=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:34]([N:38]1[C:42](=[O:43])[C:41]([NH:44][CH2:45][CH2:46][OH:47])=[C:40]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[S:39]1(=[O:55])=[O:54])([CH3:37])([CH3:36])[CH3:35].CC1C=CC(S(Cl)(=O)=O)=CC=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:47][CH2:46][CH2:45][NH:44][C:41]2[C:42](=[O:43])[N:38]([C:34]([CH3:37])([CH3:35])[CH3:36])[S:39](=[O:54])(=[O:55])[C:40]=2[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Reactant: CC(C)(C)N1C(=O)C(NCCO)=C(c2ccccc2)S1(=O)=O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)OCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Yield: 76 %

Procedure:
The title compound was prepared as described for 3-[(2-tert-butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]propyl 4-methylbenzenesulfonate from 2-tert-butyl-4-[(2-hydroxyethyl)amino]-5-phenylisothiazol-3(2H)-one 1,1-dioxide (Example 76) and 4-methylbenzenesulfonyl chloride with a reaction time of 17 h. The reaction mixture was purified by silica gel column chromatography (Horizons Biotage) using 50-100% DCM in petroleum ether 40-60° C. as eluent to give the title compound (1.93 g, 76%) as a solid; 1H NMR (500 MHz, CDCl3): δ 7.76 (d, 1H), 7.46-7.35 (m, 7H), 5.44 (t, 1H), 3.85 (t, 2H), 3.18-3.12 (m, 2H), 2.49 (s, 3H), 1.74 (s, 9H); Mass Spectrum M+H+ 479.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]2[NH:11][C:12]([C:17]3[CH:22]=[C:21]([O:23][CH2:24][CH3:25])[CH:20]=[CH:19][N:18]=3)=[CH:13][C:14](=[O:16])[CH:15]=2)[CH:5]=1)[CH3:2].[H-].[Na+].[CH3:28]I.O>CN(C)C=O>[CH2:24]([O:23][C:21]1[CH:20]=[CH:19][N:18]=[C:17]([C:12]2[CH:13]=[C:14]([O:16][CH3:28])[CH:15]=[C:10]([C:6]3[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:9]=[CH:8][N:7]=3)[N:11]=2)[CH:22]=1)[CH3:25]
Reactant: CI
Reactant: CCOc1ccnc(-c2cc(=O)cc(-c3cc(OCC)ccn3)[nH]2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccnc(-c2cc(OC)cc(-c3cc(OCC)ccn3)n2)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
In an argon atmosphere, 506 mg (1.5 mmol) of 4,4″-diethoxy-1′H-[2,2′;6′,2″]terpyridin-4′-one (L17, Example 23) are added at 0° C. to a suspension of 78 mg (approximately 60% dispersion in paraffin oil, 1.95 mmol) of sodium hydride in 15 ml of absolute N,N-dimethylformamide. The mixture is then stirred for 15 minutes at 0° C. and for 15 minutes at room temperature. After cooling again, 0.12 ml (1.95 mmol) of methyl iodide is added. Stirring is then carried out at room temperature for a further 45 minutes. 15 ml of water are added and filtration is carried out, yielding 4,4″-diethoxy-4′-methoxy-[2,2′;6′,2″]terpyridine in the form of a beige powder. 1H-NMR (360 MHz, CDCl3): 1.39 (t, 6 H, J=7.2 Hz); 3.90 (s, 3H); 4.12 (q, 4H, J=7.2 Hz); 6.73 (dd, 2H, J=5.6, 2.5 Hz); 7.88 (s, 2H); 8.01 (d, 2H, J=2.5 Hz); 8.39 (d, 2H, 5.6 Hz). MS (EI pos, 70 eV), m/z=351 (90, [M+]); 350 (70); 336 (100); 323 (70); 295 (45).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([C:15]([OH:17])=O)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:18][S:19]([C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[N:27]([NH2:31])[CH:26]=[C:25]2[CH3:32])(=[O:21])=[O:20].C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>CN(C=O)C.CCOC(C)=O>[CH3:18][S:19]([C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[N:27]([NH:31][C:15]([C:11]1[C:12]([CH3:14])=[N:13][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][CH:10]=1)=[O:17])[CH:26]=[C:25]2[CH3:32])(=[O:21])=[O:20]
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)O
Reactant: Cc1cn(N)c2ccc(S(C)(=O)=O)cc12
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1cc(C)c2cc(S(C)(=O)=O)ccc21
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 13.7 %

Procedure:
A solution of 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (1.77 mmol) and 5-methanesulfonyl-3-methyl-indol-1-ylamine (452 mg, 1.95 mmol) in DMF (15 mL) is stirred at rt for 1 h. The mixture is treated with DMTMM (538 mg, 1.95 mmol) and stirred at 60° C. for 1.5 h. The mixture is diluted with EtOAc (50 mL), and washed with saturated aqueous Na2CO3 (50 mL). The organic layer is separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 0%-100% EtOAc in heptane, and then by triturating in Et2O to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (5-methanesulfonyl-3-methyl-indol-1-yl)-amide (106 mg, 14%). MS: 439 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 9.15 (s, 1H), 8.37 (d, 1H), 8.24 (m, 2H), 7.82 (m, 1H), 7.59 (d, 1H), 7.54 (m, 1H), 7.34 (s, 1H), 7.29 (m, 1H), 3.13 (s, 3H), 2.83 (s, 3H), 2.42 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][P:4]([O:7][CH2:8][CH2:9][C:10]1[CH:22]=[CH:21][C:13]([C:14]([O:16]C(C)(C)C)=[O:15])=[CH:12][CH:11]=1)([CH3:6])=[O:5])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:3][P:4]([O:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[CH:21][CH:22]=1)([CH3:6])=[O:5])[CH3:2]
Reactant: CCOP(C)(=O)OCCc1ccc(C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOP(C)(=O)OCCc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 4-(2-{[ethoxy(methyl)phosphoryl]oxy}ethyl)benzoate (108 mg, 0.33 mmol) in DCM (0.66 mL) was added TFA (0.60 mL, 7.8 mmol). After stirring at room temperature for 30 minutes, the solution was concentrated in vacuo to give the title compound as a colorless oil. 1H NMR (CDCl3, 600 MHz) δ 7.85 (d, J=8.2 Hz, 2H), 7.37 (d, J=8.2 Hz, 2H), 4.10-4.16 (m, 2H), 3.80-3.88 (m, 2H), 2.95 (t, J=6.4 Hz, 2H), 1.32 (d, J=17.3 Hz, 3H), 1.13 (t, J=7.1 Hz, 3H). MS cal'd 272 (MH+), exp 272 (MH+).