Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:35]3[CH:36]=[CH:37][C:32]([O:31][CH3:30])=[CH:33][CH:34]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-n2c(C(=O)N3CCC(F)(F)CC3)cc3cc(OC4CCN(C(C)C)CC4)ccc32)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 6, the title compound was synthesized from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (intermediate 1) and 4-methoxyphenylboronic acid. The title compound was obtained in 38% yield as yellow foam. MS (m/e): 512.2 (MH+, 100%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].[NH4+].[Cl-]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[O:17][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCI
Reactant: O=Cc1ccc(OCc2ccccc2)c(O)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCCCCCCCOc1cc(C=O)ccc1OCc1ccccc1
Yield: 83.2 %

Procedure:
To the solution of 4-(benzyloxy)-3-hydroxybenzaldehyde (190 mg, 0.83 mmol) in anhydrous DMF (2.0 mL) was added 60% NaH (40 mg, 1.00 mmol) at 0° C. followed by the addition of 1-iodooctane (300 mg, 1.25 mmol). The reaction mixture was stirred at room temperature (r.t.) overnight and NH4Cl solution was then added. The mixture was extracted with ethyl acetate 3 times and the combined organic layers were dried and concentrated under vacuum. The resulting residue was purified through flash column chromatography (Hexane:Ethyl Acetate=10:1) to yield 4-(benzyloxy)-3-(octyloxy)benzaldehyde (235 mg, 83%) as light yellow oil, which was subsequently subjected to hydrogenolysis in ethyl acetate in the presence of 10% Pd/C. After filtration and concentration, the crude residue was purified by column chromatography (Hexane:Ethyl Acetate=5:1) to give 3 (125 mg, 72%) as light yellow oil. 1H NMR (CDCl3, 300 MHz) δ 9.80 (s, 1H), 7.36-7.42 (m, 2H), 7.03 (d, J=8.6 Hz, 1H), 6.44 (s, 1H), 4.09 (t, J=6.9 Hz, 2H), 1.82 (hexatet, J=6.7 Hz, 2H), 1.20-1.50 (m, 10H), 0.87 (t, J=6.8 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 191.09, 151.96, 146.70, 129.90, 127.42, 114.44, 109.68, 69.30, 31.86, 29.37, 29.28, 29.09, 26.03, 22.73, 14.17; ESI-HRMS for [M+H]+ C15H23O3: calcd 251.1647, found 5251.1638.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:14][CH2:15][CH3:16])[CH2:5][C:6]1([C:12]#[N:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH3:2].[Na].O>C(O)C>[NH2:13][CH2:12][C:6]1([CH2:5][CH:4]([O:3][CH2:1][CH3:2])[O:14][CH2:15][CH3:16])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CCOC(CC1(C#N)CCCCC1)OCC
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCOC(CC1(CN)CCCCC1)OCC

Procedure:
90 g of di-(ethyloxy)ethyl-cyclohexane-carbonitrile are dissolved in 1 l of ethanol, and 60 g of sodium are added. After dissolution of the metal, 100 ml of water are added, and the solvent is substantially removed in vacuo. 300 ml of water are added to the residue, and it is extracted three times with 200 ml of ether. The ethereal phase is dried over sodium sulfate, concentrated, and distilled in vacuo.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[OH-].[Na+].Br[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][O:31]CC2C=CC=CC=2)=[CH:25][CH:24]=1>N1C=CC=CC=1.O>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][OH:31])=[CH:25][CH:24]=2)=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: Brc1ccc(CCOCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: OCCc1ccc(Oc2ccc(Oc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.1 %

Procedure:
To a 1 L round bottom flask were charged 4-phenoxyphenol (95.0 g, 0.51 mol). THF (100 mL), sodium hydroxide (24 g, 0.6 mol), and DI water (80 mL). The mixture was magnetically stirred at room temperature for 30 minutes, followed by removal of solvent under reduced pressure. The white solid was then dried under vacuum (70 mTorr) at 150° C. overnight and cooled to room temperature. To the flask were then added 1-bromo-4-[2-(phenylmethoxy)ethyl]benzene (150 g, 0.51 mol) and anhydrous pyridine (100 mL). The mixture was purged with nitrogen for 15 minutes, followed by the addition of cuprous chloride (5 g, 0.05 mol). The mixture was then purge with nitrogen for additional 15 min and then sealed under nitrogen and magnetically stirred in a 130° C. oil bath for a week. After removal of pyridine under vacuum, the crude product was dissolved in methylene chloride (600 mL) and washed with 2N HCl (200 mL×3), 2N NaOH (200 mL×3). After removal of solvent under reduced pressure, the crude product was recrystallized from methanol/ethyl acetate (9/1, v/v). The product was then hydrogenated at 100 PSI in THF using palladium 10% on carbon as catalyst to give crude 2-[4-(4-phenoxyphenoxy)phenyl]ethanol. This crude product was then distilled under vacuum followed by recrystallization from hexanes/ethyl acetate (1/1, v/v) to give the product as white crystals (122 g, 78% over two steps).
Reaction SMILES: [C:1]([CH2:3][C:4]([N:6]([CH2:14][CH2:15][CH2:16][CH3:17])[C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:8])=[O:5])#[N:2].[OH-].[Na+]>CO>[CH2:10]([N:9]1[C:1]([NH2:2])=[CH:3][C:4](=[O:5])[N:6]([CH2:14][CH2:15][CH2:16][CH3:17])[C:7]1=[O:8])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCNC(=O)N(CCCC)C(=O)CC#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCn1c(N)cc(=O)n(CCCC)c1=O
Yield: 99.5 %

Procedure:
N,N-Di-n-butylurea (34.45 g, 0.2 mmol), cyanoacetic acid (19.56 g, 0.23 mol), and acetic anhydride (81.66 ml, 0.8 mol) were heated at 80° C. for 2 h under nitrogen and solvent was removed by rotary evaporation to yield N-(2-cyanoacetyl)-N,N'-dibutylurea. The N-(2-cyanoacetyl)-N,N'-dibutylurea was dissolved in methanol (100 ml) and 4N NaOH (100 ml) was added. The reaction mixture was cooled for 30 min with stirring and the solid was filtered and dried to yield 1,3-di-n-butyl-6-aminouracil (47.04 g, 99.5%) as a colorless solid, m.p. 90.1°-92.4° C.; 1H NMR (DMSO-d6) δ1.72-1.93 (m, 6H, 2×CH3, 1.18-1.33 (m, 4H, 2×CH2), 1.39-1.52 (M, 4H, 2×CH2), 3.70 (t, 2H, N--CH2), 3.76 (t, 2H, N--CH2), 4.64 (s, 1H, H-4), 6.77 (br s, exchangeable with D2O, 2H, NH2).
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([C:19]([F:22])([F:21])[F:20])[CH:10]=1)C.[OH-].[Na+].Cl>O.C(O)C>[F:16][C:15]([F:17])([F:18])[C:13]1[CH:14]=[C:9]([CH:10]=[C:11]([C:19]([F:21])([F:22])[F:20])[CH:12]=1)[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:23])=[O:3]
Reactant: CCOC(=O)CCCOc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CCCOc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 5 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
A stirred charge containing 0.05 mole of ethyl-4-[3,5-bis-(trifluoromethyl)phenoxy]butyrate, 150 ml of ethyl alcohol, 8 g (0.1 mole) of 50% aqueous solution of sodium hydroxide and 25 ml of water was heated at reflux for 5 hours and at 25°-30° C. for 18 hours. After cooling to 5° C., 800 ml of water containing 15 g (0.15 mole) of concentrated hydrochloric acid was added slowly. After stirring at 0°-10° C. for one hour, the resulting solid was collected by filtration, washed with cold water and air dried at 25°-30° C. A product with a melting point of 85°-87° C. was obtained with a yield of 87%.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH2:17])=[CH:14][CH:13]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1>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]>[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH:17][C:2]2[CH:10]=[CH:9][C:5]3[N:6]=[CH:7][NH:8][C:4]=3[CH:3]=2)=[CH:14][CH:13]=1
Reactant: NCc1ccc(F)cc1
Reactant: Brc1ccc2nc[nH]c2c1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: C1CCOC1
Product: Fc1ccc(CNc2ccc3nc[nH]c3c2)cc1

Procedure:
The compound was synthesized starting from 5-bromobenzimidazole (200 mg; 1 mmol; 1 eq.), 4-fluorobenzylamine (150 mg; 0.137 ml; 1.2 mmol; 1.2 eq.), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (9 mg; 0.024 mmol; 0.024 eq.; 2.4 mol %), Pd2 dba3 (9 mg; 0.01 mmol; 0.01 eq.; 1 mol %) and lithiumbis(trimethylsilyl)amide 1 M in THF (2.2 ml; 2.2 mmol; 2.2 eq.) according to method 1; Yield: 0.096 mg (39.8%); MS m/z: 242.4 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 4.25 (s, 2H); 6.04 (br s, 1H); 6.50 (s, 1H); 6.59 (dd, 1H, 4J=1.2 Hz, 3J=8.5 Hz); 7.09-7.13 (m, 2H); 7.26 (d, 1H, 3J=8.5 Hz); 7.38-7.41 (m, 2H); 7.83 (s, 1H); 11.88 (br s, 1H); HPLC (METHOD [A]): rt 11.21 min (99.2%)
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:22]C)[N:12]2[CH2:15][CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][O:18]2)=[C:8]([NH2:24])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl.[OH-].[Na+].C(=O)([O-])O.[Na+]>CO.O1CCOCC1.Cl>[NH2:24][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:22])[N:12]2[CH2:15][CH2:16][CH:17]1[CH2:21][CH2:20][CH2:19][O:18]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCC3CCCO3)c2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCC3CCCO3)c2n1

Procedure:
2-Butoxy-8-methoxy-9-[2-(tetrahydrofuran-2-yl)ethyl]-9H-purin-6-amine (122 mg) was dissolved in methanol (2 ml) and 4N hydrogen chloride in dioxan (1 ml) added. After 4 h the reaction mixture was made basic with 2N sodium hydroxide (2.2 ml) then the organic solvents stripped. A few drops of 2N hydrochloric acid were added and the pH adjusted back to 7-8 with saturated sodium hydrogen carbonate. The resulting solid was filtered, washed and dried to give the title compound as a solid, yield 65 mg.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([CH2:14][CH:15]2[CH2:17][CH2:16]2)=[N:4][N:3]=1.[NH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)[CH2:21][CH2:20]1>>[CH:15]1([CH2:14][C:5]2[C:6]3[C:11](=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=3)[C:2]([NH:18][CH:19]3[CH2:20][CH2:21][N:22]([CH2:25][C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[CH:27]=4)[CH2:23][CH2:24]3)=[N:3][N:4]=2)[CH2:17][CH2:16]1
Reactant: COc1ccc2c(CC3CC3)nnc(Cl)c2c1
Reactant: NC1CCN(Cc2ccc3ccccc3c2)CC1
Product: COc1ccc2c(CC3CC3)nnc(NC3CCN(Cc4ccc5ccccc5c4)CC3)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.4. by reacting 1-chloro-4-cyclopropylmethyl-7-methoxyphthalazine with 4-amino-1-(naphthalen-2-ylmethyl)piperidine.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]([N:23]1[C@H:28]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[C@@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[CH2:26][CH:25]([OH:43])[C:24]1=[O:44])[CH2:21][CH3:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:48]>C1COCC1>[Si:1]([O:18][CH2:19][C@@H:20]([N:23]1[C@H:28]([C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)[C@@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[CH2:26][CH:25]([O:43][CH3:48])[C:24]1=[O:44])[CH2:21][CH3:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1C(=O)C(O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1C(=O)C(OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
To a 0° C. solution of (5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-hydroxypiperidin-2-one (476 mg, 0.736 mmol; Example 203, Step A) in THF (7.360 mL) was added sodium hydride (58.9 mg, 1.472 mmol). After 30 minutes, iodomethane (0.092 mL, 1.472 mmol) was added. After 5 minutes, the cooling bath was removed. After 2 hours, the mixture was quenched with sat. aq. NH4Cl solution. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with sat. aq. NaCl solution, dried over Na2SO4, and concentrated to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:12])[CH2:10]Br)=[CH:4][C:3]=1[Cl:13].[C:14]1([CH2:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][CH2:29][NH:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH:9]([CH2:10][N:30]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:29][CH2:28][CH2:27][O:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21][CH2:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[OH:12])=[CH:4][C:3]=1[Cl:13]
Reactant: Nc1c(Cl)cc(C(=O)CBr)cc1Cl
Reactant: c1ccc(CCCOCCOCCCNCc2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1c(Cl)cc(C(O)CN(CCCOCCOCCCc2ccccc2)Cc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.5 %

Procedure:
1-[4-Amino-3,5-dichlorophenyl]-2-bromoethanone (0.86 g), N-[3-[2-(3-phenylpropoxy)ethoxy]propyl]benzenemethanamine (1 g) and DEA (0.43 g) were stirred together in THF (30 ml) at room temperature under nitrogen for 22 h. The mixture was filtered and the filtrate evaporated in vacuo. The residue was dissolved in methanol (40 ml), treated portionwise with sodium borohydride (0.31 g) at 0° C. under nitrogen, stirred at room temperature under nitrogen for 2 h, diluted with water (150 ml) and extracted with ethyl acetate (2×150 ml). The dried extract was evaporated in vacuo to give an oil. Purification by FCC eluting with System F (1:1) gave the title compound (1.22 g) as an oil. T.l.c. (System F 1:1) Rf 0.19
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([C:7]1[CH:31]=[CH:30][C:10]([CH2:11][C:12]23[CH2:19][CH2:18][CH2:17][N:16]2[C:15](=[O:20])[N:14]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)[C:13]3=[O:29])=[CH:9][CH:8]=1)#[N:6]>CN(C=O)C>[NH:1]1[C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH2:11][C:12]34[CH2:19][CH2:18][CH2:17][N:16]3[C:15](=[O:20])[N:14]([C:21]3[CH:22]=[C:23]([Cl:28])[CH:24]=[C:25]([Cl:27])[CH:26]=3)[C:13]4=[O:29])=[CH:30][CH:31]=2)=[N:6][N:3]=[N:2]1
Reactant: N#Cc1ccc(CC23CCCN2C(=O)N(c2cc(Cl)cc(Cl)c2)C3=O)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1N(c2cc(Cl)cc(Cl)c2)C(=O)C2(Cc3ccc(-c4nnn[nH]4)cc3)CCCN12
Temperature: 140 °C
Yield: 17.8 %

Procedure:
NaN3 (64.5 mg) was added to a solution of Example 21 (137 mg) in DMF (3 mL). The reaction mixture was sealed and heated at 140° C. for 72 hours. The reaction mixture was cooled to room temperature and the solvent removed under reduced pressure. The residue was purified by HPLC (18C-Waters 40×210 mm, 1% HOAc/CH3CN gradient) to provide the titled compound (27 mg). MS (m/z) 457 (MH+). mp. 194.8° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][C:13]1[N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[C:17](=[O:29])[C:16]([C:30]([NH:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([S:40]([CH3:43])(=[O:42])=[O:41])=[CH:36][N:35]=2)=[O:31])=[CH:15][C:14]=1[C:44]1[N:48]([CH3:49])[N:47]=[CH:46][CH:45]=1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[C:61]1([CH3:72])[C:62]([S:68]([OH:71])(=[O:70])=[O:69])=[CH:63][C:64]([CH3:67])=[CH:65][CH:66]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:6][CH:7]=1.[CH3:12][C:13]1[N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:27])([F:26])[F:28])[CH:20]=2)[C:17](=[O:29])[C:16]([C:30]([NH:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([S:40]([CH3:43])(=[O:42])=[O:41])=[CH:36][N:35]=2)=[O:31])=[CH:15][C:14]=1[C:44]1[N:48]([CH3:49])[N:47]=[CH:46][CH:45]=1.[C:61]1([CH3:72])[C:62]([S:68]([O-:71])(=[O:70])=[O:69])=[CH:63][C:64]([CH3:67])=[CH:65][CH:66]=1
Reactant: Cc1ccc(C)c(S(=O)(=O)O)c1
Agent: Cc1c(-c2ccnn2C)cc(C(=O)NCc2ccc(S(C)(=O)=O)cn2)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: Cc1ccc(C)c(S(=O)(=O)[O-])c1

Procedure:
Compound (I) p-xylene-2-sulfonate was synthesized using an analogous method to that described for the synthesis of compound (I) tosylate in Example 8a from compound (I) (50 mg, 0.092 mmol) and p-xylene-2-sulfonic acid (20 mg, 0.092 mmol). No precipitation was obtained after stirring over night. After the evaporation of 50% of the solvent and stirring for an extra night a good precipitation of the title product was obtained; yield 56 mg, 0.076 mmol, 83%. The compound (I) p-xylene-2-sulfonate (2,5-dimethylbenzenesulfonate) Form A was crystalline and gave the powder X-ray diffraction pattern shown in FIG. 8.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][NH:28][CH2:29][C@@H:30]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH3:31])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH:38](=O)[CH3:39]>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][N:28]([CH2:38][CH3:39])[CH2:29][C@@H:30]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH3:31])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: CC=O
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CNC[C@H](C)c4ccccc4)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CN(CC)C[C@H](C)c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 67, Step 1, using 1-(4′-{3-methyl-4-[((R)-2-phenyl-propylamino)-methyl]-isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester and acetaldehyde.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[C:5]([S:18]([C:21]2[CH:26]=[CH:25][C:24](OS(C(F)(F)F)(=O)=O)=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:40]1[CH:41]=[N:42][CH:43]=[N:44][CH:45]=1)CCC.[Li+].[Cl-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[F-].[K+]>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.CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[C:5]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([C:40]3[CH:41]=[N:42][CH:43]=[N:44][CH:45]=3)=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[CH:4][N:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncnc1
Reactant: Cc1cc(C)c(Nc2nc(C)ncc2S(=O)(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc2)c(C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [F-]
Solvent: CN(C)C=O
Product: Cc1cc(C)c(Nc2nc(C)ncc2S(=O)(=O)c2ccc(-c3cncnc3)cc2)c(C)c1
Temperature: 150 °C
Yield: 82.3 %

Procedure:
A mixture of trifluoromethanesulfonic acid 4-[2-methyl-4-(2,4,6-trimethylphenylamino)-pyrimidine-5-sulfonyl]-phenyl ester (95 mg, 0.18 mmol), prepared by the method described in Example 22, 5-tributylstannanyl-pyrimidine (75 mg, 0.20 mmol), LiCl (23 mg, 0.55 mmol) and DMF (4 mL) was deoxygenated with N2 for 10 min, and then Pd(PPh3)2Cl2 (13 mg, 0.018 mmol) and PPh3 (10 mg, 0.036 mmol) were added. The mixture was heated at 150° C. under N2 for 2 h and then cooled to room temperature. Saturated aqueous KF was added, and the mixture was extracted three times with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (50:50 hexanes/EtOAc) to provide the target compound (66 mg, 80%) as a white solid: mp 210–212° C.; 1H NMR (300 MHz, CDCl3) δ 9.29 (s, 1H), 8.96 (s, 1H), 8.80 (s, 1H), 8.30 (br s, 1H), 8.13 (d, J=8.5 Hz, 2H), 7.76 (d, J=8.5 Hz, 2H), 6.93 (s, 2H), 2.41 (s, 3H), 2.31 (s, 3H), 2.03 (s, 6H); APCI MS m/z 446 [(M+H)+, calcd for C24H24N5O2S, 446.2].
Reaction SMILES: OO.[CH3:3][N:4]([CH3:21])[CH:5]1[CH2:20][C:19]2[C:7](=[CH:8][C:9]3[N+:14]([O-:15])=[N:13][C:12]([CH2:16][CH3:17])=[N:11][C:10]=3[CH:18]=2)[CH2:6]1.C(O)(C(F)(F)F)=[O:23].N>C(Cl)Cl.C(Cl)(Cl)Cl>[CH3:21][N:4]([CH3:3])[CH:5]1[CH2:20][C:19]2[C:7](=[CH:8][C:9]3[N+:14]([O-:15])=[N:13][C:12]([CH2:16][CH3:17])=[N+:11]([O-:23])[C:10]=3[CH:18]=2)[CH2:6]1
Reactant: O=C(O)C(F)(F)F
Reactant: CCc1nc2cc3c(cc2[n+]([O-])n1)CC(N(C)C)C3
Agent: N
Agent: OO
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCc1n[n+]([O-])c2cc3c(cc2[n+]1[O-])CC(N(C)C)C3
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 20.7 %

Procedure:
H2O2 (70%, 0.47 mL, ca. 9.7 mmol) was added dropwise to a stirred solution of TFM (1.35 mL, 9.7 mmol) in DCM (15 mL) at 0° C. The solution was stirred at 20° C. for 10 min, then cooled to 0° C. and added to a solution of 1-oxide 115 (250 mg, 0.97 mmol) and TFA (0.16 mL, 2.07 mmol) in CHCl3 (15 mL) at 0° C. The solution was stirred at 20° C. for 5 h. The solution was made basic with dilute aqueous NH3 solution and extracted with CHCl3 (3×30 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by column chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 116 (55 mg, 21%) as an unstable brown solid: 1H NMR δ 8.30 (s, 1H, H-9), 8.25 (s, 1H, H-5), 3.07-3.37 (m, 7H, H-6, H-7, H-8, CH2), 2.36 [s, 6H, N(CH3)2], 1.43 (t, J=7.5 Hz, 3H, CH3); HRMS calcd for C14H18N4O2 (M+) m/z 274.1430, found 274.1428.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18](=[N:26][C:27]#[N:28])OC4C=CC=CC=4)[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH2:35])=[CH:32][CH:31]=1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:13][CH2:14][N:15]([C:18](=[N:26][C:27]#[N:28])[NH:35][CH2:34][C:33]4[CH:36]=[CH:37][C:30]([F:29])=[CH:31][CH:32]=4)[CH2:16][CH2:17]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: N#CN=C(Oc1ccccc1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1
Reactant: NCc1ccc(F)cc1
Solvent: c1ccncc1
Product: N#CN=C(NCc1ccc(F)cc1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1

Procedure:
7-Chloro-4-[4-(cyanimino(phenoxy)methyl)piperazin-1-yl]quinoline (107 mg, 0.27 mmol) and 4-fluorobenzylamine (62 μL, 0.54 mmol) are heated in pyridine (10 mL) for 3 h at reflux. The solvent is removed, and the residue purified by column chromatography with CH2Cl2-MeOH giving the title product as a colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:24])=[C:8]2[C:15]([Cl:16])=[C:14]([Cl:17])[N:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:9]2=[C:10](Cl)[N:11]=1)=[O:5])[CH3:2].[CH3:25][N:26](C)C(=O)C>[C-]#N.[C-]#N.[Zn+2].[Zn].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].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:24])=[C:8]2[C:15]([Cl:16])=[C:14]([Cl:17])[N:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:9]2=[C:10]([C:25]#[N:26])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Cl)c2c(c1O)c(Cl)c(Cl)n2-c1ccccc1
Reactant: CC(=O)N(C)C
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCOC(=O)c1nc(C#N)c2c(c1O)c(Cl)c(Cl)n2-c1ccccc1

Procedure:
Prepared in analogy to that of Example 111(a) from 2,3,7-trichloro-4-hydroxy-1-phenyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, Zn(CN)2, Zn dust, Pd2(dba)3, and dppf in DMA (N,N-dimethylacetamide). The title compound, ESI MS (m/z): 376 (M+H)+.