Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][C:10]([CH3:15])=[C:9]2[C:16]([OH:18])=O)=[C:4]([F:19])[CH:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][C:29]=1[F:30])[NH:26][N:25]=[CH:24]2.C(Cl)CCl.CCN(CC)CC>CN(C=O)C.CCOC(C)=O.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][C:10]([CH3:15])=[C:9]2[C:16]([NH:20][C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][C:29]=2[F:30])[NH:26][N:25]=[CH:24]3)=[O:18])=[C:4]([F:19])[CH:3]=1
Reactant: Nc1cc2cn[nH]c2cc1F
Reactant: CC1=C(C(=O)O)C(c2ccc(Cl)cc2F)CC(=O)N1
Agent: Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1=C(C(=O)Nc2cc3cn[nH]c3cc2F)C(c2ccc(Cl)cc2F)CC(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 8.1 %

Procedure:
The product of Example 3, Step 2 (200 mg, 0.71 mmol, 1.00 equiv), 5-amino-6-fluoroindazole (107 mg, 0.71 mmol, 1.0 equiv), and EDC (162 mg, 0.85 mmol, 1.20 equiv) were suspended in 1.5 mL DMF. Et3N (0.118 mL, 0.85 mmol, 1.2 equiv) was added and the solution was stirred at room temperature for 18 hrs. The reaction mixture was diluted with EtOAc and 1N HCl. The phases were separated, and the organic phase was washed twice with 1N HCl, once with satd. NaHCO3, and once with satd. NaCl. The organic phase was dried over Na2SO4, filtered, and concentrated en vacuo. The residue was purified by flash chromatography (20-100% EtOAc in Hexanes) to provide 24 mg (8%) of the title compound as an off white solid. MS (ES+) m/e 417 [M+H]+
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1)#[CH:2].[NH2:22][C:23]1[CH:28]=[CH:27][C:26](I)=[CH:25][N:24]=1>>[F:19][C:18]([F:20])([F:21])[C:15]1[CH:16]=[CH:17][C:12]([C:9]2[CH:10]=[CH:11][C:6]3[N:7]([C:3]([C:1]#[C:2][C:26]4[CH:27]=[CH:28][C:23]([NH2:22])=[N:24][CH:25]=4)=[CH:4][N:5]=3)[CH:8]=2)=[CH:13][CH:14]=1
Reactant: C#Cc1cnc2ccc(-c3ccc(C(F)(F)F)cc3)cn12
Reactant: Nc1ccc(I)cn1
Product: Nc1ccc(C#Cc2cnc3ccc(-c4ccc(C(F)(F)F)cc4)cn23)cn1

Procedure:
The title compound was prepared from 3-ethynyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (example C.24) (300 mg, 1.0 mmol) and commercially available 2-amino-5-iodopyridine (230 mg, 1.0 mmol) according to general procedure II. Obtained as a white solid (210 mg, 53%). MS (ISP) 379.2 [(M+H)+]; mp 241–244° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]([Cl:19])[C:7]=1[CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[Cl:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[S:32](Cl)(=[O:34])=[O:33]>N1C=CC=CC=1>[Cl:21][C:22]1[CH:27]=[C:26]([C:28]([F:30])([F:29])[F:31])[CH:25]=[CH:24][C:23]=1[S:32]([NH:20][C:4]1[CH:5]=[C:6]([Cl:19])[C:7]([CH2:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[C:2]([Cl:1])[CH:3]=1)(=[O:34])=[O:33]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Cl
Reactant: Nc1cc(Cl)c(Cc2ccc3ccccc3n2)c(Cl)c1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Cl)c(Cc2ccc3ccccc3n2)c(Cl)c1)c1ccc(C(F)(F)F)cc1Cl

Procedure:
2-Chloro-N-(3,5-dichloro-4-quinolin-2-ylmethyl-phenyl)-4-trifluoromethyl-benzenesulfonamide was synthesized (84%) from 3,5-dichloro-4-quinolin-2-ylmethyl-phenylamine (223), 2-chloro-4-trifluoromethylbenzenesulfonyl chloride (Maybridge) and pyridine (EM) in a similar manner as described in Examples 70-91. 1H NMR (400 MHz, DMSO-d6) δ 11.45 (br s, 1H), 8.34 (d, J=8.3 Hz, 1H), 8.24 (d, J=8.5 Hz, 1H), 8.19 (s, 1H), 8.00 (d, J=8.3 Hz, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.76 (d, J=8.3 Hz, 1H), 7.67 (td, J=7.8, 1.3 Hz, 1H), 7.54 (td, J=7.8, 1.0 Hz, 1H), 7.23 (d, J=8.5 Hz, 1H), 7.22 (s, 2H), 4.48 (s, 2H). MS (EI): m/z 543 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:63][CH:64]1[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:67]1[CH2:68][CH2:69][CH:64]([CH3:63])[CH2:65][CH2:66]1)=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: CC1CCNCC1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC1CCN(C(=O)c2cc3ncnc(NC(C)c4nc5cc(Cl)ccc5[nH]4)c3cc2Cl)CC1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 4-methyl-piperidine in DMSO at ambient temperature.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][Si](C(C)(C)C)(C)C)[CH:10]2[N:21]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[CH2:22][CH2:23][CH:9]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([OH:13])[CH:10]2[N:21]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[CH2:22][CH2:23][CH:9]12)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(O[Si](C)(C)C(C)(C)C)C2C1CCN2C(=O)OCc1ccccc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(O)C2C1CCN2C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
A solution containing 10 (868 mg, 1.8 mmol) in THF (10 mL) was cooled to 0° C. HF.pyridine reagent (1 mL, 36 mmol) was added and the reaction mixture was allowed to warm to ambient temperature. After 16 h, the reaction mixture was diluted with EtOAc and washed successively with water, aqueous NaHCO3, water, and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash silica gel chromatography (1:1 hexanes/EtOAc) to afford 600 mg (90%) of 11. 1H NMR (CDCl3, 300 MHz): δ7.29 (m, 5H), 5.10 (app dd, J=22.7, 12.5 Hz, 2H), 4.32 (m, 4H), 3.71 (m, 2H), 3.58 (m, 1H), 3.38 (m, 1H), 3.17 (m, 1H), 2.14 (m, 1H), 2.02 (m, 1H), 1.42 (s, 9H) ppm. Mass spectrum, m/z [363.2] (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][NH:6][C:7]([NH:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:15]=1)=[O:8])=O.P(Cl)(Cl)(Cl)=O>>[CH3:1][NH:2][C:3]1[O:8][C:7]([NH:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:15]=2)=[N:6][N:5]=1
Reactant: CNC(=O)NNC(=O)NCCCOc1cccc(CN2CCCCC2)c1
Solvent: O=P(Cl)(Cl)Cl
Product: CNc1nnc(NCCCOc2cccc(CN3CCCCC3)c2)o1

Procedure:
The compound is prepared by a method analogous to that of Example 40 from N-methyl-N'-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-1,2-hydrazine dicarboxamide and phosphorus oxychloride. The analytical values are summarized in Table III.
Reaction SMILES: ClCC([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=1[OH:18])=O>C(O)C.Cl>[NH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([F:16])([F:17])[F:15])=[CH:9][C:8]=1[OH:18]
Reactant: O=C(CCl)NCc1ccc(OC(F)(F)F)cc1O
Agent: Cl
Solvent: CCO
Product: NCc1ccc(OC(F)(F)F)cc1O
Yield: 95.3 %

Procedure:
2-Chloro-N-(2-hydroxy-4-trifluoromethoxy-benzyl)-acetamide (9.9 g, 37.4 mmol) was dissolved in a mixture of ethanol (100 mL)/aqueous HCl (12 M, 50 mL). The mixture was refluxed for ˜6 hours. The solvent was removed by rotary evaporation and the residue was azeotropically dried by dissolution in ethyl acetate followed by rotary evaporation (6×150 mL). The resulting solid was suspended in ethyl acetate (100 mL), collected by filtration and dried at 65° C. in a vacuum oven overnight. Recovery: 8.68 g (95.3% yield). M/Z (−HCl) of [M−H]−=208. 1H NMR (D2O) δ=7.26–7.22 (1H, sd), 6.76–6.75 (2H, br), 4.07 (2H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](C=O)=[CH:5][C:6]2[O:10][CH2:9][CH2:8][C:7]=2[CH:11]=1.[C:14]([O:22][CH2:23][CH3:24])(=[O:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C(O)(=O)C.N1CCCCC1>C1C=CC=CC=1.O>[CH3:1][O:2][CH:3]1[CH:11]=[C:7]2[CH2:8][CH2:9][O:10][C:6]2=[CH:5][C:4]1=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:14]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: COc1cc2c(cc1C=O)OCC2
Solvent: c1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(C(=O)OCC)=C1C=C2OCCC2=CC1OC

Procedure:
To a solution of 5-Methoxy-2,3-dihydrobenzofuran-6-al (295 mg, 1.66 mmol) in benzene was added diethyl malonate (265 mg, 1.66 mmol), acetic acid (20 mL, 0.35 mmol) and piperidine (30 mL, 0.30 mmol). The mixture was heated at reflux for 3 h and then poured into 100 mL of water. This mixture was extracted with three 50 mL portion of ethyl acetate. The combined organic extracts were washed with brine and dried (Na2SO4). Removal of the solvent under reduced pressure gave quatitative yield of the title compound as a yellowish oil: 1H NMR (400 MHz, CDCl3) d 8.02 (s, 1 H), 6.79 (s, 1 H), 6.78 (s, 1 H), 4.52 (t, 2 H), 4.30 (m, 4 H), 3.80 (s, 3 H), 3.18 (t, 2 H), 1.28 (m, 6 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12](C(F)(F)F)=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:19]([C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[CH3:30])=[O:20].BrC1C=CC([C:38](C2C=C([N+]([O-])=O)C=CC=2C)=[O:39])=C(Cl)C=1.COC1C=C(N)C=CC=1>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:39][CH3:38])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:19]([C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[CH3:30])=[O:20]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)c1ccc(Br)cc1Cl
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)c1ccc(Nc2ccc(C(F)(F)F)cc2)cc1Cl
Agent: COc1cccc(N)c1
Product: COc1cccc(Nc2ccc(C(=O)c3cc([N+](=O)[O-])ccc3C)c(Cl)c2)c1

Procedure:
The reaction was carried out similarly as described in the preparation of compound 414, using compound 402 (2.82 mmol) and 3-methoxy-phenylamine (3.10 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 0:100 to 30:70 as the eluent to afford the title compound.
Reaction SMILES: C([SiH](CC)CC)C.[CH2:8]([O:10][C:11]([C:13]1[NH:14][CH:15]=[C:16]([C:18](=O)[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH:17]=1)=[O:12])[CH3:9]>FC(F)(F)C(O)=O>[CH2:8]([O:10][C:11]([C:13]1[NH:14][CH:15]=[C:16]([CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[CH:17]=1)=[O:12])[CH3:9]
Reactant: CCOC(=O)c1cc(C(=O)Cc2ccc(F)cc2)c[nH]1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc(CCc2ccc(F)cc2)c[nH]1
Yield: 57 %

Procedure:
Triethylsilane (3.84 mL, 24.1 mmol) was added to a stirring, room temperature solution of 71 (2.1400 g, 7.77 mmol) in trifluoroacetic acid (TFA) (18.5 mL, 0.42 M) under N2. When the reaction was judged complete by HPLC, the TFA was removed under vacuum, and the crude product was taken up in EtOAc, washed with brine, dried with Na2SO4, filtered, concentrated, and purified by preparative reverse phase HPLC with the following conditions: 0 to 12 min, 35:65 H2O:CH3CN; 14-15 min, 35:65 to 0:100 H2O: CH3CN; 20 mL/min.; λ=254 nM; 3.67 g/mL, 0.2 mL/injection. 1.1571 g (57.0%) of 72 was obtained as a fluffy white solid. (Note: An undesired impurity has a retention time of 11.414 min by HPLC.) 1H (CDCl3, 400 MHz): δ 9.33 (1H, broad s), 7.13 (2H, dd, J=8.5, 5.6 Hz), 6.96 (2H, t, J=8.8 Hz), 6.79 (1H, s), 6.66 (1H, s), 4.33 (2H, t, J=7.1 Hz), 2.86 (2H, t, J=7.1 Hz), 2.77 (2H, t, J=7.1 Hz), 1.36 (3H, t, J=7.1 Hz) ppm. 13C (CDCl3, 100 MHz): δ 161.31, 161.22 (d, J=242 Hz), 137.46 (d, J=3.2 Hz), 129.71 (d, J=7.7 Hz), 125.22, 122.52, 120.84, 114.89 (d, J=21.9 Hz), 114.79, 60.19, 36.44, 28.73, 14.37 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 14.37; CH2 carbons: 60.19, 36.44, 28.73; CH carbons: 129.71 (d, J=7.7 Hz), 120.84, 114.89 (d, J=21.9 Hz), 114.79 ppm. HPLC: 10.797 min.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[NH:9][C:8](=[O:11])[N:7]([CH3:12])[C:6]=2[C:5](=[O:13])[NH:4][C:3]1=[O:14].[H-].[Na+].[C:17]([O:23][CH2:24]Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19].O>CS(C)=O>[C:17]([O:23][CH2:24][N:9]1[C:8](=[O:11])[N:7]([CH3:12])[C:6]2[C:5](=[O:13])[NH:4][C:3](=[O:14])[N:2]([CH3:1])[C:10]1=2)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: Cn1c(=O)[nH]c(=O)c2c1[nH]c(=O)n2C
Reactant: CC(C)(C)C(=O)OCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cn1c(=O)n(COC(=O)C(C)(C)C)c2c1c(=O)[nH]c(=O)n2C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 28.4 %

Procedure:
To a stirring solution of 3,7-dimethyluric acid (0.40 g, 2.04 mmol) in dimethylsulfoxide (20 ml) was added sodium hydride (49 mg, 2.04 mmol) in one portion. After stirring for 45 minutes, a solution of chloromethyl pivalate (0.29 g, 2.04 mmol) in dimethylsulfoxide (1 ml). After stirring for 24 hours, water (50 ml) was added. After cooling to room temperature, the solid was filtered, rinsed with water (4×20 ml), with ether (20 ml) and dried under vacuum to give 9-pivaloyloxymethyl-3,7-dimethyluric acid (0.18 g, 28% yield) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:30]=[CH:29][C:9]2[N:10]=[C:11]([NH:13][C:14]3[CH:19]=[C:18]([CH2:20][NH:21]C(C(C)(C)C)=O)[CH:17]=[CH:16][C:15]=3[Cl:28])[NH:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2].[ClH:31]>O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1[C:30]([Cl:31])=[CH:29][C:9]2[N:10]=[C:11]([NH:13][C:14]3[CH:19]=[C:18]([CH2:20][NH2:21])[CH:17]=[CH:16][C:15]=3[Cl:28])[NH:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2nc(Nc3cc(CNC(=O)C(C)(C)C)ccc3Cl)[nH]c2c1
Reactant: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1cc2[nH]c(Nc3cc(CN)ccc3Cl)nc2cc1Cl
Reaction time: 8 h

Procedure:
A mixture of 1.15 g (2.4 mmol) Ethyl-2-[5-(tert.butylcarbonylaminomethyl)-2-chlorophenylamino]-benzimidazole-5-carboxylate and 10 ml 4M HCl in Dioxane was stirred overnight. The reaction mixture was concentrated under reduced pressure to give the sub-title compound. Yield: 1.0 g (100%).
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[CH2:7][C:6](=O)[CH2:5][C:4]([CH3:10])([CH3:9])[P:3]1[C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([O:19][CH3:20])[C:12]=1[C:21]1[C:26]([CH:27]([CH3:29])[CH3:28])=[CH:25][C:24]([CH:30]([CH3:32])[CH3:31])=[CH:23][C:22]=1[CH:33]([CH3:35])[CH3:34].C(O)COCCO.O.NN.[OH-].[K+]>>[CH3:36][C:2]1([CH3:1])[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:10])[P:3]1[C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([O:19][CH3:20])[C:12]=1[C:21]1[C:26]([CH:27]([CH3:28])[CH3:29])=[CH:25][C:24]([CH:30]([CH3:32])[CH3:31])=[CH:23][C:22]=1[CH:33]([CH3:35])[CH3:34]
Reactant: COc1ccc(OC)c(P2C(C)(C)CC(=O)CC2(C)C)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: COc1ccc(OC)c(P2C(C)(C)CCCC2(C)C)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Temperature: 210 °C
Reaction time: 7 h
Yield: 26.5 %

Procedure:
A round bottom flask was charged with 2,2,6,6-tetramethyl-1-(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphinan-4-one (1.03 g, 2.02 mmol, 1.0 equiv) and purged with nitrogen for 15 minutes. Then nitrogen-sparged diethylene glycol (10.6 mL, 111 mmol, 55 equiv) was added and the flask was equipped with a Claisen adapter and a Dean-Stark trap. The flask was charged with hydrazine hydrate (0.892 mL, 10.1 mmol, 5 equiv, 55 wt % hydrazine) and potassium hydroxide (918 mg, 10.1 mmol, 5 equiv). The mixture was immersed in an oil bath at 170° C. The temperature of the bath was gradually increased to 210° C. over 1 hour and kept at that temperature for 7 hours. The reaction mixture was cooled to room temperature under a positive pressure of nitrogen. Reaction material that had condensed on the Claisen adapter was washed down into the reaction flask with ethyl acetate (5 mL). The phases were partitioned, and the organic layer was collected. The aqueous layer was washed with ethyl acetate (2×20 mL). The combined organic fractions were washed once with aqueous saturated sodium chloride, dried over sodium sulfate, filtered, and concentrated on a rotary evaporator. Purification of the crude material by silica gel column chromatography on an Isco CombiFlash system (40-g column; gradient: 2 column volumes heptane, ramp up to 85:15 heptane:ethyl acetate over 8 column volumes, hold at 85:15 for 4 column volumes) afforded the title compound as a white solid (266 mg, >99 area % by HPLC, 27% yield). 1H NMR (400 MHz, CDCl3) δ ppm 6.95 (s, 2H), 6.85 (d, J=8.8 Hz, 1H), 6.79 (d, J=8.8 Hz, 1H), 3.82 (s, 3H), 3.56 (s, 3H), 2.95 (hept, J=6.9 Hz, 1H), 2.49 (hept, J=6.7 Hz, 2H), 2.10-1.89 (m, 2H), 1.71-1.51 (m, 2H), 1.45-1.26 (m, 8H), 1.21 (d, J=6.8 Hz, 6H), 1.14 (s, 3H), 1.08 (s, 3H), 0.93 (d, J=6.7 Hz, 6H), 0.80 (d, J=8.6 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ ppm 154.3, 151.9 (d, J=11 Hz), 146.3, 145.5 (d, J=2 Hz), 140.1 (d, J=42 Hz), 132.5 (d, J=9 Hz), 127.7 (d, J=46 Hz), 119.7, 110.6, 107.1, 54.3 (d, J=62 Hz), 40.8 (d, J=4 Hz), 34.0 (d, J=5 Hz), 33.4, 30.7, 30.3 (d, J=24 Hz), 30.1 (d, J=3 Hz), 25.5, 24.2 (d, J=13 Hz), 20.8. 31P NMR (CDCl3, 202 MHz) δ ppm −6.0 (br s). HRMS (TOF-ESI+) calcd for [M, C32H49O2P]+ 496.3470. Found 496.3465.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:27]([O-])([OH:29])=[O:28].[OH-].[Na+].C([O-])(O)=O.[Na+]>CC(OC(C)=O)=O>[CH2:1]([O:8][C:9]1[C:24]([O:25][CH3:26])=[CH:23][C:22]([N+:27]([O-:29])=[O:28])=[C:11]([CH:10]=1)[C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)OCc2ccccc2)cc1OCc1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Product: COc1cc([N+](=O)[O-])c(C(=O)OCc2ccccc2)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 92.3 %

Procedure:
To a solution of benzyl 3-(benzyloxy)-4-methoxybenzoate (6.32 g, 18.1 mmol) in Ac2O (62 mL) cooled to −10° C. under an atmosphere of N2 was added fuming HNO3 (1.5 mL, 37.1 mmol) in one portion. Stirring was continued at −10° C. for 10 minutes, then at RT for 3 hours. The reaction mixture was carefully poured into ice-water and the pH adjusted to ca. pH=5 with 5N NaOH, sat. NaHCO3 and 0.5 NaOH. The mixture was extracted with CH2Cl2 (3×200 mL). The combined organics were dried (Na2SO4), filtered and concentrated in vacuo. The residue was azeotroped with heptane to give benzyl 5-(benzyloxy)-4-methoxy-2-nitrobenzoate as red colored oil (6.55 g, 16.7 mmol, 93%).
Reaction SMILES: CN(C)[CH:3]=[C:4]1[CH2:9][CH2:8][CH2:7][CH:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[C:5]1=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([NH:40][C:41]([NH2:43])=[NH:42])[CH:31]=[CH:32][C:33]=1[N:34]1[CH:38]=[C:37]([CH3:39])[N:36]=[CH:35]1>>[CH3:26][O:27][C:28]1[CH:29]=[C:30]([NH:40][C:41]2[N:43]=[CH:3][C:4]3[CH2:9][CH2:8][CH2:7][CH:6]([N:10]4[CH2:11][CH2:12][O:13][CH2:14][CH2:15]4)[C:5]=3[N:42]=2)[CH:31]=[CH:32][C:33]=1[N:34]1[CH:38]=[C:37]([CH3:39])[N:36]=[CH:35]1
Reactant: CN(C)C=C1CCCC(N2CCOCC2)C1=O
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Solvent: O=[N+]([O-])O
Product: COc1cc(Nc2ncc3c(n2)C(N2CCOCC2)CCC3)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared from 2-[1-dimethylamino-methylidene]-6-morpholin-4-yl-cyclohexanone (260 mg, 1.0 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (223 mg, 0.60 mmol) using in analogous manner the procedure described in example 45b). Obtained as a white solid (38 mg, 15%). MS ISP (m/e): 421.1 (100) [(M+H)+]. mp 214-216° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[C:11]#[C:12][C:13]1[N:17]([CH3:18])[CH:16]=[N:15][CH:14]=1.CN1CCOCC1.C(Cl)(=O)C(Cl)=O.[Cl:32][C:33]1[CH:34]=[C:35]([CH:37]=[CH:38][C:39]=1[CH2:40][N:41]1[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]1)[NH2:36].NC1C=CC=CC=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:32][C:33]1[CH:34]=[C:35]([NH:36][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([C:11]#[C:12][C:13]3[N:17]([CH3:18])[CH:16]=[N:15][CH:14]=3)[CH:4]=2)[CH:37]=[CH:38][C:39]=1[CH2:40][N:41]1[CH2:42][CH2:43][N:44]([CH3:47])[CH2:45][CH2:46]1
Reactant: Cc1ccc(C(=O)O)cc1C#Cc1cncn1C
Reactant: CN1CCN(Cc2ccc(N)cc2Cl)CC1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN1CCOCC1
Solvent: Nc1ccccc1
Solvent: ClCCl
Product: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(Cl)c2)cc1C#Cc1cncn1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-methyl-3-[(1-methyl-1H-imidazol-5-yl)ethynyl]benzoic acid (18 mmol) is dissolved in methylene chloride (100 mL). To this solution is added 3 equivalents of 4-methylmorpholine (NMM) followed by 1.05 equivalents of oxalyl chloride. After stirring at ambient temperature for 30 minutes, 0.8 equivalents of 3-Chloro-4-((4-methylpiperazin-1-yl)methyl)aniline (prepared as above) is added along with 5 mole % of DMAP. After initially stirring at ambient temperature, the mixture is brought to reflux and stirred overnight. After 16 h an additional 0.2 equivalents of the aniline is added, bringing the total charge to 1 equivalent. The mixture can then be stirred for an additional 2 h, quenched with water, and the layers separated. The aqueous layer can be extracted with methylene chloride (2×50 mL) and the combined extracts can be washed with water. The combined methylene chloride layers can then be evaporated and the residue dissolved in 100 mL of ethyl acetate (20 mL). After standing for 1 h, the product is allowed to crystallize. The mixture is cooled. e.g. to 0° C., filtered, and the solid product is washed with cold ethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:31])=[C:12]([C:26](OCC)=[O:27])[C:13](=[O:25])[N:14]3[CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[N:9][CH:8]=2)=[CH:4][CH:3]=1.[OH:34][CH2:35][CH2:36][NH2:37]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:31])=[C:12]([C:26]([NH:37][CH2:36][CH2:35][OH:34])=[O:27])[C:13](=[O:25])[N:14]3[CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[N:9][CH:8]=2)=[CH:32][CH:33]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCC2=O)c1=O
Reactant: NCCO
Product: O=C(NCCO)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-(4-fluorobenzyl)-4-hydroxy-2-oxo-1-[2-(2-oxopyrrolidin-1-yl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-hydroxyethylamine by methods similar to those described in Example 6. The product was obtained as a white solid: 1H NMR (CDCl3) δ 10.38 (1H, br m), 8.60 (1H, s), 8.07 (1H, s), 7.24 (2H, m), 7.00 (2H, t, J=8.6 Hz), 4.36 (2H, t, J=7 Hz), 4.15 (2H, s), 3.87 (2H, t, J=5 Hz), 3.66 (2H, m), 3.51 (2H, t, J=8 Hz), 3.45 (2H, t, J=7 Hz), 2.37 (2H, t, J=8 Hz), 2.00 (2H, m).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[C:5]([CH3:17])=[CH:4][N:3]=1.[NH2:18][C:19]1[C:24]([O:25][CH3:26])=[CH:23][C:22]([N:27]2[CH2:32][CH2:31][CH:30]([NH:33]C(=O)OC(C)(C)C)[CH2:29][CH2:28]2)=[C:21]([CH3:41])[CH:20]=1>>[NH2:33][CH:30]1[CH2:31][CH2:32][N:27]([C:22]2[C:21]([CH3:41])=[CH:20][C:19]([NH:18][C:2]3[N:7]=[C:6]([C:8]4[C:16]5[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=5)[NH:10][CH:9]=4)[C:5]([CH3:17])=[CH:4][N:3]=3)=[C:24]([O:25][CH3:26])[CH:23]=2)[CH2:28][CH2:29]1
Reactant: COc1cc(N2CCC(NC(=O)OC(C)(C)C)CC2)c(C)cc1N
Reactant: Cc1cnc(Cl)nc1-c1c[nH]c2ccccc12
Product: COc1cc(N2CCC(N)CC2)c(C)cc1Nc1ncc(C)c(-c2c[nH]c3ccccc23)n1

Procedure:
Starting materials: 3-(2-chloro-5-methylpyrimidin-4-yl)-1H-indole (INTERMEDIATE 1) tert-butyl 1-(4-amino-5-methoxy-2-methylphenyl)piperidin-4-ylcarbamate (INTERMEDIATE 29).