Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]2=[C:6]3[C:11](=[C:12]([NH2:14])[N:13]=[C:4]2[CH:3]=1)[N:10]=[CH:9][C:8](/[CH:15]=[CH:16]/[CH3:17])=[CH:7]3.[H][H]>C(OCC)(=O)C.CO.[Pd]>[CH3:1][C:2]1[CH:19]=[CH:18][C:5]2=[C:6]3[C:11](=[C:12]([NH2:14])[N:13]=[C:4]2[CH:3]=1)[N:10]=[CH:9][C:8]([CH2:15][CH2:16][CH3:17])=[CH:7]3
Reactant: C/C=C/c1cnc2c(N)nc3cc(C)ccc3c2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCc1cnc2c(N)nc3cc(C)ccc3c2c1
Reaction time: 3 h

Procedure:
To a solution of (E)-8-methyl-2-(prop-1-enyl)benzo[f][1,7]naphthyridin-5-amine (from the previous step) in ethyl acetate/methanol (1:4, 0.05 M) was added 10% wt palladium on carbon (0.2 eq.). Hydrogen gas was introduced via a balloon, and the reaction was stirred for 3 hours. The mixture was filtered through a pad of celite, washing with dichloromethane. The filtrate was concentrated en vaccuo and purified by a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give 8-methyl-2-propylbenzo[f][1,7]naphthyridin-5-amine as offwhite solid. 1H NMR (CDCl3): δ 8.59 (d, 1H), 8.41 (d, 1H), 8.10 (d, 1H), 7.43 (s, 1H), 7.13 (dd, 1H), 5.94 (bs, 2H), 2.78 (t, 2H), 2.44 (s, 3H), 1.75 (m, 2H), 0.95 (t, 3H). LRMS [M+H]=252.1
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([OH:24])=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:9]2=[N:10][CH:11]=1)=[O:5])C.[OH-].[Na+].Cl>C(O)C>[OH:24][C:7]1[C:6]([C:4]([OH:5])=[O:3])=[CH:11][N:10]=[C:9]2[N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[N:13]=[CH:14][C:8]=12
Reactant: CCOC(=O)c1cnc2c(cnn2Cc2ccc(OC)cc2)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(Cn2ncc3c(O)c(C(=O)O)cnc32)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
4-Hydroxy-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester was dissolved in ethanol (20 mL), and a sodium hydroxide solution (5 M, 6 mL) was added thereto. The resulting mixture was stirred at 70° C. for 2 hours, and a hydrochloric acid solution (5 M, 6 mL) was added thereto under ice-cooling. The precipitate was collected by filtration and washed with water. The obtained solid was suspended in a methanol-toluene solvent mixture and concentrated under reduced pressure to give 4-hydroxy-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (2.89 g, 98%) as a colorless powder.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].Cl.F[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[N:18][CH:17]=[CH:16]2>CC(N(C)C)=O>[CH:19]1[C:20]2[C:15](=[CH:14][C:13]([O:8][C@H:5]3[CH2:6][CH2:7][C@H:2]([NH2:1])[CH2:3][CH2:4]3)=[CH:22][CH:21]=2)[CH:16]=[CH:17][N:18]=1
Reactant: NC1CCC(O)CC1
Reactant: Fc1ccc2cnccc2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: N[C@H]1CC[C@H](Oc2ccc3cnccc3c2)CC1
Reaction time: 0.5 h

Procedure:
6.1 g (53 mmol) of 4-amino-cyclohexanol were dissolved in 50 ml of dimethyl acetamide and 4.24 g (106 mmol) of sodium hydride (60%) were added at room temperature. After the reaction mixture was stirred for 30 minutes under argon, a solution of 6.49 g (35.3 mmol) of 6-fluoro-isoquinoline hydrochloride was added and the mixture was stirred at room temperature overnight. For workup, the solvent was removed in vacuo and the residue was dissolved in dichloromethane and washed twice with water. The organic layer was separated, dried with magnesium sulfate and evaporated to yield 8.64 g of the crude product, which was used without further purification. Rt=0.77 min (Method B). Detected mass: 243.1 (M+H+).
Reaction SMILES: C[O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][N:5]=1.[OH-].[Na+].Cl>CO>[NH2:10][C:8]1[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][N:5]=[C:4]([C:3]([OH:14])=[O:2])[CH:9]=1
Reactant: COC(=O)c1cc(N)c([N+](=O)[O-])cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1cc(C(=O)O)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of methyl-4-amino-5-nitropicolinate (200 mg, 1.01 mmol) and NaOH (aq, 1M, 2.0 mL, 2.0 mmol) in methanol was stirred at ambient temperature for 10 min. The mixture was acidified by addition of HCl (aq, 1M, 2.1 mL, 2.1 mmol) and concentrated i. vac. and the aqueous residing mixture filtered. The solid was washed with water and dried i. vac.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11](O)=O)=[CH:5][CH:4]=1)#[N:2].[C:14]1([N:20]([CH2:32][CH2:33][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:21](=[O:31])[C:22]2[CH:27]=[CH:26][C:25]([NH:28][CH3:29])=[C:24]([NH2:30])[CH:23]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl.CO>[C:14]1([N:20]([CH2:32][CH2:33][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:21]([C:22]2[CH:27]=[CH:26][C:25]3[N:28]([CH3:29])[C:11]([CH2:10][NH:9][C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=4)=[N:30][C:24]=3[CH:23]=2)=[O:31])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: N#Cc1ccc(NCC(=O)O)cc1
Reactant: CNc1ccc(C(=O)N(CCCC(=O)OC(C)(C)C)c2ccccc2)cc1N
Solvent: CO
Solvent: ClCCl
Product: Cn1c(CNc2ccc(C#N)cc2)nc2cc(C(=O)N(CCCC(=O)OC(C)(C)C)c3ccccc3)ccc21
Yield: 65 %

Procedure:
Prepared analogously to Example 25c from N-(4-cyanophenyl)glycine and 3-amino-4-methylaminobenzoic acid-N-phenyl-N-(3-tert-butyloxycarbonylpropyl)amide. Yield: 65% of theory; Rf value: 0.17 (silica gel; dichloromethane/methanol=19:1).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]([C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=5)[N:24]([CH3:32])[N:23]=4)[N:20]=3)[N:15]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[CH:14]=2)=[O:12])[CH3:9])[O:6][CH:7]=1.C(N(CC)CC)C.[CH3:48][S:49](Cl)(=[O:51])=[O:50]>ClCCl>[F:31][C:27]1[CH:26]=[C:25]2[C:30]([C:22]([C:19]3[N:20]=[C:21]4[C:13]([C:11]([NH:10][C@@H:8]([C:5]5[O:6][CH:7]=[C:3]([CH2:2][O:1][S:49]([CH3:48])(=[O:51])=[O:50])[N:4]=5)[CH3:9])=[O:12])=[CH:14][N:15]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:39])([CH3:38])[CH3:40])[C:16]4=[N:17][CH:18]=3)=[N:23][N:24]2[CH3:32])=[CH:29][CH:28]=1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1nc(CO)co1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1nc(COS(C)(=O)=O)co1
Temperature: 0 °C
Reaction time: 2 h
Yield: 114.2 %

Procedure:
In a round-bottomed flask, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-hydroxymethyl-oxazol-2-yl)-ethyl]-amide (115 mg, 0.20 mmol) was dissolved in dichloromethane (1 ml). The solution was cooled to 0° C. and triethylamine (0.04 ml, 0.29 mmol) and methanesulfonyl chloride (19 μl, 0.24 mmol) were added. The reaction mixture was stirred at 0° C. for 2 h then quenched with water and extracted with dichloromethane (2×). The organic layers were combined, dried over sodium sulfate, filtered and concentrated to afford 147 mg of methanesulfonic acid 2-((R)-1-{[2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-amino}-ethyl)-oxazol-4-ylmethyl ester as a yellow foam which was used without further purification.
Reaction SMILES: C([N:4]1[CH:8]([C:9](=[O:11])[CH3:10])[CH2:7][CH2:6][C:5]1=[O:12])(=O)C.[C:13](OCC)(=[O:15])[CH3:14]>C(O)(=O)C.[Pt](=O)=O>[C:13]([O:11][CH:9]([CH:8]1[NH:4][C:5](=[O:12])[CH2:6][CH2:7]1)[CH3:10])(=[O:15])[CH3:14]
Reactant: CCOC(C)=O
Reactant: CC(=O)C1CCC(=O)N1C(C)=O
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CC(=O)OC(C)C1CCC(=O)N1
Reaction time: 17 h
Yield: 46 %

Procedure:
1,5-Diacetylpyrrolidin-2-one (10.6 g) is hydrogenated at 875 psi at 100° C. over 0.5 g of platinum dioxide in 50 ml of ethyl acetate. The conversion after about 17 hours is about 40 percent. The mixture is freed of the catalyst and solvent and is then hydrogenated again in 50 ml of acetic acid over 1.0 g of platinum dioxide for about 19 hours. The conversion is now about 50 percent by nuclear magnetic resonance analysis. This product mixture is distilled at 0.15 mm Hg to give 5.35 g (50 percent), of unreacted 1,5-diacetylpyrrolidin-2-one. The residue upon bulb-to-bulb distillation (140° C. bath temperature, 0.15 mm) gives 4.85 g (46 percent yield, 92 percent selectivity) of 5-(1-acetoxyethyl)pyrrolidin-2-one, containing a very small amount of 1,5-diacetylpyrrolidin-2-one.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[N:8]=2)[CH:2]=1.[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25]Cl>>[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25][O:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:9]2[N:8]=[C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH:12]=[CH:11][N:10]=2)=[CH:15][CH:16]=1
Reactant: Oc1ccc(Nc2nccc(-c3cccnc3)n2)cc1
Reactant: CN(C)CCCCl
Product: CN(C)CCCOc1ccc(Nc2nccc(-c3cccnc3)n2)cc1

Procedure:
A 5.46 g portion of 4-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenol was reacted with 3-dimethylaminopropyl chloride by the procedure of Example 255, giving 2.9 g of the desired product, mp 85°-87° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([OH:10])=O)[CH2:3][CH2:2]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:53][C:54]1[CH:55]=[C:56]([C:60]2[N:69]=[C:68]([NH:70][C:71]3[CH:72]=[C:73]4[C:77](=[CH:78][CH:79]=3)[N:76]([C:80]([O:82][C:83]([CH3:86])([CH3:85])[CH3:84])=[O:81])[N:75]=[CH:74]4)[C:67]3[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=3)[N:61]=2)[CH:57]=[CH:58][CH:59]=1>C(Cl)Cl>[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][C:8]([NH:53][C:54]2[CH:55]=[C:56]([C:60]3[N:69]=[C:68]([NH:70][C:71]4[CH:72]=[C:73]5[C:77](=[CH:78][CH:79]=4)[N:76]([C:80]([O:82][C:83]([CH3:86])([CH3:85])[CH3:84])=[O:81])[N:75]=[CH:74]5)[C:67]4[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=4)[N:61]=3)[CH:57]=[CH:58][CH:59]=2)=[O:10])[CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(N)c4)nc4ccccc34)ccc21
Reactant: O=C(O)CN1CCOCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(NC(=O)CN5CCOCC5)c4)nc4ccccc34)ccc21
Temperature: 25 °C
Reaction time: 0.21 h

Procedure:
A suspension of 2-morpholinoacetic acid (16 mg, 0.11 mmol), PyBOP (57 mg, 0.11 mmol), DIEA (96 μL, 0.55 mmol) in CH2Cl2 (0.5 mL) was stirred at RT for 10-15 minutes. This solution of activated acid was added to a suspension of tert-butyl 5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (100 mg, 0.22 mmol) and CH2Cl2 (1 mL). The reaction mixture was stirred at RT for 1.5 h. Activated another 0.5 equivalent of the acid as described above and it was once again added to the reaction mixture and stirred for 1.5 h. Added two more 0.5 equivalents of activated acid while stirring 1.5 hr between each addition. Diluted with more CH2Cl2 and extracted with H2O (3×). Organic layer was dried under Na2SO4 and concentrated in vacuo to give the desired oil product tert-butyl 5-(2-(3-(2-morpholinoacetamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]([C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)[N:3]=1.[C:22](N1C=CN=C1)([N:24]1C=CN=C1)=O.CN>CN(C=O)C.C1COCC1>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH:24][CH3:22])=[O:18])=[CH:15][CH:14]=2)[N:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1ccc(-n2nc(Br)c3ccccc3c2=O)cc1
Agent: CN
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(-n2nc(Br)c3ccccc3c2=O)cc1
Reaction time: 4 h
Yield: 77.9 %

Procedure:
4-(4-Bromo-1-oxo-1H-phthalazin-2-yl)benzoic acid (0.15 g, 0.43 mmol) and 1,1′-carbonyldiimidazol (0.10 g, 0.65 mmol) were dissolved in DMF (10 ml) at RT. Methyl amine (0.33 ml of a 2M solution in THF, 0.65 mmol) were added and stirring was continued for 4 h. Evaporation of the solvent under reduced pressure, dilution with DCM, extraction with a saturated aqueous NaHCO3 solution and evaporation of the solvent in vacuum gave the title compound (0.12 g, 77% yield) 1H-NMR: (400 MHz, D6-DMSO) 8.55 (1H, d), 8.38 (1H, d), 8.10 (1H, t), 8.03 (2H, d), 8.02 (2H, d), 7.73 (2H, d), 2.82 (3H, d).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:22])[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:15][C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:4][CH:3]=1.C[O:24][C:25](=[O:47])[C@@H:26]([CH2:45]O)[NH:27]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([O:22][CH2:45][C@H:26]([C:25]([OH:47])=[O:24])[NH2:27])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[O:15][C:16]3[C:21]2=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](CO)NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: Cc1ccc(C2(O)c3ccccc3Oc3ccccc32)cc1
Product: Cc1ccc(C2(OC[C@@H](N)C(=O)O)c3ccccc3Oc3ccccc32)cc1

Procedure:
from 9-(4-methylphenyl)-9H-xanthen-9-ol (Example 1q) and Nα -(9-fluorenylmethoxycarbonyl)-D-serine methyl ester;
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH2:13][CH3:14])=[N:7]2.[NH2:15][C:16]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:17]=1[O:18][C:19]1[CH:30]=[CH:29][C:22]([C:23]([N:25]([O:27][CH3:28])[CH3:26])=[O:24])=[CH:21][CH:20]=1>>[Cl:35][C:33]1[CH:32]=[CH:31][C:17]([O:18][C:19]2[CH:30]=[CH:29][C:22]([C:23]([N:25]([O:27][CH3:28])[CH3:26])=[O:24])=[CH:21][CH:20]=2)=[C:16]([NH:15][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:34]=1
Reactant: CON(C)C(=O)c1ccc(Oc2ccc(Cl)cc2N)cc1
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Product: CCCc1ccc2c(Nc3cc(Cl)ccc3Oc3ccc(C(=O)N(C)OC)cc3)ccnc2n1

Procedure:
The product from Example 2g (75 mg, 0.36 mmol) was reacted with the product from Example 128b (111 mg, 0.36 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (76.3 mg, 36%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.88-1.03 (m, 3H) 1.70-1.91 (m, 2H) 2.88-3.00 (m, 2H) 3.18 (s, 3H) 3.42 (s, 3H) 6.71 (d, J=7.35 Hz, 1H) 6.94 (d, J=8.82 Hz, 2H) 7.36 (d, J=8.82 Hz, 1H) 7.50 (d, J=8.82 Hz, 2H) 7.59-7.66 (m, 1H) 7.71-7.79 (m, 2H) 8.53 (d, J=6.99 Hz, 1H) 8.84 (d, J=8.82 Hz, 1H) 10.89 (s, 1H) 14.54 (s, 1H); MS (ESI+) m/z 477 (M+H−TFA)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1([F:29])[CH2:18][CH2:17][N:16]([CH:19]([C:22]2[CH:23]=[N:24][C:25]([CH3:28])=[N:26][CH:27]=2)[CH2:20][NH2:21])[CH2:15][CH2:14]1>>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([N:16]1[CH2:15][CH2:14][C:13]([F:29])([F:12])[CH2:18][CH2:17]1)[C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[N:26][CH:27]=1)=[O:6]
Reactant: Cc1ncc(C(CN)N2CCC(F)(F)CC2)cn1
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Product: Cc1ncc(C(CNC(=O)c2ccc(Cl)cc2Cl)N2CCC(F)(F)CC2)cn1

Procedure:
From 2,4-dichlorobenzoic acid and 2-(4,4-difluoropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethanamine.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[Na+].[Na+].[C:10]([NH:13][C@H:14]1[C@H:22]([C@@H:23]([C@@H:25]([CH2:27][OH:28])[OH:26])[OH:24])[O:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C@@H:15]1[NH:29][C:30]#[N:31])(=[O:12])[CH3:11]>CO>[C:10]([NH:13][C@H:14]1[C@H:22]([C@@H:23]([C@@H:25]([CH2:27][OH:28])[OH:26])[OH:24])[O:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C@@H:15]1[NH:29][C:30]([NH2:31])=[N:2][OH:3])(=[O:12])[CH3:11]
Reactant: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)OC(C(=O)O)=C[C@@H]1NC#N
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)OC(C(=O)O)=C[C@@H]1NC(N)=NO
Temperature: 21 °C
Reaction time: 0.25 h
Yield: 32.6 %

Procedure:
Hydroxylamine hydrochloride (1.1 g, 15.85 mmol)(dried under vacuum over P2O5) was dissolved in dried (over 3 A mol. sieves) methanol (20 ml) and sodium carbonate (0.835 g, 7.9 mmol) was added. This was stirred at 21° C. under N2 for 15 min., then solid was filtered off. To the filtrate was then added the product of Example 1, step (i) (500 mg, 1.585 mmol) and stirring under N2 at 21° C. continued for 16 hr. White solid was filtered off, air dried, then dried under high vacuum to give the title compound (Yield, 180 mg).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]12[CH2:17][CH2:16][C:15](=[O:18])[N:14]1[CH2:13][CH2:12][CH2:11][NH:10]2.[Cl:19][CH:20]([Cl:24])[C:21](Cl)=[O:22]>C1(C)C=CC=CC=1>[Cl:19][CH:20]([Cl:24])[C:21]([N:10]1[C:9]2([CH3:8])[N:14]([C:15](=[O:18])[CH2:16][CH2:17]2)[CH2:13][CH2:12][CH2:11]1)=[O:22]
Reactant: CC12CCC(=O)N1CCCN2
Reactant: O=C(Cl)C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC12CCC(=O)N1CCCN2C(=O)C(Cl)Cl
Temperature: -10 °C
Reaction time: 4 h
Yield: 66.8 %

Procedure:
10.5 g (0.105 mole) of triethylamine are added to a solution of 15.4 g (0.1 mole) of 6-methyl-9-oxo-1,5-diazabicyclo[4.3.0]nonane in 100 ml of toluene. The mixture is cooled to -10° C. and 14.8 g (0.1 mole) of dichloroacetyl chloride are added dropwise at from -10° to -5° C. The batch is stirred for a further 4 hours and the triethylamine hydrochloride which has precipitated is filtered off. After evaporating the toluene from the filtrate, crystals separate out, and these can be recrystallized from a 1:3 toluene/acetone mixture. 17.7 g of 5-dichloroacetyl-6-methyl-9-oxo-1,5-diazabicyclo[4.3.0]nonane, of melting point 144°-147° C., are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][NH:11][C:10](=[O:13])[C:9]=2[CH3:14])=[CH:4][CH:3]=1.[N+:15]([O-])([OH:17])=[O:16]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:12][NH:11][C:10](=[O:13])[C:9]=2[CH3:14])=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16]
Reactant: CC1=C(c2ccc(F)cc2)CNC1=O
Reactant: O=[N+]([O-])O
Product: CC1=C(c2ccc(F)c([N+](=O)[O-])c2)CNC1=O

Procedure:
In a manner similar to that described in Preparation 8, 4-(4-fluorophenyl)-1,5-dihydro-3-methyl-2H-pyrrol-2-one is reacted with nitric acid to provide the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11].C([O-])([O-])=O.[Na+].[Na+].[CH3:31][C:32]1[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O>COCCOC>[CH3:31][C:32]1[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][C:33]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11]
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CSc1ccccc1Br
Reactant: Cc1cccc(B(O)O)c1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1cccc(-c2ccccc2SCC(=O)N(NC(=O)c2ccccc2)C(C)C)c1C
Yield: 16 %

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-phenylsulfanyl)-acetyl]-N′-isopropyl-hydrazide (50 mg, 0.123 mmol) in DME (4 ml)/2M Na2CO3 (0.645 ml, 1.29 mmoles) was treated with 2,3-dimethylphenylboronic acid (36.9 mg, 0.246 mmol) and Pd[PPh3]4 (70.2 mg, 0.061 mmol) for 65 hours at 90° C. The reaction mixture was partitioned between water and DCM. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was adsorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexane gradient. Further purification by RP HPLC afforded the product (8.5 mg, 16.4%). MS m/e 433.24 (M+H+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20](I)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:22]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)#[CH:23]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:23]#[C:22][C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1cccnc1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc2c(I)cnn12
Product: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc2c(C#Cc3cccnc3)cnn12

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-3-iodo-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (example C.4) (420 mg, 1.0 mmol) and commercially available 3-Ethynylpyridine (102 mg, 0.9 mmol) according to general procedure II. Obtained as an orange solid (230 mg, 58%). MS (ISP) 398.9 [(M+H)+]; mp 214-215° C.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[C:23]1[CH:28]=[C:27]([CH:29]=[O:30])[CH:26]=[CH:25][C:24]=1[O:31][CH3:32])[C:8](=[O:11])[O:9][CH3:10].C[Si](C)(C)[C:44]([F:47])([F:46])[F:45].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:1][C:2]([F:40])([F:41])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:37])([F:39])[F:38])[CH:35]=1)[CH2:6][N:7]([CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[C:23]1[CH:28]=[C:27]([CH:29]([OH:30])[C:44]([F:47])([F:46])[F:45])[CH:26]=[CH:25][C:24]=1[O:31][CH3:32])[C:8](=[O:11])[O:9][CH3:10]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C=O)ccc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C(O)C(F)(F)F)ccc1OC
Temperature: 25 °C

Procedure:
To a solution of methyl [3,5-bis(trifluoromethyl)benzyl]{[5′-formyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate (Example 73, 184 mg, 0.31 mmol) in anhydrous tetrahydrofuran at 0° C., 0.5 M trimethyl(trifluoromethyl) silane (2.5 mL, 1.24 mmol) and a catalytic amount of tetrabutylammonium fluoride were added. The reaction was stirred with gradual warming to room temperature. Once the reaction was complete, it was quenched with saturated ammonium chloride solution. The organic was extracted with methylene chloride, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The title compound was obtained by preparative thin layer chromatography using 1:4 acetone:hexane. 1H NMR (CDCl3, 600 MHz) δ 7.74 (s, 1H), 7.61 (m, 1H), 7.15-7.56 (m, 6H), 6.99 (m, 1H), 4.97 (m, 1H), 4.19-4.38 (m, 4H), 3.61-3.76 (m, 6H). LC-MS (M+Na) 686.9 (4.28 min).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](N1C=CN=C1)=[O:11])[CH2:2]2.[F:17][C:18]1[CH:19]=[C:20]([CH:24]([C:26]2[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=2)[OH:25])[CH:21]=[CH:22][CH:23]=1>>[F:17][C:18]1[CH:19]=[C:20]([CH:24]([O:25][C:10](=[O:11])[O:9][C@@H:3]2[CH:4]3[CH2:5][CH2:6][N:1]([CH2:8][CH2:7]3)[CH2:2]2)[C:26]2[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: Cc1cccc(C(O)c2cccc(F)c2)c1
Reactant: O=C(O[C@H]1CN2CCC1CC2)n1ccnc1
Product: Cc1cccc(C(OC(=O)O[C@H]2CN3CCC2CC3)c2cccc(F)c2)c1

Procedure:
The desired product was prepared by reacting imidazole-1-carboxylic acid (R)-1-aza-bicyclo[2.2.2]oct-3-yl ester with (3-fluoro-phenyl)-m-tolyl-methanol.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][O:18][C:19]3[CH:20]=[N:21][C:22]([C:30]4[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:31]=4[F:38])=[C:23]([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:24]=3)[CH:12]=2)[CH2:5][C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+]>C1COCC1.CO>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][O:18][C:19]3[CH:20]=[N:21][C:22]([C:30]4[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:31]=4[F:38])=[C:23]([CH2:25][C:26]([CH3:29])([CH3:27])[CH3:28])[CH:24]=3)[CH:12]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(c1ccnc(COc2cnc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ncc(OCc3cc(C(CC(=O)O)C4CC4)ccn3)cc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.2 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(2-(((6-(2-fluoro-5-methoxyphenyl)-5-neopentylpyridin-3-yl)oxy)methyl)pyridin-4-yl)propanoate (182 mg) in THF (2.0 mL) and methanol (1.0 mL) was added 1N aqueous sodium hydroxide solution (2.0 mL), and the mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (164 mg) as a white amorphous solid.