Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:17][C@@H:18]([CH3:24])[C:19]([O:22][CH3:23])([CH3:21])[CH3:20])[C@H:4]([C@@H:6]1[C@:14]2([CH3:15])[C@H:9]([C@@H:10]([OH:16])[CH2:11][CH2:12][CH2:13]2)[CH2:8][CH2:7]1)[CH3:5].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl>[CH3:1][O:2][CH:3]([CH2:17][C@@H:18]([CH3:24])[C:19]([O:22][CH3:23])([CH3:21])[CH3:20])[C@H:4]([C@@H:6]1[C@:14]2([CH3:15])[C@H:9]([C:10](=[O:16])[CH2:11][CH2:12][CH2:13]2)[CH2:8][CH2:7]1)[CH3:5]
Reactant: COC(C[C@@H](C)C(C)(C)OC)[C@@H](C)[C@H]1CC[C@H]2[C@@H](O)CCC[C@]12C
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC(C[C@@H](C)C(C)(C)OC)[C@@H](C)[C@H]1CC[C@H]2C(=O)CCC[C@]12C

Procedure:
The compound of Example 10H (27 mg, 0.079 mmol) was dissolved in 1 mL of dichloromethane; 150 mg of pyridinium dichromate and 10 mg of pyridinium p-toluenesulfonate were added, and the resultant mixture was stirred overnight at ambient temperature. Diatomaceous earth (˜500 mg) was added, and the solvents were removed in vacuo. The residue was taken up in ethyl acetate and loaded onto a plug of silica. Elution with a gradient of 50% to 100% ethyl acetate in hexanes, and concentration of the combined eluate, gave a product which was carried forward without further purification.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C:2]1=[O:7].[CH2:8]([C:11]1[C:19]2[O:18][N:17]=[C:16]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:15]=2[CH:14]=[CH:13][C:12]=1[O:25][CH2:26][CH2:27][CH2:28]Br)[CH2:9][CH3:10].C([O-])([O-])=O.[Cs+].[Cs+].C(O)(C(F)(F)F)=O>CN(C=O)C.O>[CH2:8]([C:11]1[C:19]2[O:18][N:17]=[C:16]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:15]=2[CH:14]=[CH:13][C:12]=1[O:25][CH2:26][CH2:27][CH2:28][N:1]1[C:5](=[O:6])[CH2:4][CH2:3][C:2]1=[O:7])[CH2:9][CH3:10]
Reactant: CCCc1c(OCCCBr)ccc2c(CC(C)(C)C)noc12
Reactant: O=C1CCC(=O)N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCCc1c(OCCCN2C(=O)CCC2=O)ccc2c(CC(C)(C)C)noc12
Reaction time: 18 h

Procedure:
Pyrrolidine-2,5-dione (17 mg, 0.172 mmol) and 7-propyl-3-neopentyl-6-(3-bromopropyloxy)-1,2-benzisoxazole, from Example 9 above, (42 mg, 0.114 mmol) were combined in DMF (7 ml) with Cs2CO3 (56 mg, 0.17 mmol) at room temperature. The mixture was stirred 18 hours. The mixture was diluted with 2 ml H2O and acidified with TFA. The resulting mixture was purified by elution from a RP-18 reversed phase HPLC column with a 90:10 to 0:100 H2O:CH3CN gradient to yield 1-(3-{[7-propyl-3-(neopentyl)-1,2-benzisoxazol-6-yl]oxy}propyl)pyrrolidine-2,5-dione.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[CH2:16]([OH:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>>[CH2:16]([O:22][C:7](=[O:8])[C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCO
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Product: CCCCCCOC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Yield: 85 %

Procedure:
Using 3,5-dinitrobenzoyl chloride (74.3 g, 322.5 mmol) and hexyl alcohol (33.0 g, 323.6 mmol), n-hexyl-3,5-dinitrobenzoate was obtained (81.1 g, yield: 85%) in the same manner as in Example 1.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH:19]3[CH2:24][CH2:23][N:22]([CH:25]([CH3:29])[CH2:26][CH2:27][NH2:28])[CH2:21][CH2:20]3)[O:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[O:11]2)=[CH:6][CH:5]=1.[CH3:32][C:33]1[N:41]=[CH:40][CH:39]=[C:38]([CH3:42])[C:34]=1[C:35](O)=[O:36]>>[CH3:32][C:33]1[N:41]=[CH:40][CH:39]=[C:38]([CH3:42])[C:34]=1[C:35]([NH:28][CH2:27][CH2:26][CH:25]([N:22]1[CH2:21][CH2:20][CH:19]([C:10]2([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:30])[F:31])=[CH:5][CH:6]=3)[O:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[O:11]2)[CH2:24][CH2:23]1)[CH3:29])=[O:36]
Reactant: CC(CCN)N1CCC(C2(c3ccc(OC(F)(F)F)cc3)Oc3ccccc3O2)CC1
Reactant: Cc1ccnc(C)c1C(=O)O
Product: Cc1ccnc(C)c1C(=O)NCCC(C)N1CCC(C2(c3ccc(OC(F)(F)F)cc3)Oc3ccccc3O2)CC1
Yield: 31.1 %

Procedure:
Using general procedure E, 3-{4-[2-(4-trifluoromethoxy-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butylamine (see EXAMPLE 275) (135 mg, 0.31 mmol) and 2,4-dimethylnicotinic acid (51 mg, 0.34 mmol) afforded COMPOUND 276 (55 mg, 31%). 1H NMR (CDCl3) δ 0.83-1.17 (m, 2H), 0.95 (d, 3H, J=6.6 Hz), 1.46-1.63 (m, 3H), 1.67-1.80 (m, 1H), 1.86-1.99 (m, 2H), 2.31 (s, 3H), 2.33-2.40 (m, 1H), 2.54 (s, 3H), 2.67-2.81 (m, 3H), 3.25-3.35 (m, 1H), 3.79-3.89 (m, 1H), 6.76-6.86 (m, 4H), 6.99 (d, 1H, J=5.1 Hz), 7.17 (d, 2H, J=8.1 Hz), 7.40-7.44 (m, 2H), 8.11 (br s, 1H), 8.42 (d, 1H, J=4.8 Hz). 13C NMR (CDCl3) δ 13.57, 19.19, 22.63, 25.94, 26.56, 31.64, 40.02, 44.32, 45.92, 52.42, 60.54, 108.92, 118.07, 120.78, 121.86, 122.91, 127.68, 133.99, 138.89, 144.02, 147.35, 149.21, 149.76, 154.55, 168.73. ES-MS m/z 570 (M+H). Anal. Calcd. for C31H34N3F3O4.0.28CH2Cl2: C, 63.31; H, 5.87; N, 7.08. Found: C, 63.01; H, 5.88; N, 7.47.
Reaction SMILES: [CH3:1][C:2]([CH3:26])([CH2:23][CH2:24][CH3:25])[CH2:3][O:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[C:10]([O:20][CH3:21])[N:11]2C2CCCCO2)=[C:7]([NH2:22])[N:6]=1.[C:27]([OH:33])([C:29]([F:32])([F:31])[F:30])=[O:28]>CO>[F:30][C:29]([F:32])([F:31])[C:27]([OH:33])=[O:28].[CH3:1][C:2]([CH3:26])([CH2:23][CH2:24][CH3:25])[CH2:3][O:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[C:10]([O:20][CH3:21])[NH:11]2)=[C:7]([NH2:22])[N:6]=1
Reactant: CCCC(C)(C)COc1nc(N)c2nc(OC)n(C3CCCCO3)c2n1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CCCC(C)(C)COc1nc(N)c2nc(OC)[nH]c2n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 2-[(2,2-dimethylpentyl)oxy]-8-methoxy-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (323 mg) in dry MeOH (3.23 mL) was added TFA (0.323 mL) and the reaction was stirred at room temperature for 48 h. The reaction was concentrated in vacuo to give a yellow residue. The residue was triturated with Et2O and was filtered to give the title compound as an off-white solid (252 mg).
Reaction SMILES: C([N:14]1[C@:22]2([CH2:24][OH:25])[O:23][C@:15]1([C@H:18]([C@@H:20]2[OH:21])[OH:19])[CH2:16][OH:17])(C1C=CC=CC=1)C1C=CC=CC=1.[H][H]>CO.O.[Pd].[C]>[NH:14]1[C@:22]2([CH2:24][OH:25])[O:23][C@:15]1([C@H:18]([C@@H:20]2[OH:21])[OH:19])[CH2:16][OH:17]
Reactant: OC[C@]12O[C@](CO)([C@@H](O)[C@@H]1O)N2C(c1ccccc1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: O
Product: OC[C@]12N[C@](CO)(O1)[C@@H](O)[C@@H]2O
Yield: 91 %

Procedure:
A mixture of N-benzhydryl-2,5-anhydro-2,5-imino-D-glucitol (Formula XI, R3 =Ph2CH 8.40 g, 25.5 mmol) and 0.42 g of 20% PD(OH)2 /carbon in 100 mL of MeOH was set shaking on a Parr apparatus under 60 psig of hydrogen overnight. This solution was then filtered and concentrated. Hexane (ca. 300 mi) was added, and the solvent was then removed from a white solid, which was washed with ca. 200 mL of hexane. The product was recrystallized from ETOH/CH3CN to give 3.79 g (91%) of white needles, mp 139°-142.50° C. (corrected). Both 1H and 13C NMR in D2O supported the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:39])[CH:5]=[C:6]([Cl:38])[C:7]=1[CH2:8][C@@H:9]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([F:32])[F:31])=[C:25]([O:33][CH2:34][CH:35]2[CH2:37][CH2:36]2)[CH:24]=1)[O:10][C:11]([O:13]C1C=CC([N+]([O-])=O)=CC=1)=[O:12].O[C:41]1[CH:42]=[CH:43][C:44]([O:60][CH3:61])=[C:45]([N:47]([CH2:52][CH2:53][N:54]2[CH2:59][CH2:58][O:57][CH2:56][CH2:55]2)[S:48]([CH3:51])(=[O:50])=[O:49])[CH:46]=1.O>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:38][C:6]1[CH:5]=[N+:4]([O-:39])[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C@@H:9]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([F:32])[F:31])=[C:25]([O:33][CH2:34][CH:35]2[CH2:36][CH2:37]2)[CH:24]=1)[O:10][C:11]([O:13][C:41]1[CH:42]=[CH:43][C:44]([O:60][CH3:61])=[C:45]([N:47]([CH2:52][CH2:53][N:54]2[CH2:55][CH2:56][O:57][CH2:58][CH2:59]2)[S:48]([CH3:51])(=[O:50])=[O:49])[CH:46]=1)=[O:12]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: COc1ccc(O)cc1N(CCN1CCOCC1)S(C)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(OC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1N(CCN1CCOCC1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 7 h
Yield: 39.2 %

Procedure:
To a solution of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((4-nitrophenoxy)carbonyloxy)ethyl)pyridine I-oxide (prepared in an analogous manner to that described in Scheme 3, Step 1) (0.250 g, 0.427 mmol) and DMAP (0.052 g, 0.427 mmol) in dry DMF (5 ml), N-(5-hydroxy-2-methoxyphenyl)-N-(2-morpholinoethyl)methanesulfonamide (0.180 g, 0.545 mmol) was added, and the resulting mixture was stirred at RT for 7 hours. The reaction mixture was treated with water and extracted with DCM (3×). The combined organic layers were washed with brine and dried over Na2SO4; the solvent was removed under vacuum and the crude was purified by flash chromatography on silica gel column (DCM:acetone=6:4) affording (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((4-methoxy-3-(N-(2-morpholinoethyl)methylsulfonamido)phenoxy)carbonyloxy)-ethyl)pyridine 1-oxide (0.130 g, 0.167 mmol, 39.2% yield, LC-MS purity (BPI): 100%, MS/ESI+ 776.34 [MH]+, [δD]−27.42, c=0.542, DCM).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[Li]CCCC.[CH3:14][N:15]([CH3:23])[CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1>C(Cl)Cl>[Br:8][C:4]1[N:3]=[C:2]([C:19]2([OH:22])[CH2:20][CH2:21][CH:16]([N:15]([CH3:23])[CH3:14])[CH2:17][CH2:18]2)[CH:7]=[CH:6][CH:5]=1
Reactant: CN(C)C1CCC(=O)CC1
Reactant: Brc1cccc(Br)n1
Agent: [Li]CCCC
Solvent: ClCCl
Product: CN(C)C1CCC(O)(c2cccc(Br)n2)CC1
Temperature: -78 °C
Yield: 67 %

Procedure:
Under a nitrogen atmosphere, dissolve 2,6-dibromopyridine (10 g, 42.4 mmol) in anhydrous DCM (250 mL). Cool to −78° C. Add a solution of n-BuLi (1.6 M in hexanes) (29 mL, 46.2 mmol) very slowly via a syringe. After the addition, stir the reaction at −78° C. for 1 hr. Add a solution of 4-dimethylamino-cyclohexanone (5.4 g, 38.5 mmol) in anhydrous DCM (10 mL) dropwise to the reaction mixture via a syringe. Stir the reaction at −78° C. for 90 min. then allow to slowly warm to room temperature over 4 hr. Quench the reaction with saturated NaHCO3 solution. Dilute with more DCM, wash with more saturated NaHCO3 solution. Separate the organic layer, dry over anhydrous sodium sulfate, then evaporate the solvent under reduced pressure. Purify the residue by chromatography (silica gel, 6% 2M NH3-MeOH in DCM) to yield the desired 1-(6-bromo-pyridin-2-yl)-4-dimethylamino-cyclohexanol as a mixture of diastereomers (7.7 g, 67% yield): MS (ES): m/z=299 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]([CH:12]1[N:20]([C:21](=[O:43])[C@@H:22]([NH:29][C:30](=[O:42])[C@@H:31]([N:33](C)[C:34](=O)OC(C)(C)C)[CH3:32])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[CH2:13]1)=[O:11].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[NH:9][C:10]([C@H:12]1[N:20]([C:21](=[O:43])[C@@H:22]([NH:29][C:30](=[O:42])[C@@H:31]([NH:33][CH3:34])[CH3:32])[CH:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[CH2:13]1)=[O:11]
Reactant: C[C@@H](C(=O)N[C@H](C(=O)N1c2ncccc2CC1C(=O)Nc1c(F)cccc1F)C1CCOCC1)N(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@@H](C)C(=O)N[C@H](C(=O)N1c2ncccc2C[C@H]1C(=O)Nc1c(F)cccc1F)C1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a solution of tert-butyl (2S)-1-((1S)-2-(2-(2,6-difluorophenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-2-oxo-1-(tetrahydropyran-4-yl)ethylamino)-1-oxopropan-2-yl(methyl)carbamate (54 mg, 89.8 μmol, Eq: 1.00) in DCM (1 mL) was added TFA (1 mL, 13.0 mmol, Eq: 145) and the resulting solution was stirred at rt for 1 h. The reaction mixture was concentrated in vacuo and the residue was treated with saturated aqueous NaHCO3 (10 mL). The resulting mixture was extracted with DCM (2×10 mL), the combined organic layers dried over Na2SO4, and then concentrated in vacuo. Treatment of the residue with diethyl ether/hexanes gave (S)-1-[(S)-2-((S)-2-methylamino-propionylamino)-2-(tetrahydropyran-4-yl)-acetyl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (2,6-difluoro-phenyl)-amide as a white solid (45 mg), m/z=502 (M+H).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10].[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:11]([NH:18][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccccc1
Reactant: OCCOCCOCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCCOCCOCCNCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.7 %

Procedure:
2-[2-(2-Chloroethoxy)ethoxy]ethanol 31 (9.273 g, 55 mmol) and benzylamine (26.3 mL, 240 mmol) were dissolved in absolute acetonitrile (150 mL) whereupon potassium carbonate (25.0 g, 180 mmol) was added. The suspension was heated at reflux with vigorous stirring under an argon atmosphere for 18 hours. The suspension was allowed to cool to room temperature, diluted with acetonitrile (100 mL) and filtered through a Celite™ pad. The acetonitrile was removed under reduced pressure and the unreacted benzylamine distilled from the concentrated pale greenish oil under high vacuum (90° C., 5 torr). The resulting viscous oil (14.2 g) was purified by flash chromatography using 13% methanol in dichloromethane as the eluent. Fractions contained the desired product (Rf=0.45) were combined, solvent removed under reduced pressure, and the residue dried in vacuo to yield the title compound as a viscous oil (10.1 g, 77%). CIMS (MH+): m/e 240. 1H-NMR (CDCl3): δ 7.31 (m, 5H, phenyl), 3.79 (s, 2H, CH2-Ph), 3.70-3.61 (m, 12 H, OCH2CH2O). 13C-NMR (CDCl3): δ 140.3, 129.0, 128.8, 127.6, 73.3, 70.9, 70.8, 70.7, 62.0, 54.4, 49.0.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([NH:12][CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1.O>CN(C)C=O>[C:15]1([CH2:14][CH2:13][N:12]([CH2:24][C:25]2[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=2)[C:9]2[S:10][CH:11]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: c1ccc(CCNc2nc(-c3ccccc3)cs2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN(CCc2ccccc2)c2nc(-c3ccccc3)cs2)cc1
Reaction time: 0.5 h
Yield: 47.9 %

Procedure:
To a solution of 4-phenyl-N-(2-phenylethyl)-1,3-thiazol-2-amine (4.63 g, 16.5 mmol) in N,N-dimethylformamide (50 mL) was added sodium hydride (60% in oil, 990 mg, 24.8 mmol), and the mixture was stirred for 30 min. Methyl 4-(bromomethyl)benzoate (4.54 g, 19.8 mmol) was added and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (3.39 g, yield 48%) as a yellow oil.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:8][CH:7]=[CH:6][C:5]=1[NH:15][C:16]([CH:18]1[CH2:23][CH:22]2[CH:20]([CH2:21]2)[N:19]1[C:24](=[O:39])[CH2:25][N:26]1[C:34]2[C:29](=[CH:30][C:31]([OH:35])=[CH:32][CH:33]=2)[C:28]([C:36](=[O:38])[CH3:37])=[N:27]1)=[O:17].Br[CH2:41][CH2:42][O:43][CH3:44]>CN(C=O)C>[F:3][C:4]1[C:9]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:8][CH:7]=[CH:6][C:5]=1[NH:15][C:16]([C@@H:18]1[CH2:23][C@@H:22]2[C@@H:20]([CH2:21]2)[N:19]1[C:24](=[O:39])[CH2:25][N:26]1[C:34]2[C:29](=[CH:30][C:31]([O:35][CH2:41][CH2:42][O:43][CH3:44])=[CH:32][CH:33]=2)[C:28]([C:36](=[O:38])[CH3:37])=[N:27]1)=[O:17]
Reactant: CC(=O)c1nn(CC(=O)N2C(C(=O)Nc3cccc(OC(F)(F)F)c3F)CC3CC32)c2ccc(O)cc12
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOc1ccc2c(c1)c(C(C)=O)nn2CC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)Nc1cccc(OC(F)(F)F)c1F
Reaction time: 0.08 h

Procedure:
To a suspension of sodium hydride (60% in Mineral oil, 4.8 mg, 0.121 mmol) in DMF (5 mL) at 0° C. was added 1R,3S,5R)-2-[2-(3-acetyl-5-hydroxy-indazol-1-yl)-acetyl]-2-aza-bicyclo[3.1.0]hexane-3-carboxylic acid (2-fluoro-3-trifluoromethoxy-phenyl)-amide (60 mg, 0.115 mmol). After stirring for 5 min, 1-bromo-2-methoxyethane (0.016 mL, 0.173 mmol) was added and the reaction mixture was stirred at RT for 16 h. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated. The crude residue was purified by preparative HPLC (Waters Sunfire C18-ODB, 5 um, 30×100 mm, flow: 40 mL/min, gradient: 0-18.5 min 5% to 100% CH3CN, 18.5-20 min 100% CH3CN, H2O and CH3CN containing 0.1% TFA). Further purification by flash chromatography on silica gel (c-hexane/EtOAc 1:0 to 0:1) afforded the title compound. MS (UPLC-MS): 579.3. tR (HPLC conditions f): 2.07 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[C:22]1(/[CH:28]=[CH:29]/[CH2:30][C:31](O)=[O:32])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl.CN(C)C=O>[O:21]=[C:20]1[C:4]2[C:5]3[C:6](=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]=3[CH:10]=[C:2]([NH:1][C:31](=[O:32])[CH2:30]/[CH:29]=[CH:28]/[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:3]=2)[CH:17]=[N:18][NH:19]1
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Reactant: O=C(O)C/C=C/c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(C/C=C/c1ccccc1)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Yield: 69.2 %

Procedure:
Preparation of example 120 from the title compound of Example 7 (hydrochloride) (44 mg, 0.141 mmol), (E)-4-phenyl-but-3-enoic acid (27 mg, 0.169 mmol), triethylamine (0.059 mL, 0.423 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (64 mg, 0.169 mmol) in CH2Cl2 (0.4 mL) and N,N-dimethylformamide (0.4 mL) was carried out analogously to Example 11. When the reaction was judged complete, the mixture was filtered to collect the solids which were then washed with methanol. After drying under vacuum, the title compound (41 mg, 0.0.095 mmol) was obtained as a yellow powder in 68% yield.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[C:11]([Cl:18])[N:10]=1.[Cl:19][C:20]1[CH:21]=[C:22]([NH2:28])[C:23]([O:26][CH3:27])=[N:24][CH:25]=1>C(#N)C>[Cl:18][C:11]1[N:10]=[C:9]([NH:28][C:22]2[C:23]([O:26][CH3:27])=[N:24][CH:25]=[C:20]([Cl:19])[CH:21]=2)[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=1
Reactant: COc1ncc(Cl)cc1N
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ncc(Cl)cc1Nc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 8 h
Yield: 39.2 %

Procedure:
Triethylamine (2.7 mL) and a catalytic amount of 4-diaminopyrimidine were added to a solution of 2,6-dichloro-3-nitropyridine (639 mg, 3.31 mmol) and 5-chloro-2-methoxy pyridin-3-amine (Preparation 23, 501 mg, 3.16 mmol) in acetonitrile (20 mL) and the resulting mixture was stirred overnight at 90° C. Solvent was then removed under reduced pressure until a solid precipitated. The solid was filtered, washed with acetonitrile and dried. The solid was then treated with dichloromethane, filtered, washed with more dichloromethane and the combined filtrate and washings were concentrated to dryness under reduced pressure to yield the title compound (390 mg 30%) as an orange solid.
Reaction SMILES: Br.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[C:13]1[N:14]=[C:15]([NH2:18])[S:16][CH:17]=1.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.Cl>N1C=CC=CC=1>[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:10])([F:12])[F:11])=[CH:5][C:4]=1[C:13]1[N:14]=[C:15]([NH:18][S:25]([C:22]2[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=2)(=[O:27])=[O:26])[S:16][CH:17]=1
Reactant: Nc1nc(-c2cc(C(F)(F)F)ccc2F)cs1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2nc(-c3cc(C(F)(F)F)ccc3F)cs2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 0.5 g of 4-(2-fluoro-5-trifluoromethyl-phenyl)-thiazol-2-ylamine hydrobromide with 0.30 g of p-toluenesulfonyl chloride was stirred for 3 hours with 2 ml of pyridine. The resulting, red colored suspension was poured into 30 ml of 1N hydrochloric acid and the mixture was extracted with ethyl acetate. The organic phase was dried with magnesium sulphate and concentrated. The residue was dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.3 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. 0.36 g of N-[4-(2-fluoro-5-trifluoromethyl-phenyl)-thiazol-2-yl]-4-methyl-benzenesulfonamide separated as colorless crystals upon neutralization with concentrated hydrochloric acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[CH:22]([CH3:28])[NH:21][CH2:20][CH2:19]2>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:21]3[CH2:20][CH2:19][C:18]4[C:23](=[CH:24][C:25]([O:26][CH3:27])=[C:16]([O:15][CH3:14])[CH:17]=4)[CH:22]3[CH3:28])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: COc1cc2c(cc1OC)C(C)NCC2
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: COc1cc2c(cc1OC)C(C)N(C(=O)c1cc3ncc(Cl)cn3n1)CC2

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6,7-dimethoxy-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([CH3:8])=[CH:6][CH:7]=1.[CH3:10][C:11]([CH3:18])([C:15](Cl)=[O:16])[C:12](Cl)=[O:13].[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([CH3:8])=[C:6]2[C:7]=1[C:15](=[O:16])[C:11]([CH3:18])([CH3:10])[C:12]2=[O:13]
Reactant: Cc1ccc(Cl)cc1C
Reactant: CC(C)(C(=O)Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc(Cl)c2c(c1C)C(=O)C(C)(C)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To a mixture of 35.5 ml of 4-chloro-o-xylene and 29.84 g of dimethylmalonyl chloride in 150 ml of dry dichloromethane was added slowly 34.7 g of AlCl3 under the current of nitrogen gas at -10° C. The reaction mixture was stirred at room temperature for 2 hours, quenched with 200 g of ice, and separated the organic layer. The aqueous layer was extracted with dichloromethane. The combined organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography to afford 34.99 g of the title compound as yellow solid.
Reaction SMILES: [NH2:1][C:2]([C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][C:14]=2[O:22][CH3:23])[CH2:5][CH2:4]1.[BH4-].[Na+]>>[NH2:1][C:2]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)([C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)[CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:20])[OH:21])=[CH:15][C:14]=2[O:22][CH3:23])[CH2:5][CH2:4]1
Reactant: COc1cc(C(C)=O)ccc1OCCCN1CCC(C(N)(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Product: COc1cc(C(C)O)ccc1OCCCN1CCC(C(N)(c2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
Using the procedure of Example 20, 1-[4-[3-[4-[aminobis(4-fluorophenyl)methyl]-1-piperidinyl]propoxy]-3-methoxyphenyl]-1-ethanone is reduced with sodium borohydride to give the title compound.