Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:16][C:17]2[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:11][CH2:12][CH2:13][CH2:14][OH:15])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.CCN(CC)CC.ClC(OC1C=C[C:40]([N+:43]([O-:45])=O)=CC=1)=O.[OH2:46]>C(Cl)Cl>[CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:16][C:17]2[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:40]([NH:43][OH:45])=[O:46])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: O
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Cc1cnc(CN(CCCCO)Cc2ncccc2C(C)C)c(C)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cnc(CN(CCCCOC(=O)NO)Cc2ncccc2C(C)C)c(C)c1
Reaction time: 8 h
Yield: 42 %

Procedure:
To a mixture of 4-[(3,5-dimethyl-pyridin-2-ylmethyl)-(3-isopropyl-pyridin-2-ylmethyl)-amino]-butan-1-ol (0.230 g, 0.673 mmol) and Et3N (0.136 g, 1.35 mmol) in dry CH2Cl2 (8 mL) was added 4-nitrophenyl chloroformate (0.163 g, 0.808 mmol). After the mixture was stirred overnight, water (20 mL) was added and the mixture was extracted with CH2Cl2 (3×20 mL). The extracts were combined, and dried over anhydrous Na2SO4 to afford a yellow oil. The oil was dissolved in CH2Cl2 (5 mL), and NH2OHHCl (0.046 g, 0.66 mmol) and Et3N (0.101 g, 1.00 mmol) were added. The mixture was stirred for 24 h, and water (20 mL) was added. The mixture was extracted CH2Cl2 (3×20 mL). The extracts were combined and dried over anhydrous Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was purified by flash chromatography on a silica gel column (6:1 EtOAc/MeOH), affording a pale yellow solid (0.113 g, 42%) after precipitation from CH2Cl2/hexanes by evaporation under vacuum. 1H NMR (CDCl3) δ 0.99 (d, 6H, J=6.9 Hz), 1.46-1.61 (m, 4H), 2.17 (s, 3H), 2.27 (s, 3H), 2.52-2.57 (m, 2H), 2.96 (septet, 1H, J=6.9 Hz), 3.72 (s, 2H), 3.73 (s, 2H), 4.03 (t, 2H, J=5.7 Hz), 7.15 (dd, 1H, J=4.8, 7.8 Hz), 7.26 (s, 1H), 7.53 (dd, 1H, J=1.2, 7.8 Hz), 7.76 (s, br. 1H), 8.18 (s, 1H), 8.32 (dd, 1H, J=1.2, 4.8 Hz); 13C NMR (CDCl3) δ 18.03, 22.48, 2.28, 26.88, 27.29, 54.03, 57.91, 58.58, 65.39, 123.10, 132.21, 133.21, 133.96, 139.18, 144.26, 145.51, 146.01, 153.81, 155.54, 159.25. ES-MS m/z 423 (M+Na). Anal. Calcd. for C22H32N4O3.0.3CH2Cl2.0.2C6H14: C, 63.68; H, 8.05; N, 12.64. Found: C, 63.58; H, 8.10; N, 12.82.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].CC1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][N+:10]=1[O-]>C(O)C>[C:5]([O:4][CH2:1][C:2]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][N:10]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc([N+](=O)[O-])cc[n+]1[O-]
Solvent: CCO
Product: CC(=O)OCc1cc([N+](=O)[O-])ccn1
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
200 mL of acetic anhydride was heated to 100° C., followed by gradual addition of 2-methyl-4-nitropyridine N-oxide (25.0 g, 162 mmol). After the addition, the mixture was gradually heated, and was kept at 130° C. for 20 minutes. Then, the reaction mixture was cooled to 80° C., followed by dropwise addition of 200 mL of ethanol to stop the reaction.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1Br.[Li]CCCC.[CH:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1.CCCCCC>[CH3:1][O:2][CH:3]([O:19][CH3:20])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1[CH:26]([OH:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=Cc1ccccc1
Reactant: COC(OC)c1cc(OCc2ccccc2)ccc1Br
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(OC)c1cc(OCc2ccccc2)ccc1C(O)c1ccccc1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-bromo-5-benzyloxy benzaldehyde dimethylacetal (Tet. Lett., 22, 5027 (1981)) (130 g) in THF (2.0 L), cooled to -78° C., was added dropwise a solution of n-BuLi (210 ml, 1.91M) in hexane. After 15 min., a solution of benzaldehyde (48 mL) in THF (50 ml) was added dropwise. The cooling bath was removed, then the reaction mixture was warmed slowly (40 min.) to -10° C. and quenched with a saturated NH4Cl solution. The reaction mixture was diluted with Et2O (2.0L). The organic phase decanted, washed with H2O (3×), brine, dried over MgSO4 and the solvents evaporated. The residue was chromatographed on silica gel (hexane/EtOAc 95:5 to 85:15) to give the title product as a foam.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][N:28]=1>CN(C)C=O.C(OCC)(=O)C>[CH3:8][C:7]1[CH:6]=[CH:5][C:4]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:3][C:2]=1[O:1][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][N:28]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Cc1ccc(NC(=O)OCc2ccccc2)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(NC(=O)OCc2ccccc2)cc1Oc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.4 %

Procedure:
To a solution of benzyl (3-hydroxy-4-methylphenyl)carbamate (83.1 g, 321 mmol) in N,N-dimethylformamide (300 mL) were added cesium carbonate (157 g, 482 mmol) and 2-chloro-5-nitropyridine (50.9 g, 321 mmol), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate (500 mL) and washed with water (1 L), and the obtained aqueous layer was extracted with ethyl acetate (2×200 mL). The combined organic layer was washed with saturated brine (100 mL) and purified by basic silica gel (ethyl acetate). The obtained solution was concentrated under reduced pressure. The obtained residue was washed with ethyl acetate/hexane (1:1) to give the title compound (91.8 g, 75%) as a pale-yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)=[O:13])=[CH:5]2
Reactant: C1COCCN1
Reactant: O=C(O)c1cc2cc(O)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cc2cc(O)ccc2[nH]1)N1CCOCC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 82.8 %

Procedure:
A mixture of 1.77 g (0.01 mol) 5-hydroxy-indole-2-carboxylic acid in 25 ml DMF were cooled to 0° C. and treated with 3.53 g (0.011 mol) 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl uronium tetrafluoroborat, 0.96 g (0.011 mol) morpholine and 8.6 ml (0.05 mol) N-ethyldiisopropylamine. The mixture was allowed to warm to room temperature and stirred for additional 16 h. After evaporation to dryness the residue was taken up in 75 ml ethyl acetate, 75 ml THF, 100 ml water and 50 ml 10% NaHCO3 solution. The aqueous phase was extracted with 50 ml ethyl acetate and 50 ml THF. The combined organic layers were washed with 100 ml NaCl satur.aq., dried with Na2SO4, filtered and evaporated to dryness. The residue was suspended in 30 ml of a mixture of ethyl acetate/methanol 9/1, filtered and again suspended in 20 ml of a mixture of ethyl acetate/methanol 9/1. The residue was washed in diethyl ether and dried at 40° C. under vacuum to yield 2.04 g (83%) of the title compound as white solid. MS (m/e): 247.4 (MH+, 100%).
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:8](=O)[CH2:7][CH2:6][N:5]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:4]1.[C:15]1([CH2:21][N:22]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:23][CH2:24][CH2:25][NH2:26])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.S1C=CC=C1.[H][H]>CO.[Pt]>[C:28]1([CH2:27][N:22]([CH2:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:23][CH2:24][CH2:25][NH:26][CH:8]2[CH2:7][CH2:6][N:5]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:4][CH:3]2[O:2][CH3:1])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: NCCCN(Cc1ccccc1)Cc1ccccc1
Reactant: [H][H]
Reactant: CCOC(=O)N1CCC(=O)C(OC)C1
Agent: [Pt]
Solvent: c1ccsc1
Solvent: CO
Product: CCOC(=O)N1CCC(NCCCN(Cc2ccccc2)Cc2ccccc2)C(OC)C1
Yield: 100.7 %

Procedure:
A mixture of ethyl 3-methoxy-4-oxo-1-piperidinecarboxylate (0.248 mol) and N,N-bis(phenylmethyl)-1,3-propanediamine (0.248 mol) in methanol (600 ml) was hydrogenated at 50° C. with platinum on activated carbon (5%, 5 g) as a catalyst in the presence of thiophene (4%, 5 ml). After uptake of hydrogen (1 equivalent), the catalyst was filtered off and the filtrate was evaporated, yielding 109.8 g of (±)-ethyl 4-[[3-[bis-(phenylmethyl)amino]propyl]amino]-3-methoxy-1-piperidinecarboxylate (interm. 1).
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH:9]=[C:8]1[CH2:7][C:6](=[O:22])[CH2:5][C@@H:4]2[CH3:23].[C:24]1([Si:30]([C:78]2[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=2)([C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=2)[O:31][C@H:32]2[CH2:49][CH2:48][C@@:47]3([CH2:50][OH:51])[C:34](=[CH:35][CH2:36][C@@H:37]4[C@@H:46]3[CH2:45][CH2:44][C@@:42]3([CH3:43])[C@H:38]4[CH2:39][CH2:40][C@@H:41]3[O:52][Si:53]([C:66]3[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=3)([C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)[C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[CH2:33]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:23][C@@H:4]1[C@@:3]2([CH:2]=[O:1])[C:8](=[CH:9][CH2:10][C@@H:11]3[C@@H:20]2[CH2:19][CH2:18][C@@:16]2([CH3:17])[C@H:12]3[CH2:13][CH2:14][C:15]2=[O:21])[CH2:7][C:6](=[O:22])[CH2:5]1.[C:78]1([Si:30]([C:72]2[CH:73]=[CH:74][CH:75]=[CH:76][CH:77]=2)([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[O:31][C@H:32]2[CH2:49][CH2:48][C@@:47]3([CH:50]=[O:51])[C:34](=[CH:35][CH2:36][C@@H:37]4[C@@H:46]3[CH2:45][CH2:44][C@@:42]3([CH3:43])[C@H:38]4[CH2:39][CH2:40][C@@H:41]3[O:52][Si:53]([C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)([C:60]3[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=3)[C:66]3[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=3)[CH2:33]2)[CH:79]=[CH:80][CH:81]=[CH:82][CH:83]=1
Reactant: C[C@H]1CC(=O)CC2=CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21CO
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C[C@@H](O[Si](c5ccccc5)(c5ccccc5)c5ccccc5)CC[C@@]43CO)[C@@H]1CC[C@@H]2O[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Product: C[C@H]1CC(=O)CC2=CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21C=O
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C[C@@H](O[Si](c5ccccc5)(c5ccccc5)c5ccccc5)CC[C@@]43C=O)[C@@H]1CC[C@@H]2O[Si](c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Substituting 17β,19-dihydroxy-1α,17α-dimethyl-5-androsten-3-one, 19-hydroxy-1α-methyl-5-androstene-3,17-dione, 17β,19-dihydroxy-4α,6,17α-trimethyl-5-androsten-3-one, 17β-(2'-tetrahydropyranyloxy)-5-androsten-19-ol and 3β,17β-di(triphenylsiloxy)-5-androsten-19-ol for the 17α-methyl-5-androstene-3β,17β,19-triol 3,17-diacetate above results in the preparation of 17β-hydroxy-1α,17α-dimethyl-5-androstene-3,19-dione, 1α-methyl-5-androstene-3,17,19-trione, 17β-hydroxy-4α,6,17α-trimethyl-5-androstene-3,19-dione, 17β-(2'-tetrahydropyranyloxy)-5-androsten-19-one and 3β,17β-di(triphenylsiloxy)-5-androsten-19-one, respectively.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([NH2:11])=[N:8][CH:9]=2)[N:4]([CH3:12])[N:3]=1.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][C:22]=1[F:30])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[C:10]3[C:5](=[N:6][C:7]([NH2:11])=[N:8][CH:9]=3)[N:4]([CH3:12])[N:3]=2)=[CH:23][C:22]=1[F:30])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cn1nc(Br)c2cnc(N)nc21
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cn1nc(-c2ccc(OCc3ccccc3)c(F)c2)c2cnc(N)nc21
Temperature: 25 °C

Procedure:
3-Bromo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine (Intermediate 3) (0.33 g, 1.46 mmol) and 4-benzyloxy-3-fluoro phenylboronic acid (0.43 g, 1.75 mmol) are suspended in 1,4-dioxane (5 ml) in a microwave vial flushed with argon. A solution of Cs2CO3 (1.43 g, 4.38 mmol) in water (1.5 ml) is added followed by Pd(PPh3)4 (0.085 g, 0.073 mmol) and the reaction mixture is heated using microwave radiation at 150° C. for 0.5 hours. After cooling to room temperature the reaction mixture is diluted with EtOAc (100 ml) and washed with saturated NaHCO3. The organic portion is dried over MgSO4, filtered, concentrated in vacuo and the resulting crude solid is triturated with EtOAc (˜20 ml) to afford the title compound as an off-white solid.
Reaction SMILES: [C:1]1([N:7]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:10](=O)[C:8]2=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[N:23][CH:24]=1>>[Cl:25][C:22]1[N:23]=[CH:24][C:19]([N:18]=[C:10]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:8]2=[O:9])=[CH:20][CH:21]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: O=C1C(=O)N(c2ccccc2)c2ccccc21
Product: O=C1C(=Nc2ccc(Cl)nc2)c2ccccc2N1c1ccccc1
Temperature: 140 °C
Yield: 59 %

Procedure:
1-phenylisatin (23.0 mg, 0.10 mmol) and 5-amino-2-chloropyridine (12.8 mg, 0.10 mmol) were mixed and heated at 140° C. for 7 h. The resulting crude product was purified by preparative TLC using hexane/ethyl acetate (8:2) as the eluent, giving the desired product as a yellow solid (19.7 mg, 59%). 1H NMR (400 MHz) δ 8.15 (d, J=8, 1H), 7.6–7.2 (m, 9H), 6.85–6.75 (m, 2H); ESI-MS m/z found 334 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[N:13]=[CH:14][C:15]([OH:18])=[N:16][CH:17]=1.CS(O[CH2:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31]2[O:35][N:34]=[C:33]([CH:36]([CH3:38])[CH3:37])[N:32]=2)[CH2:27][CH2:26]1)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[N:16][C:15]([O:18][CH2:24][CH:25]2[CH2:30][CH2:29][N:28]([C:31]3[O:35][N:34]=[C:33]([CH:36]([CH3:38])[CH3:37])[N:32]=3)[CH2:27][CH2:26]2)=[CH:14][N:13]=1
Reactant: CS(=O)(=O)c1ccc(-c2cnc(O)cn2)c(F)c1
Reactant: CC(C)c1noc(N2CCC(COS(C)(=O)=O)CC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1noc(N2CCC(COc3cnc(-c4ccc(S(C)(=O)=O)cc4F)cn3)CC2)n1

Procedure:
The title compound (0.13 g, 49%) was prepared as a white solid from 5-[2-fluoro-4-(methylsulfonyl)phenyl]-2-pyrazinol (and tautomers thereof) (0.15 g, 0.56 mmol), {1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl methanesulfonate (prepared as in Example 100, Steps 1-4, 0.23 g, 0.76 mmol) and K2CO3 (0.16 g, 1.12 mmol) in DMF (6 mL) in a manner similar to Example 152, Step 3. The crude product was purified by chromatography on a silica gel column eluted with 50% EtOAc/hexanes to give the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.66 (s, 1H), 8.33 (d, 1H, J=1.0 Hz), 8.23 (t, 1H, J=7.8 Hz), 7.82 (dd, 1H, Ja=8.2 Hz, Jb=1.7 Hz), 7.76 (dd, 1H, Ja=10.2 Hz, Jb=1.6 Hz), 4.40-4.30 (m, 2H), 4.29 (d, 2H, J=6.3 Hz), 3.25-3.10 (m, 2H), 3.09 (s, 3H), 2.98 (septet, 1H, J=7.0 Hz), 2.20-2.05 (m, 1H), 2.05-1.90 (m, 2H), 1.60-1.40 (m, 2H), 1.32 (d, 6H, J=6.8 Hz); LRMS (ESI), m/z 476 (M+H).
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([C:11](=[C:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)[CH3:2].[C:27](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[CH2:25]([N:3]([CH2:1][CH3:2])[C:4](=[O:24])[C:5]1[CH:6]=[CH:7][C:8]([C:11](=[C:18]2[CH2:23][CH2:22][N:21]([CH3:27])[CH2:20][CH2:19]2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9][CH:10]=1)[CH3:26]
Reactant: CCN(CC)C(=O)c1ccc(C(=C2CCNCC2)c2ccccc2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CCN(CC)C(=O)c1ccc(C(=C2CCN(C)CC2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.2 %

Procedure:
N,N-Diethyl-4-[(piperidin-4-ylidene)-phenyl-methyl]-benzamide (0.34 g, 1.0 mmol) was disolved in acetonitrile (5 mL). Potassium carbonate (0.14 g, 1.0 mmol) and methyl iodide (63 μL, 1.0 mmol) was added with stirring at 25° C. After 30 min., the reaction mixture was evaporated and put onto silica gel for purification by chromatography using 0 to 10% MeOH(10% NH4OH) in CH2Cl2 to give 48 mg of the final product (28% of converted starting material), which was converted to the hydrochloride salt by treatment with HCl in ether.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:4]=1[CH2:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[OH:17][C:18]1[CH:27]=[CH:26][C:21]([O:22][CH2:23][CH2:24]Br)=[CH:20][CH:19]=1.C([O-])(O)=O.[Na+]>>[ClH:1].[F:2][C:3]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:4]=1[CH2:5][CH:6]1[CH2:7][CH2:8][N:9]([CH2:24][CH2:23][O:22][C:21]2[CH:26]=[CH:27][C:18]([OH:17])=[CH:19][CH:20]=2)[CH2:10][CH2:11]1
Reactant: Oc1ccc(OCCBr)cc1
Reactant: Cc1ccc(CC2CCNCC2)c(F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccc(CC2CCN(CCOc3ccc(O)cc3)CC2)c(F)c1

Procedure:
The title compound was prepared from 4-(2-fluoro-4-methylbenzyl)piperidine hydrochloride (375 mg, 1.54 mmol), 2-(4-hydroxyphenoxy)ethyl bromide (352 mg, 1.62 mmol) and NaHCO3 (265 mg, 3.16 mmol) as a near colorless powder (430 mg): mp 164-165° C.; 1H NMR (CD3OD) 1.51-1.70 (m, 2H), 1.84-2.00 (m, 3H), 2.31 (s, 3H), 2.63 (d, J=5.7 Hz, 2H), 2.94-3.12 (m, 2H), 3.44-3.70 (m, 4H), 4.26 (t, J=4.8 Hz, 2H), 6.74 (d, J=9.3 Hz, 2H), 6.82-6.96 (m, 4H), 7.07-7.14 (m, 1H); Anal. Calcd for C21H27ClFNO2 : C, 66.39; H. 7.16; N, 3.69. Found: C, 66.62; H, 6.99; N, 3.54.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([NH:11][CH2:12][C:13]([C:28]([F:31])([F:30])[F:29])([OH:27])[CH2:14][C:15]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[O:25]C)([CH3:17])[CH3:16])=[CH:3][CH:2]=1.B(Br)(Br)Br.C(Cl)Cl>C(Cl)Cl.CO>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([NH:11][CH2:12][C:13]([C:28]([F:30])([F:29])[F:31])([OH:27])[CH2:14][C:15]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[OH:25])([CH3:17])[CH3:16])=[CH:3][CH:2]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1ccnc2ccccc12)C(F)(F)F
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CC(C)(CC(O)(CNc1ccnc2ccccc12)C(F)(F)F)c1cc(F)ccc1O
Yield: 71 %

Procedure:
Analogously to Example 2, 200 mg (0.46 mmol) of 1-(quinolin-4-ylamino)-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)pentan-2-ol and 9 ml of 1 M boron tribromide-CH2Cl2 solution are reacted. After chromatography on silica gel with CH2Cl2-methanol (0-15%), 138 mg of product is obtained.
Reaction SMILES: Cl[CH2:2][N:3]1[C:7](=[O:8])[C:6]2=[CH:9][CH:10]=[CH:11][CH:12]=[C:5]2[C:4]1=[O:13].[CH:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[C:16]([OH:23])[CH:15]=1.[H-].[Na+]>CN(C)C=O.C(O)(=O)C>[N+:20]([C:19]1[CH:14]=[CH:15][C:16]([O:23][CH2:2][N:3]2[C:7](=[O:8])[C:6]3=[CH:9][CH:10]=[CH:11][CH:12]=[C:5]3[C:4]2=[O:13])=[CH:17][CH:18]=1)([O-:22])=[O:21]
Reactant: O=C1c2ccccc2C(=O)N1CCl
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1COc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
N-(Chloromethyl)phthalimide (4.2 g) and the yellow dye, p-nitrophenol (3.0 g) were dissolved sequentially in 100 ml of dimethylformamide (DMF). Sodium hydride (2.0 g of a 50% oil dispersion) was added and the solution stirred for three days at room temperature. The mixture was diluted with 500 ml 1% aqueous acetic acid to precipitate out the desired product: 5.6 g, m.p. 145°-148° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[N:9][C:8]2[CH:7]=[C:6]([N:17]([CH2:21][CH2:22][Cl:23])[CH2:18][CH2:19][Cl:20])[CH:5]=[CH:4][C:3]1=2.Cl.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[CH3:59][O:60][C:61](=[O:65])[C@H:62]([CH3:64])[NH2:63]>CN(C=O)C>[CH3:59][O:60][C:61](=[O:65])[C@@H:62]([NH:63][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C:10]1[N:2]([CH3:1])[C:3]2[CH:4]=[CH:5][C:6]([N:17]([CH2:21][CH2:22][Cl:23])[CH2:18][CH2:19][Cl:20])=[CH:7][C:8]=2[N:9]=1)[CH3:64]
Reactant: Cn1c(CCCC(=O)O)nc2cc(N(CCCl)CCCl)ccc21
Reactant: COC(=O)[C@H](C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](C)NC(=O)CCCc1nc2cc(N(CCCl)CCCl)ccc2n1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.2 %

Procedure:
A 250 mL three neck round bottom flask equipped with a stir bar, thermocouple, cooling bath, addition funnel and nitrogen in/outlet was charged with 10 g (25.3 mmol) of bendamustine hydrochloride, 10.6 g (27.8 mmol) of HATU and 100 mL of DMF. The batch was cooled to 1.9° C. where 8.8 mL (6.54 g, 50.6 mmol) of DIPEA was added over 2 minutes. The reaction exothermed to 9° C. and became orange. A solution of 3.57 g (25.6 mmol) of L-alanine methyl ester hydrochloride and 6.2 mL (4.57 g, 35.4 mmol) of DIPEA in 20 mL of DMF was added drop-wise over 10 minutes at 4.9-5.7° C. The reaction was slowly warmed to RT over one hour and stirred for three hours at which time an in process assay indicated the reaction was complete. The batch was quenched onto 400 mL of 1:1 ethyl acetate/DI water. The layers were separated, the organic was washed with 10% sodium hydrogen phosphate (1×200 mL), 8% sodium bicarbonate 91×200 mL) and brine (1×200 mL), before drying over sodium sulfate, filtering and evaporating to dryness in vacuo. The residue was purified by chromatography using 100 g of silica gel 60, 230-400 mesh, eluting with 1% MeOH/MDC (3 L), 2.5% MeOH/MDC (1 L) and 5% MeOH/MDC (500 mL) collecting ˜100 mL fractions. The product containing fractions were combined and concentrated to dryness in vacuo to yield 7.1 g (16.0 mmol, 63.3%) of the desired product as a white solid with an HPLC purity of 97.4 A %. 1H NMR (400 MHz, DMSO-d6) δ 8.25 (d, J=6.92 Hz), 1H), 7.40 (d, J=8.84 Hz, 1H), 6.92 (d, J=2.2 Hz, 1H), 6.86 (dd, J=2.32, 8.88 Hz), 4.25 (q, 1H), 3.72 (s, 8H), 3.71 (s, 3H), 3.62 (s, 3H), 2.87 (t, J=7.48 Hz, 2H), 2.25 (t, J=7.52 Hz, 2H), 1.99 (m, 2H), 1.26 (d, J=7.32 Hz, 3H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:25])=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][C:14]=2[O:21][CH2:22][O:23][CH3:24])[N:10]=1.C(P(CCCC)CCCC)CCC.[CH2:39]([N:46]1[CH:50]=[C:49]([C:51]([O:53][CH2:54][CH3:55])=[O:52])[C:48](O)=[N:47]1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH2:39]([N:46]1[CH:50]=[C:49]([C:51]([O:53][CH2:54][CH3:55])=[O:52])[C:48]([O:20][CH2:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:9]3[N:10]=[C:6]([C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)[O:7][C:8]=3[CH3:25])=[C:14]([O:21][CH2:22][O:23][CH3:24])[CH:15]=2)=[N:47]1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: COCOc1cc(CO)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OCOC)c1
Reaction time: 2 h
Yield: 88 %

Procedure:
To a mixture of (4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-(methoxymethoxy)phenyl)methanol (8.50 g), tributylphosphine (9.95 g), ethyl 1-benzyl-3-hydroxy-1H-pyrazole-4-carboxylate (6.06 g) and tetrahydrofuran (300 mL) was added 1,1′-(azodicarbonyl)dipiperidine (12.41 g) at room temperature, and the mixture was stirred for 2 hrs. The precipitated crystals were removed by filtration and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to give ethyl 1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-(methoxymethoxy)benzyl)oxy]-1H-pyrazole-4-carboxylate as colorless crystals (12.42 g, yield 88%) from a fraction eluted with ethyl acetate-hexane (1:2, v/v). Recrystallization from ethyl acetate-hexane gave colorless needle crystals. melting point: 120-121° C.