Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12]OC(=O)[N:9]1[C:14](=[O:36])[CH:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([O:27]CC2C=CC=CC=2)=[CH:22][C:21]=1[Cl:35])[CH2:16][CH:17]=O)[C:2]1C=CC=CC=1.NC1CC[O:41][CH2:40]C1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:26][C:25]1[CH:24]=[C:23]([OH:27])[CH:22]=[C:21]([Cl:35])[C:20]=1[CH2:19][C@@H:15]1[CH2:16][CH2:17][N:9]([CH:8]2[CH2:1][CH2:2][O:41][CH2:40][CH2:12]2)[C:14]1=[O:36]
Reactant: NC1CCOCC1
Reactant: O=CCC(Cc1c(Cl)cc(OCc2ccccc2)cc1Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C1[C@H](Cc2c(Cl)cc(O)cc2Cl)CCN1C1CCOCC1
Yield: 71.6 %

Procedure:
Treat a solution of 4-(4-(R)-benzyl-2-oxo-oxazolidin-3-yl)-3-(4-benzyloxy-2,6-dichloro-benzyl)-4-oxo-butyraldehyde (Preparation 27) (10.4 g, 20 mmol) and 4-aminotetrahydropyran (2 g, 20 mmol) in dichloromethane (100 mL) with acetic acid (1 mL, 20 mmol). Stir the reaction 1 hr at room temperature then add sodium triacetoxyborohydride (12.6 g, 60 mmol) and stir for an additional 4 hr at room temperature. Quench with water and separate the organic layer. Wash with brine, dry over magnesium sulfate, filter, and remove the solvent under vacuum. Purify by silica gel column chromatography using hexanes:ethyl acetate to afford 4.93 g (57%) of desired product: MS (m/z): 434 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][C:29](O)=[O:30])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:32][NH:33][C@H:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH3:35]>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:16]=[CH:17][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][C:29](=[O:30])[N:33]([CH3:32])[C@H:34]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH3:35])=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCC(=O)O)cc3)cc2)CC1
Reactant: CN[C@@H](C)c1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCC(=O)N(C)[C@@H](C)c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using 1-{4′-[4-(2-carboxy-ethyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and methyl-((S)-1-phenyl-ethyl)-amine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:7][CH2:8][N:9]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:10][C:11]=1[NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:5])[CH3:2].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([CH:6]1[CH2:7][CH2:8][N:9]([C:20]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:21])[CH2:10][CH:11]1[NH:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(NCc2ccccc2)CN(C(=O)OC(C)(C)C)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1NCc1ccccc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 43.8 %

Procedure:
To a mixture of 5-benzylamino-3,6-dihydro-2H-pyridine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (10.2 g, 28.9 mmol) in toluene (110 mL) was added NaBH(OAc)3 (30 g, 141.5 mmol) and freshly activated 4 A0 powder molecular sieve (24 g) with vigorous stirring. The reaction mixture was cooled to 0° C., then acetic acid (32.5 mL, 566 mmol) was added drop-wise in such a way that reaction mixture temperature remained below 5° C. After the addition of acetic acid was complete, the mixture was allowed to warm to ambient temperature and stirred for 16 h. The reaction mixture was filtered and concentrated to remove most of the acetic acid. The crude residue was dissolved in ethyl acetate (125 mL) and saturated aqueous NaHCO3 solution (100 mL) was slowly added to neutralize the residual acid under stirring. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure (11.25 g, crude). The residue was purified (FCC, SiO2, ethyl acetate/hexanes, gradient 0-40%) to yield the title compound (4.59 g, 45%). MS (ESI) mass calcd. for C20H30N2O2, 362.46; m/z found, 363.3 [M+H]+. 1H NMR (DMSO-d6): 7.53-6.76 (m, 5H), 4.10-3.96 (m, 3H), 3.89-3.87 (m, 1H), 3.66 3.54 (m, 1H), 3.05-2.60 (m, 4H), 1.80-1.65 (m, 2H), 1.60-1.45 (m, 1H), 1.40 (s, 9H), 1.14 (t, J=7.1, 3H).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[N:22]1([CH:27]2[CH2:30][NH:29][CH2:28]2)[CH:26]=[CH:25][N:24]=[N:23]1.C1CCN2C(=NCCC2)CC1>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:29]4[CH2:30][CH:27]([N:22]5[CH:26]=[CH:25][N:24]=[N:23]5)[CH2:28]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: c1cn(C2CNC2)nn1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CC(n4ccnn4)C3)c(F)cc2c1=O
Yield: 91.8 %

Procedure:
1-Cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (50 mg, 0.18 mmol) was reacted with 3-(1,2,3-triazol-1-yl) azetidine hydrochloride (72 mg, 0.45 mmol) in 3 ml of dry pyridine in the presence of 68.5 mg (0.45 mmol) of DBU at 80° C. for 16 h. The yellow solution was then evaporated to dryness, water was added to the residue, solid was collected and dried to yield 64 mg (92%) of the desired product. m.p. 315°-316° C. 1H NMR (TFA) δ: 9.26 (s, 1H), 8.75 (d, 1.2Hz, 1H), 8.60 (d, 1.2Hz, 1H), 8.10 (d, 11.8Hz, 1H), 6.35-6.0 (m, 1H), 5.8-5.15 (m, 4H), 4.65-4.3 (m, 1H), 1.9-1.3 (m, 4H). Anal. calcd. for C18H15F2N 5 O3H2O: C, 53.33; H, 4.23; N, 17.28. Found: C, 53.68; H, 4.23; N, 17.28.
Reaction SMILES: [F:1][C:2]([F:31])([C:27]([F:30])([F:29])[F:28])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:26]=[CH:25][C:10]([C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([O-:24])=[O:23])=[CH:16][CH:15]=2)=[O:12])=[CH:9][CH:8]=1.CCCCCC.FC(F)(F)CCCOC1C=CC(C(OC2C=CC(/C=C/C(O[CH2:62][CH2:63][C:64]3[CH:69]=[CH:68][C:67]([NH2:70])=[CH:66][C:65]=3[NH2:71])=O)=CC=2)=O)=CC=1>CN(C)C=O.O.[Zn]>[F:1][C:2]([F:31])([C:27]([F:28])([F:29])[F:30])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:26]=[CH:25][C:10]([C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([O:24][CH2:62][CH2:63][C:64]3[CH:69]=[CH:68][C:67]([NH2:70])=[CH:66][C:65]=3[NH2:71])=[O:23])=[CH:16][CH:15]=2)=[O:12])=[CH:9][CH:8]=1
Reactant: Nc1ccc(CCOC(=O)/C=C/c2ccc(OC(=O)c3ccc(OCCCC(F)(F)F)cc3)cc2)c(N)c1
Reactant: O=C([O-])/C=C/c1ccc(OC(=O)c2ccc(OCCCC(F)(F)C(F)(F)F)cc2)cc1
Agent: [Zn]
Solvent: O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: Nc1ccc(CCOC(=O)/C=C/c2ccc(OC(=O)c3ccc(OCCCC(F)(F)C(F)(F)F)cc3)cc2)c(N)c1

Procedure:
5.35 g (8.38 mmol) of (2E)3-{4-[(4-(4,4,5,5,5-pentafluoropentoxy)benzoyl)oxy]phenyl}acrylate are dissolved in a mixture of 54 ml of N,N-dimethylformamide and 6 ml water. 13.9 g (51.4 mmol) ferric chloride hexahydrate are added. 5.60 g (85.7 mmol) Zinc powder are added portionwise within 60 min. The mixture is allowed to react for 2 hours. The reaction mixture is then partitioned between ethyl acetate and water and filtered. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtered and concentrated by rotary evaporation. Filtration of the residue on 200 g silica gel using toluene:ethyl acetate (1:3) as eluant and crystallization form ethylacetate:hexane mixture yielded 3.30 g 2-(2,4-Diaminophenyl)ethyl (2E)3-{4-[(4-(4,4,5,5,5-pentafluoropentoxy)benzoyl)oxy]phenyl}acrylate as yellowish crystals 2-(2,4-Diaminophenyl)ethyl (2E)3-{4-[(4-(4,4,4-trifluorobutoxy)benzoyl)oxy]phenyl}acrylate is prepared analogous to example 4 using (2E)-3-(4-{[4-(4,4,4-trifluorobutoxy)benzoyl]oxy}phenyl)acrylic acid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[C:10]([F:11])=[CH:9][C:8](F)=[C:7]([F:13])[C:6]=1[F:14])[CH3:2].C(N(CC)CC)C.[C:23]([O:27][C:28](=[O:35])[NH:29][C@H:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)([CH3:26])([CH3:25])[CH3:24]>C(#N)C>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[C:10]([F:11])=[CH:9][C:8]([N:32]2[CH2:33][CH2:34][C@H:30]([NH:29][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:35])[CH2:31]2)=[C:7]([F:13])[C:6]=1[F:14])[CH3:2]
Reactant: CCOC(=O)c1c(F)cc(F)c(F)c1F
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1c(F)cc(N2CC[C@H](NC(=O)OC(C)(C)C)C2)c(F)c1F
Yield: 69.8 %

Procedure:
A solution of 2,3,4,6-tetrafluorobenzoic acid ethyl ester (Example 1b, 5.1 g, 22.9 mmol), triethylamine (22 mL, 157 mmol), and (S)-pyrrolidin-3-ylcarbamic acid tert-butyl ester (5.2 g, 27.9 mmol) in acetonitrile (60 mL) is stirred at room temperature for 64 hours. The mixture is concentrated in vacuo and the residue dissolved in chloroform, washed with NaHCO3 and then brine, dried over Na2SO4, filtered, and concentrated under vacuum to afford a solid. The solid is purified by column chromatography (1:1:7 ethyl acetate/chloroform/hexanes) to afford the title compound (6.21 g). 1H NMR (CDCl3): δ 6.07 (ddd, 1H), 4.78–4.63 (bd, 1H), 4.49–4.22 (m, 3H), 3.80–3.68 (m, 1H), 3.66–3.28 (m, 3H), 2.33–2.13 (m, 1H), 2.04–1.83 (m, 1H), 1.45 (s, 9H), 1.36 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH3:9])[CH:5]=[CH:4][N:3]=1.[O:11]1[CH2:16][CH2:15][N:14]([S:17]([C:20]2[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=2)[C:23]([NH:25][NH2:26])=[O:24])(=[O:19])=[O:18])[CH2:13][CH2:12]1>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6](/[C:8](=[N:26]/[NH:25][C:23](=[O:24])[C:22]2[CH:27]=[CH:28][CH:29]=[C:20]([S:17]([N:14]3[CH2:15][CH2:16][O:11][CH2:12][CH2:13]3)(=[O:18])=[O:19])[CH:21]=2)/[CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: NNC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1
Reactant: CC(=O)c1ccnc(Cl)c1
Solvent: CO
Solvent: CC(=O)O
Product: C/C(=N\NC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1)c1ccnc(Cl)c1
Temperature: 120 °C
Yield: 60 %

Procedure:
1-(2-Chloropyridin-4-yl)ethanone (20 mg, 0.129 mmol) and 3-(morpholinosulfonyl)benzohydrazide (36.7 mg, 0.129 mmol) were dissolved in methanol (4 mL) in the presence of acetic acid as a catalyst, and the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. Following cooling, the solvent was removed by vacuum and the resulting crude material was purified by flash column chromatography affording the title compound in a 60% yield. 1H NMR (400 MHz, CDCl3): δ 9.43 (m, 1H), 8.39 (m, 2H), 8.15 (d, 1H, J=8.0 Hz), 7.93 (d, 1H, J=7.6 Hz), 7.70 (t, 1H, J=7.6 Hz), 7.52 (m, 1H), 3.73 (m, 4H), 3.02 (m, 4H), 2.35 (s, 3H). ESI-MS: 423.1 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([NH:13][C@H:14]([C:18]([NH:20][CH:21]([CH:30]([OH:43])[CH2:31][O:32][C:33]1[C:38]([F:39])=[C:37]([F:40])[CH:36]=[C:35]([F:41])[C:34]=1[F:42])[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([NH:13][C@H:14]([C:18]([NH:20][CH:21]([C:30](=[O:43])[CH2:31][O:32][C:33]1[C:34]([F:42])=[C:35]([F:41])[CH:36]=[C:37]([F:40])[C:38]=1[F:39])[CH2:22][C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12]
Reactant: CC(C)[C@H](NC(=O)c1cc2ccccc2n1C)C(=O)NC(CC(=O)OC(C)(C)C)C(O)COc1c(F)c(F)cc(F)c1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)c1cc2ccccc2n1C)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)COc1c(F)c(F)cc(F)c1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92.3 %

Procedure:
To a solution of N-[(1-methyl-indole-2-carbonyl)valinyl]-3-amino-4-hydroxy-5-(2,3,5,6-tetrafluorophenyloxy)-pentanoic acid, tert-butyl ester (141 mg, 0.23 mmol) in CH2Cl2 (5.0 ml) was added Dess-Martin periodinane (128 mg, 0.3 mmol) and the solution stirred for 10 min. at room temperature. The reaction was quenched with Na2S2O4, diluted with EtOAc, washed with NaHCO3, and brine, dried over Na2SO4, filtered and concentrated in vaciio. The crude product was purified by chromatography (1:1 IEtOAc/hexane) to give the titled product as a white solid (129 mg, 92%).
Reaction SMILES: C(NC(=O)C(F)(F)F)CC.C(NC(=O)C(F)(F)F)CCCC.C(NC(=O)C(F)(F)F)CCCCCCC.C(NC(=O)C(F)(F)F)CCCCCCCCC.[CH2:55]([NH:71][C:72](=[O:77])[C:73]([F:76])([F:75])[F:74])[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66]CCCC.C(NC(=O)C(F)(F)F)CCCCCCCCCCCCCCCCC>>[CH2:55]([NH:71][C:72](=[O:77])[C:73]([F:75])([F:76])[F:74])[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66]
Reactant: CCCCCCCCCCCCCCCCNC(=O)C(F)(F)F
Agent: CCCCCCCCCCCCCCCCCCNC(=O)C(F)(F)F
Agent: CCCCCCCCCCNC(=O)C(F)(F)F
Agent: CCCCCCCCNC(=O)C(F)(F)F
Product: CCCCCCCCCCCCNC(=O)C(F)(F)F

Procedure:
The following similar compounds were all prepared in the same manner, all with similar NMR, acceptable microanalyses, mass spectra, and single spot on TLC: N-propyl-trifluoroacetamide, N-pentyl-trifluoroacetamide, N-octyl-trifluoroacetamide, N-decyl-trifluoroacetamide, N-hexadecyl-trifluoroacetamide, N-octadecyl-trifluoroacetamide.
Reaction SMILES: S[C:2]1[O:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C1C=CC=CC=1>[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:2]2[O:3][C:4]3[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:23][CH2:22]1
Reactant: O=[N+]([O-])c1ccc2nc(S)oc2c1
Reactant: CN1CCNCC1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CN1CCN(c2nc3ccc([N+](=O)[O-])cc3o2)CC1
Reaction time: 2 h

Procedure:
A 200 mg portion of 2-mercapto-6-nitrobenzoxazole dissolved in 40 ml of anhydrous benzene was mixed with 680 mg of phosphorus pentachloride, and the mixture was refluxed under heating for 48 hours. Under cooling with ice, 2.04 g of N-methylpiperazine dissolved in 5 ml of anhydrous benzene was added to the resulting solution, and the reaction was carried out for 2 hours at the same temperature. After adding the same amount of N-methylpiperazine, the reaction was continued for additional 72 hours at room temperature. Precipitated materials in the reaction solution were removed by filtration, and the resulting filtrate was concentrated under a reduced pressure. The thus obtained residue was dissolved in 300 ml of ethyl acetate, washed three times with water, dehydrated with sodium sulfate and then concentrated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography (chloroform:methanol=15:1) to obtain 230 mg of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[S:12]([NH:15][CH2:16][CH2:17][OH:18])(=[O:14])=[O:13].[F:19][C:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[CH:22][C:21]=1[C:35]1[CH:36]=[N:37][C:38]([NH2:41])=[N:39][CH:40]=1>>[NH2:41][C:38]1[N:39]=[CH:40][C:35]([C:21]2[CH:22]=[CH:23][C:24]([C:2]3[C:3]([S:12]([NH:15][CH2:16][CH2:17][OH:18])(=[O:14])=[O:13])=[CH:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=3)=[CH:25][C:20]=2[F:19])=[CH:36][N:37]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: O=S(=O)(NCCO)c1cc(C(F)(F)F)ccc1Br
Product: Nc1ncc(-c2ccc(-c3ccc(C(F)(F)F)cc3S(=O)(=O)NCCO)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 2-bromo-N-(2-hydroxyethyl)-5-(trifluoromethyl)benzene-sulfonamide and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrimidin-2-amine. MS (ESI): mass calcd. for C19H16F4N4O3S, 456.09; m/z found, 457.0 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.57-8.53 (d, J=1.4, 2H), 8.38-8.35 (m, 1H), 8.00-7.96 (dd, J=8.1, 1.5, 1H), 7.63-7.60 (d, J=8.0, 1H), 7.59-7.54 (m, 1H), 7.38-7.36 (dd, J=6.1, 1.6, 1H), 7.36-7.34 (m, 1H), 3.51-3.45 (t, J=5.9, 2H), 2.95-2.86 (t, J=5.9, 2H).
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][O:12][CH2:13][C:14](=[O:34])[CH2:15][C:16]([O:18][CH2:19][CH2:20][CH:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:17])C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][CH2:9][CH2:10][CH2:11][O:12][CH2:13][C:14](=[O:34])[CH2:15][C:16]([O:18][CH2:19][CH2:20][CH:21]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:17]
Reactant: O=C(COCCCOCc1ccccc1)CC(=O)OCCC(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C(COCCCO)CC(=O)OCCC(c1ccccc1)c1ccccc1

Procedure:
4.33 g (9.41 mmol) of 3,3-diphenylpropyl 4-(3-benzyloxypropoxy)-3-oxobutanoate was hydrogenated in the presence of a catalytic amount of 5% palladium/carbon in 50 ml of ethanol under 5 atm. for 14 days. After an ordinary after treatment followed by the purification by the silica gel chromatography (hexane/ethyl acetate=1/1), the title compound was obtained.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH:12]1[CH2:20][CH2:19][CH2:18][CH:14]([C:15]([NH2:17])=[O:16])[CH2:13]1.CN1C(=O)CCC1>O>[F:8][C:5]1[CH:6]=[CH:7][C:2]([N:12]2[CH2:20][CH2:19][CH2:18][CH:14]([C:15]([NH2:17])=[O:16])[CH2:13]2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: NC(=O)C1CCCNC1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Solvent: O
Solvent: CN1CCCC1=O
Product: NC(=O)C1CCCN(c2ccc(F)cc2[N+](=O)[O-])C1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
The mixture consisting of 1.62 g of 2,5-difluoronitrobenzene, 1.9 g of nipecotamide and 10 ml of NMP was heated with stirring to 80° C. for 2 hours. After the mixture had been allowed to cool, 30 ml of water were added and the mixture was stirred at RT for 30 minutes. The precipitated solid was filtered off with suction and dried under reduced pressure.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1([CH2:17][OH:18])[CH2:16][CH2:15][C:10]2(OCC[O:11]2)[CH2:9][CH2:8]1.Cl>C1COCC1>[OH:18][CH2:17][C:7]1([C:2]2[N:1]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:16][CH2:15][C:10](=[O:11])[CH2:9][CH2:8]1
Reactant: OCC1(c2ncccn2)CCC2(CC1)OCCO2
Agent: Cl
Solvent: C1CCOC1
Product: O=C1CCC(CO)(c2ncccn2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.5 %

Procedure:
To a solution of (8-pyrimidin-2-yl-1,4-dioxa-spiro[4,5]dec-8-yl)-methanol (295 mg, 1.18 mmol) in THF (10 mL) was added 3 N aqueous HCl (10 mL) at 25° C. After being stirred at 25° C. for 24 h, THF was removed under reduced pressure and the reaction was neutralized (saturate aqueous NaHCO3) and extracted (4×10% MeOH/DCM). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to provide 4-(hydroxymethyl)-4-(pyrimidin-2-yl)cyclohexanone (238 mg, 1.15 mmol, 98%) as a pale yellow solid.
Reaction SMILES: [Na].C([O:4][C:5](=O)[CH2:6][C:7]#[N:8])C.[CH3:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[CH2:14][NH:15][NH2:16].N#N>C(O)C.O>[NH2:8][C:7]1[NH:16][N:15]([CH2:14][C:13]2[CH:17]=[CH:18][CH:19]=[C:11]([CH3:10])[CH:12]=2)[C:5](=[O:4])[CH:6]=1
Reactant: Cc1cccc(CNN)c1
Reactant: CCOC(=O)CC#N
Agent: N#N
Agent: [Na]
Solvent: O
Solvent: CCO
Product: Cc1cccc(Cn2[nH]c(N)cc2=O)c1

Procedure:
4.6 g of sodium are dissolved in 100 ml of ethanol. A mixture of 12 g of cyanoacetic acid ethyl ester and 13.6 g of 3-methylbenzylhydrazine is added to this solution. The mixture is heated to the boil for 5 hours while stirring and passing N2 into it. After driving off the solvent, taking up the residue in water, extracting with ether and clarifying with animal charcoal, acidification with acetic acid yields colorless crystals which after again being recrystallised from ethanol melt at 92°. The yield is 10.3 g of the compound identified above, corresponding to 51% of theory.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[N:8]=1)=[O:6].Cl>[Pt](=O)=O.C(O)C>[OH:1][CH2:2][CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][CH:9]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[NH:8]1)=[O:6]
Reactant: COc1ccc(-c2cccc(C(=O)NCCO)n2)cc1OC
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Product: COc1ccc(C2CCCC(C(=O)NCCO)N2)cc1OC
Reaction time: 8 h

Procedure:
A quantity of 3.0 g (10 mmoles, 1 eq) of 6-(3,4-dimethoxy-phenyl)-pyridine-2-carboxylic acid (2-hydroxy-ethyl)-amide and 0.23 g (1.0 mmoles, 0.1 eq) of platinum dioxide are added into 35 mL of ethanol and 2.0 ml concentrated HCl. The suspension is hydrogenated under 50 psi of H2 at room temperature overnight. After TLC shows no starting material existing, the reaction is filtered through Celite and solvent is removed. The residue is taken in ethyl acetate, washed with saturated Na2CO3 and brine, dried over Na2SO4 and concentrated to give 6-(3,4-dimethoxy-phenyl)-piperidine-2-carboxylic acid (2-hydroxy-ethyl)-amide as a yellowish oil. The oil is triturated with ethyl acetate and hexanes to afford a white solid (1.6 g, 52%). Analysis: NMR (300 MHz, CDCl3): 7.18 (1H, t), 6.90 (2H, m), 6.82 (1H, m), 3.87 (6H, d), 3.66 (3H, m), 3.39 (3H, m), 2.00 (2H, m), 1.80 (1H, m) and 1.22 (2H, m). MS (LC-MS): Calculated for C16H24N2O4 308.37. Found 309.34 (M+1).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:28][CH:29]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:30][CH2:31][OH:32])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:9]=2)=[N:6][CH:7]=1.I(C1C=CC=CC=1C(O)=O)(=O)=O>C1COCC1>[F:1][C:2]1[C:3]([NH:28][CH:29]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:30][CH:31]=[O:32])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:19])=[O:20])[CH:9]=2)=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC(CCO)C(C)(C)C)n3)c3cc(F)cnc32)cc1
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC(CC=O)C(C)(C)C)n3)c3cc(F)cnc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of racemic 3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethylpentan-1-ol, 82a, (1.60 g, 3.10 mmol) in THF (64 mL) was added 2-iodoxybenzoic acid (Ibx) (3.86 g, 6.21 mmol). The reaction mixture was heated to reflux under at atmosphere of nitrogen for 30 minutes. After cooling the mixture to room temperature, the solids were filtered. An aqueous saturated NaHCO3 solution was added to the filtrate and the biphasic mixture was stirred for 30 minutes. The mixture was further diluted with dichloromethane and the phases separated. The aqueous layer was extracted again with dichloromethane. The combined organic phases were dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue was purified via silica gel chromatography (EtOAc/Hexanes) to afford 1.59 g of the desired product
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[Sn](Cl)Cl>Cl>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[N:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH2:16]1)[NH2:8]
Reactant: CN1CCN(c2ccc([N+](=O)[O-])cc2Cl)CC1
Agent: Cl
Agent: Cl[Sn]Cl
Product: CN1CCN(c2ccc(N)cc2Cl)CC1
Reaction time: 1 h
Yield: 94.2 %

Procedure:
To a stirred solution of 1-(2-chloro-4-nitrophenyl)-4-methylpiperazine (2.43 g, 9.5 mmol) in 2N HCl (35 mL) at RT was added tin (II) chloride (7.2 g, 38 mmol). After 1 h, the solids were collected by filtration and dissolved in aqueous 1 N NaOH (300 mL). The aqueous solution was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and evaporated to afford the title compound (2.02 g, 95%).