Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[C:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=1.[K+].[C:18]([C:20]1[N:21]=[C:22]([C:33]([O-])=[O:34])[N:23]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:24]=1)#[N:19]>CO.C(Cl)Cl>[C:6]([C:5]1[CH:9]=[CH:10][C:2]([NH:1][C:33]([C:22]2[N:23]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:24]=[C:20]([C:18]#[N:19])[N:21]=2)=[O:34])=[C:3]([C:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=2)[CH:4]=1)(=[O:7])[NH2:8]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: NC(=O)c1ccc(N)c(C2=CCCCC2)c1
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(C(N)=O)cc1C1=CCCCC1
Yield: 98 %

Procedure:
The title compound was prepared by the procedure of Example 11, step (f) using 4-amino-3-cyclohex-1-enyl-benzamide (as prepared in the previous step, 100 mg, 0.462 mmol) and potassium 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate (as prepared in Example 11, step (d), 155 mg, 0.509 mmol). Silica gel chromatography (1-2% MeOH/DCM) afforded the title compound (210 mg, 98%) as a white solid. Mass spectrum (ESI, m/z): Calcd. for C24H31N5O3Si, 466.2 (M+H), found 466.1.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]([F:20])([F:19])[C:8]1[CH:9]=[C:10]([N:14]2[CH:18]=[CH:17][CH:16]=[N:15]2)[CH:11]=[CH:12][CH:13]=1.CN(C)[CH:23]=[O:24]>>[F:20][C:7]([F:6])([F:19])[C:8]1[CH:9]=[C:10]([N:14]2[CH:18]=[C:17]([CH:23]=[O:24])[CH:16]=[N:15]2)[CH:11]=[CH:12][CH:13]=1
Reactant: CN(C)C=O
Reactant: FC(F)(F)c1cccc(-n2cccn2)c1
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cnn(-c2cccc(C(F)(F)F)c2)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
Into a 500 ml., 2-neck flask, fitted with a condenser and a magnetic stirrer, containing 60.5 ml. (0.78 M.) of absolute dimethylformamide (dried over 3A sieves) is slowly added, while the temperature is maintained at less than 10° C., 36.9 ml. (0.39 M.) of phosphorus oxychloride, after which time the reaction mixture is allowed to stand at room temperature until a bright red color develops (typically, between 30 and 60 minutes). To the resultant reaction mixture is then added 23.2 g. (0.109 M.) of 1-(m-trifluoromethylphenyl)-pyrazole, while the temperature is maintained at between 50° and 70° C. The reaction mixture is then slowly heated to 100° C. and allowed to stand overnight, while the temperature is maintained at 100° C. The reaction mixture is then cooled, quenched in ice water and allowed to stand overnight at room temperature. The resultant precipitated solids are then filtered and washed successively with water and petroleum ether. The solvent is then removed under vacuum to yield 1-(m-trifluoromethylphenyl)pyrazole-4-carboxaldehyde (Yield: 57%). A second crop was also obtained, m.p. 80°-82° C. (Yield: 63%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[C:6]([C:8]2(Cl)[NH:13][C:12]([NH2:14])=[N:11][CH:10]=[CH:9]2)[CH:7]=1.[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[C:6]([C:8]2[N:13]=[C:12]([NH2:14])[N:11]=[C:10]([NH:33][C:30]3[CH:31]=[CH:32][C:27]([CH3:26])=[CH:28][CH:29]=3)[CH:9]=2)[CH:7]=1
Reactant: COc1ccccc1COc1ccc(Br)cc1C1(Cl)C=CN=C(N)N1
Reactant: Cc1ccc(N)cc1
Product: COc1ccccc1COc1ccc(Br)cc1-c1cc(Nc2ccc(C)cc2)nc(N)n1
Yield: 36 %

Procedure:
Following the method described in Example 4, 6-[5-bromo-2-(2-methoxy-benzyloxy)-phenyl]-6-chloro-pyrimidin-2-ylamine and 4-methyl-phenylamine provided the title compound (36% yield). 1H NMR (CD3OD) δ 3.82 (s, 3H, CH3), 5.25 (s, 2H, CH2), 6.32 (s, 1H, Ar), 6.89-6.98 (m, 2H, Ar), 7.21-7.30 (m, 6H, Ar), 7.59-7.72 (m, 3H, Ar).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][C:6]([C:7](OC)=[O:8])=[CH:5][N:4]=1.[BH4-].[Na+]>CO>[F:13][C:2]([F:1])([F:14])[C:3]1[N:4]=[CH:5][C:6]([CH2:7][OH:8])=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccc(C(F)(F)F)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
To a solution of Example 85A (4.1 g, 20.0 mmol) in 100 mL of methanol was added 7.6 g of NaBH4 in portions at 0° C. The resulting mixture was stirred at room temperature overnight, then quenched with water (100 mL). Most of the methanol was removed in vacuo. The residue was extracted with ethyl acetate (100 mL×3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel column (petroleum ether:ethyl acetate=5:1) to afford the title compound (2.8 g, 79.1%). 1H NMR (400 MHz, CDCl3): δ 8.68 (s, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.70 (s, J=8.0 Hz, 1H), 4.84 (s, 2H), 2.48 (s, br, 1H).
Reaction SMILES: [CH:1]1[C:13]2[C:12](=[CH:14][C:15](O)=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.Cl.[CH3:48][O:49][C:50](=[O:59])[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][NH2:58]>[Cl-].[Na+].O.CN(C=O)C>[CH3:48][O:49][C:50](=[O:59])[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][NH:58][C:15](=[O:16])[CH:14]=[C:12]1[C:13]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: COC(=O)CCCCCCCN
Reactant: O=C(O)C=C1c2ccccc2-c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)CCCCCCCNC(=O)C=C1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.9 %

Procedure:
2-(9H-fluoren-9-ylidene)acetic acid (222 mg, 1 mmol) and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (394 mg, 2 mmol), hydroxyl-benzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and 8-aminocaprylic acid methyl ester hydrochloride (251 mg, 1.2 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (328 mg, 87% yield) as a white solid. LC-MS (m/z) 378 (M+1).
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([O:12][C:13]2[CH:14]=[CH:15][C:16]3[N:17]([C:19]([N:22]([CH3:24])[CH3:23])=[N:20][N:21]=3)[CH:18]=2)[CH2:4][CH2:3]1.ClC(Cl)(Cl)C[O:28][C:29](=O)[NH:30][C:31]1[N:32]([C:40]2[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=2)[N:33]=[C:34]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH:35]=1.CCN(C(C)C)C(C)C.N>CN(C=O)C.CO.C(Cl)Cl>[C:36]([C:34]1[CH:35]=[C:31]([NH:30][C:29]([NH:1][C@@H:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C@H:5]([O:12][C:13]3[CH:14]=[CH:15][C:16]4[N:17]([C:19]([N:22]([CH3:24])[CH3:23])=[N:20][N:21]=4)[CH:18]=3)[CH2:4][CH2:3]2)=[O:28])[N:32]([C:40]2[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=2)[N:33]=1)([CH3:39])([CH3:37])[CH3:38]
Reactant: CN(C)c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Agent: N
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N(C)C)n4c3)c3ccccc32)cc1
Yield: 52 %

Procedure:
A solution of Intermediate 59c (80 mg, 0.25 mmol), (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 150 mg, 0.370 mmol) and DIPEA (129 mg, 1.00 mmol) in DMF (2 mL) was stirred at 60° C. for 30 min. The reaction mixture was applied to an SCX-2 cartridge (10 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 0-5% [2M NH3 in MeOH] in DCM, gave the title compound as an off-white solid (75 mg, 52%). LCMS (Method 5): Rt 4.39 min, m/z 579.1 [MH+]. 1H NMR (400 MHz, d4-MeOH): 1.29 (9H, s), 1.83-2.17 (3H, m), 2.17-3.00 (1H, m), 2.38 (3H, s), 2.92 (6H, s), 4.88 (1H, dd, J 8.5, 5.4), 5.41 (1H, t, J 3.0), 6.33 (1H, s), 7.14-7.36 (9H, m), 7.50 (1H, d, J 9.7), 7.70 (1H, d, J 1.4).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:43]=[C:44]([S:48]([N:51]2[CH2:56][CH2:55][N:54]([CH2:57][CH3:58])[CH2:53][CH2:52]2)(=[O:50])=[O:49])[CH:45]=[CH:46][CH:47]=1>>[CH2:57]([N:54]1[CH2:53][CH2:52][N:51]([S:48]([C:44]2[CH:43]=[C:42]([N:27]3[C:17]4[N:18]=[C:19]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)[N:20]=[C:15]([C:12]5[CH:11]=[N:10][C:9]([N:8]([CH2:7][C:6]6[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=6)[CH2:30][C:31]6[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=6)=[N:14][CH:13]=5)[C:16]=4[CH2:29][CH2:28]3)[CH:47]=[CH:46][CH:45]=2)(=[O:49])=[O:50])[CH2:56][CH2:55]1)[CH3:58]
Reactant: CCN1CCN(S(=O)(=O)c2cccc(Br)c2)CC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: CCN1CCN(S(=O)(=O)c2cccc(N3CCc4c(-c5cnc(N(Cc6ccc(OC)cc6)Cc6ccc(OC)cc6)nc5)nc(N5CCOCC5)nc43)c2)CC1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg) and 1-(3-bromo-benzenesulfonyl)-4-ethyl-piperazine (prepared from 3-bromo-benzenesulfonyl chloride and N-ethylpiperazine in acetonitrile, 68 mg) instead of 4-bromobenzoic acid methyl ester in Example 1-D-08, in the same manner as Example 1-D-08, a crude product of (5-{7-[3-(4-ethyl-piperazine-1-sulfonyl)-phenyl]-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}-pyrimidin-2-yl)-bis-(4-methoxy-benzyl)-amine was obtained, and then the PMB groups were removed according to the above Deprotection method 1, to obtain the desired compound (D-96) as an ivory powder (45 mg, 43%).
Reaction SMILES: [O:1]1[C:5]2([CH2:15][CH2:14][C:8]3([CH2:12][CH2:11][NH:10][C:9]3=[O:13])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Br[C:17]1[CH:22]=[CH:21][C:20]([CH:23]([OH:27])[CH:24]([F:26])[F:25])=[CH:19][CH:18]=1>>[F:25][CH:24]([F:26])[CH:23]([C:20]1[CH:19]=[CH:18][C:17]([N:10]2[CH2:11][CH2:12][C:8]3([CH2:14][CH2:15][C:5]4([O:4][CH2:3][CH2:2][O:1]4)[CH2:6][CH2:7]3)[C:9]2=[O:13])=[CH:22][CH:21]=1)[OH:27]
Reactant: O=C1NCCC12CCC1(CC2)OCCO1
Reactant: OC(c1ccc(Br)cc1)C(F)F
Product: O=C1N(c2ccc(C(O)C(F)F)cc2)CCC12CCC1(CC2)OCCO1

Procedure:
The title compound was prepared in analogy to example 133, step 4 from 1,4-dioxa-10-aza-dispiro[4.2.4.2]tetradecan-9-one (described in example 133, step 3) and 1-(4-bromo-phenyl)-2,2-difluoro-ethanol as yellow solid. MS (m/e): 368.166 [MH+].
Reaction SMILES: Cl.[I:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH2:14])[CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:5][CH:4]=1.F[C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][N:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O.C(OCC)(=O)C>[I:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([NH:14][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][N:17]=2)[CH2:10][CH:11]([CH3:12])[CH3:13])=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccc(F)nc1
Reactant: CC(C)CC(N)c1ccc(I)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(CC(C)C)c2ccc(I)cc2)nc1
Temperature: 100 °C
Yield: 52.1 %

Procedure:
1-(4-Iodophenyl)-3-methylbutan-1-amine hydrochloride (1.14 g, 3.49 mmol), methyl 6-fluoronicotinate (0.568 g, 3.66 mmol), and potassium carbonate (1.45 g, 10.5 mmol) were combined in N,N-dimethylformamide (11.6 mL) and heated to 100° C. for 3.5 hours. The reaction was then cooled to room temperature and diluted with water and ethyl acetate. The layers were separated and the aqueous was extracted 3 times with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by column chromatography (0-30% ethyl acetate/heptane) provided methyl 6-(1-(4-iodophenyl)-3-methylbutylamino)nicotinate (0.772 g, 52%) as a white solid. 1H NMR (400 MHz, CDCl3, δ): 8.69 (d, J=1.8 Hz, 1H), 7.89 (dd, J=8.8, 2.3 Hz, 1H), 7.60-7.64 (m, 2H), 7.04-7.08 (m, 2H), 6.16 (d, J=8.4 Hz, 1H), 5.49 (d, J=6.4 Hz, 1H), 4.62-4.69 (m, 1H), 3.82 (s, 3H), 1.54-1.76 (m, 3H), 0.90-0.97 (m, 6H). MS (M+1): 425.2.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([CH3:18])[C:3]=1[NH:19][C:20](=[O:31])[C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1F.[CH2:32]([NH2:34])[CH3:33].O>C(#N)C>[CH3:18][C:4]1[CH:5]=[C:6]([C:8]([F:17])([C:9]([F:11])([F:10])[F:12])[C:13]([F:16])([F:15])[F:14])[CH:7]=[C:2]([CH3:1])[C:3]=1[NH:19][C:20](=[O:31])[C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[NH:34][CH2:32][CH3:33]
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cc([N+](=O)[O-])ccc1F
Reactant: CCN
Solvent: CC#N
Solvent: O
Product: CCNc1ccc([N+](=O)[O-])cc1C(=O)Nc1c(C)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a solution of N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-2-fluoro-5-nitrobenzamide (5.0 g, 11 mmol) (see Example I4) in acetonitrile (100 ml) was added a solution of N-ethylamine in water (70% by weight) (2.23 ml, 28 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes. The reaction mixture was concentrated and the residue purified by chromatography over silica gel (eluent: ethyl acetate) to give N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-2-ethylamino-5-nitrobenzamide (4.8 g, 91% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:27][CH2:26][CH2:25][S:24]3(=[O:29])=[O:28])=[CH:19][C:18]=2[O:30]C)=[O:16])[CH2:11][CH2:10]1.ClCCl.B(Br)(Br)Br.C(=O)([O-])O.[Na+]>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:27][CH2:26][CH2:25][S:24]3(=[O:29])=[O:28])=[CH:19][C:18]=2[OH:30])=[O:16])[CH2:13][CH2:14]1
Reactant: COc1cc(N2CCCS2(=O)=O)ccc1C(=O)N1CCN(c2ccc(C)cc2C)CC1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3O)CC2)c(C)c1
Temperature: -78 °C
Yield: 49.6 %

Procedure:
[4-(2,4-Dimethylphenyl)piperazin-1-yl][4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-methoxyphenyl]methanone (0.35 g) described in Example 89 was dissolved in dichloromethane (20 mL), 1 mol/L boron tribromide dichloromethane solution (4 mL) was added while stirring at −78° C. under cooling, and the mixture was stirred while rising the temperature to room temperature. Into the reaction mixture was poured ice water, and the mixture was neutralized with sodium hydrogen carbonate and extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform:methanol) to give the title compound (168 mg).
Reaction SMILES: C1(C)C=C(C)C=C(C)C=1Cl.[OH:11][C@H:12]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)[C@H:13]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:14]O.[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>N1C=CC=CC=1>[OH:11][C@H:12]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)[C@H:13]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:14][N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: COc1ccc([C@@H](O)[C@@H](CO)NC(=O)OCc2ccccc2)cc1
Reactant: C1CCNC1
Agent: Cc1cc(C)c(Cl)c(C)c1
Solvent: c1ccncc1
Product: COc1ccc([C@@H](O)[C@@H](CN2CCCC2)NC(=O)OCc2ccccc2)cc1
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 65.7 %

Procedure:
Mesityl chloride (0.28 mL, 3.6 mmol) was added slowly to a cold (−10° C.) solution of benzyl (1R,2R)-1,3-dihydroxy-1-(4-methoxyphenyl)propan-2-ylcarbamate (1.07 g, 3.23 mmol) in pyridine (1.5 mL). The mixture was stirred for 30 min and then pyrrolidine (2.7 mL, 33 mmol) was added slowly to the mixture. The mixture was heated to 45° C. for 6 hours and then the solvent was removed to dryness. After purification by column chromatography (SiO2, using a mixture of CH2Cl2, MeOH, NH4OH), the product was obtained as a clear oil (0.816 g, 66% yield).
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C:51]([CH3:57])([CH3:56])[C:52]([O:54][CH3:55])=[O:53])[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.[CH2:58]([C:63]1[CH:71]=[CH:70][C:66]([C:67](Cl)=[O:68])=[CH:65][CH:64]=1)[CH2:59][CH2:60][CH2:61][CH3:62]>>[CH3:56][C:51]([N:46]1[CH2:45][C:44]2[C:48](=[CH:49][C:41]([C:38]3[CH:37]=[CH:36][C:35]([NH:34][C:67](=[O:68])[C:66]4[CH:70]=[CH:71][C:63]([CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])=[CH:64][CH:65]=4)=[CH:40][CH:39]=3)=[CH:42][CH:43]=2)[C:47]1=[O:50])([CH3:57])[C:52]([O:54][CH3:55])=[O:53]
Reactant: CCCCCc1ccc(C(=O)Cl)cc1
Reactant: COC(=O)C(C)(C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: CCCCCc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N(C(C)(C)C(=O)OC)C4)cc2)cc1
Yield: 93 %

Procedure:
The compound of example 524 was prepared analogous to compound of example 97 by reaction of compound of example 515 with 4-(n-pentyl)-benzoyl chloride.
Reaction SMILES: [CH3:1]C([O-])(C)C.[K+].[CH2:7]([O:9][C:10](=[O:27])[CH2:11][N:12]1[CH2:16][C:15](=O)[C@@H:14]([NH:18][C:19]([C:21]2[S:22][C:23]([Cl:26])=[CH:24][CH:25]=2)=[O:20])[CH2:13]1)[CH3:8]>C1COCC1.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOC(C)=O>[CH2:7]([O:9][C:10](=[O:27])[CH2:11][N:12]1[CH2:16][C:15](=[CH2:1])[C@@H:14]([NH:18][C:19]([C:21]2[S:22][C:23]([Cl:26])=[CH:24][CH:25]=2)=[O:20])[CH2:13]1)[CH3:8]
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)CN1CC(=O)[C@@H](NC(=O)c2ccc(Cl)s2)C1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C1CN(CC(=O)OCC)C[C@@H]1NC(=O)c1ccc(Cl)s1
Temperature: 0 °C
Yield: 76.5 %

Procedure:
39.3 To a cooled (0° C.), stirred suspension of 44 mg potassium tert-butylate in 3 ml THF under an argon atmosphere were added 149 mg methyltriphenylphosphonium bromide. The yellow slurry was then stirred for 1 h 30, slowly warming up to room temperature. A solution of 100 mg {(S)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-oxo-pyrrolidin-1-yl}-acetic acid ethyl ester in 2 ml THF was then added. The mixture was heated to reflux and stirred for 2 hrs. The mixture (dark brown slurry) was cooled to r.t., diluted with EtOAc, washed with sat. aq. NH4C1, H2O and brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel, gradient: CH2Cl2->CH2Cl2/MeOH 95:5) to give 76 mg {(R)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-methylene-pyrrolidin-1-yl}-acetic acid ethyl ester (contaminated with 43 w % triphenylphosphin oxide). Amorphous gum. MS 329.0 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[F:10].[CH3:11][Li]>C1COCC1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH3:11])=[CH:4][C:3]=1[F:10]
Reactant: [Li]C
Reactant: O=Cc1ccc(Cl)c(F)c1
Solvent: C1CCOC1
Product: CC(O)c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Chloro-3-fluoro-benzaldehyde (5.14 g, 32.4 mmol) was dissolved in THF (100 mL) and place at −78° C. under nitrogen atmosphere. Methyl Lithium (1.6 M in diethyl ether, 22.3 mL) was added to the reaction during a period of 3 minutes maintianing the same temperature. After the addition, the reaction was stirred at room temperature for 1 h. Then, the reaction was poured over ice water and extracted with ethyl acetate and hydrochloric acid 1N. The organic layer was collected, dried with sodium sulfate, filtered and concentrated under vacuum to produce a crude, which it was chromatograph over silica gel using 50% hexane-ethyl Acetate as solvent to yield 5.1 g of 1-(4-chloro-3-fluoro-phenyl)-ethanol. 1H NMR (400 MHz, Cl3CD) δ 7.37 (t, J=8.14 Hz, 1H), 7.20 (dd, J=1.86, 10.00 Hz, 1H), 7.09 (dd, J=1.86, 8.14 Hz, 1H), 4.89 (m, 1H), 1.93 (br s, 1H), 1.49 (d, J=6.51, 3H).
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([Cl:9])[CH:6]=[CH:7][CH:8]=1.[Cl:10][C:11]1[N:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:12]=1[C:13](O)=[O:14].[Cl-].[NH4+]>O1CCCC1>[Cl:10][C:11]1[C:12]([C:13](=[O:14])[C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[CH:4]=2)=[CH:16][CH:17]=[C:18]([CH3:20])[N:19]=1
Reactant: Cc1ccc(C(=O)O)c(Cl)n1
Reactant: Clc1cccc(Br)c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)c2cccc(Cl)c2)c(Cl)n1
Temperature: 25 °C
Yield: 44.3 %

Procedure:
Magnesium (4.8 g, 200 mmol) was added to a tetrahydrofuran (400 ml) solution of 3-bromochlorobenzene (38 g, 200 mmol), and the mixture was stirred at room temperature. Since spontaneous exothermic reaction occurred, the stirring was continued until the exothermicity was ceased. The reaction solution was cooled to -40° C., mixed with 2-chloro-6-methylnicotinic acid (9.2 g, 53 mmol) and then stirred overnight at room-temperature. The reaction solution was mixed with saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, magnesium sulfate was removed by filtration and then the filtrate was concentrated under a reduced pressure. Thereafter, the resulting residue was purified by silica gel column chromatography (chloroform) to give 2-chloro-3-(3-chlorobenzoyl)-6-methylpyridine (6.25 g, 44%) as an oily material.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:25][CH:26]1[CH2:31][CH2:30][C:29](=[O:32])[NH:28][C:27]1=[O:33].C(N(CC)CC)C.C(O)(=O)C>C(#N)C.O>[NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:25][CH:26]1[CH2:31][CH2:30][C:29](=[O:32])[NH:28][C:27]1=[O:33])=[O:6]
Reactant: Cc1cccc(C(=O)O)c1N
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC(=O)O
Solvent: O
Solvent: CC#N
Product: Cc1cccc(C(=O)NC2CCC(=O)NC2=O)c1N
Temperature: 25 °C
Reaction time: 5 h
Yield: 51.9 %

Procedure:
A mixture of 2-amino-3-methylbenzoic acid (2.1 g, 14 mmol) and CDI (1.9 g, 12 mmol) in acetonitrile (25 mL) was stirred at room temperature for 5 hours. To the suspension, was added 3-amino-piperidine-2,6-dione hydrogen chloride (2.3 g, 14 mmol), triethylamine (7.2 mL, 66 mmol) and acetic acid (8 mL, 132 mmol), and the mixture was heated to reflux for 16 hours. To the mixture, was added water (75 mL) and stirred at room temperature for 2 hours. The suspension was filtered and washed with water (50 mL) and ethyl acetate (20 mL) to give 2-amino-N-(2,6-dioxo-piperidin-3-yl)-3-methyl-benzamide as a white solid (1.9 g, 61% yield): 1H NMR (DMSO-d6) δ 1.92-1.99 (m, 1H, CHH), 2.06 (s, 3H, CH3), 2.04-2.14 (m, 1H, CHH), 2.51-2.56 (m, 1H, CHH), 2.73-2.85 (m, 1H, CHH), 4.69-4.78 (m, 1H, NCH), 6.22 (brs, 2H, NH2), 6.50 (t, J=8 Hz, 1H, Ar), 7.10 (d, J=8 Hz, 1H, Ar), 7.40 (d, J=8 Hz, 1H, Ar), 8.47 (d, J=8 Hz, 1H, NH), 10.83 (s, 1H, NH); LCMS: MH=262.