Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[C:5]([Cl:13])[CH:4]=1.[NH3:14]>CN(C=O)C>[Cl:13][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][C:6]=1[C:9]([F:12])([F:11])[F:10])[CH2:2][NH2:14]
Reactant: N
Reactant: FC(F)(F)c1ccc(CBr)cc1Cl
Solvent: CN(C)C=O
Product: NCc1ccc(C(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A solution of 4-bromomethyl-2-chloro-1-trifluoromethylbenzene (3.0 g, 11 mmol) in DMF (25 ml) was added dropwise to a mixture of 25% aqueous ammonia (50 ml) and DMF (25 ml). The reaction mixture was stirred at room temperature for 60 hours. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate (100 ml) and washed with a saturated aqueous solution of sodium hydrogen carbonate (100 ml). The aqueous phase was extracted with ethyl acetate (2×60 ml). The combined organic layers were dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (90 g), using first ethyl acetate/heptane (1:3) together with 3% triethylamine and subsequently DCM/methanol/25% aqueous ammonia as eluent, to give 250 mg of 3-chloro-4-(trifluoromethyl)benzylamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][NH:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[C:21]([C:23]4[O:24][C:25]([CH3:28])=[N:26][N:27]=4)[CH:20]=[CH:19][C:18]=3[CH3:29])=[CH:13][CH:12]=2)=[O:10])=[CH:5][CH:4]=1.[CH:32]1([CH2:35]Br)[CH2:34][CH2:33]1>>[CH:32]1([CH2:35][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:31][CH:30]=2)[C:9]([C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[C:21]([C:23]4[O:24][C:25]([CH3:28])=[N:26][N:27]=4)[CH:20]=[CH:19][C:18]=3[CH3:29])=[CH:15][CH:16]=2)=[O:10])[CH2:34][CH2:33]1
Reactant: COc1ccc(CNC(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)cc1
Reactant: BrCC1CC1
Product: COc1ccc(CN(CC2CC2)C(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)cc1

Procedure:
N-(Cyclopropylmethyl)-N-(4-methoxybenzyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from N-(4methoxybenzyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide and cyclopropylmethyl-bromide using method L. LCMS; retention time 3.70 min, MH+ 468.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:4].[Cl:16][C:17]1[CH:29]=[CH:28][C:20]([O:21][C:22]([CH3:27])([CH3:26])[C:23](O)=[O:24])=[CH:19][CH:18]=1>>[CH3:4][CH:3]([NH:2][C:23](=[O:24])[C:22]([O:21][C:20]1[CH:28]=[CH:29][C:17]([Cl:16])=[CH:18][CH:19]=1)([CH3:27])[CH3:26])[CH:5]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8]
Reactant: CC(C)CC(c1ccccc1)C(C)N
Reactant: CC(C)(Oc1ccc(Cl)cc1)C(=O)O
Agent: Cl
Product: CC(C)CC(c1ccccc1)C(C)NC(=O)C(C)(C)Oc1ccc(Cl)cc1

Procedure:
2-Amino-5-methyl-3-phenylhexane hydrochloride salt from Reference Example 26 (30 mg) was reacted with the acid chloride prepared from of 2-(4-chlorophenoxy)-2-methyl-propionic acid (37 mg) according to the procedure described in Example 62-63 to afford the title compound after purification by preparative TLC on silica gel eluted with 20% EtOAC-hexane. 1H NMR: (500 MHz, CDCl3): δ 0.83 and 0.85 (2d, 6H), 0.96 (d, 3H), 1.34 (m, 1H), 1.45 (m, 1 H), 1.53 (s, 3H), 1.59 (s, 3H), 2.73 (m, 1H), 4.24 (m, 1H), 6.41 (d, 1H), 6.8-7.4 (m, 9H). LC-MS: Rt=4.5 min. m/e=388.3 (M+1).
Reaction SMILES: [CH2:1]([N:3]([Si](C)(C)C)[CH2:4][CH3:5])C.[CH3:10][O:11][S:12]([O-:15])(=[O:14])=[O:13].[CH3:16][NH+:17]1[CH2:21][CH2:20][N:19](C)[CH:18]1Cl>C(Cl)(Cl)Cl>[CH3:10][O:11][S:12]([O-:15])(=[O:14])=[O:13].[CH3:1][NH+:3]1[CH2:4][CH2:5][N:19]([CH3:20])[CH:18]1[N:17]([CH3:21])[CH3:16]
Reactant: CN1CC[NH+](C)C1Cl
Reactant: CCN(CC)[Si](C)(C)C
Agent: COS(=O)(=O)[O-]
Solvent: ClC(Cl)Cl
Product: CN(C)C1N(C)CC[NH+]1C
Yield: 85.1 %

Procedure:
1.33 g (11.34 mmol) of N,N-diethyltrimethylsilylamine are added over the course of 5 minutes at room temperature and with vigorous stirring to 2.50 g (10.22 mmol) of 1,3-dimethyl-2-chloroimidazolidinium methylsulfate in 10 ml of dry chloroform. The solvent is distilled off, and the residue is washed three times with 5 ml of diethyl ether and subsequently dried under a reduced pressure of 7.0 Pa and at 50° C. for 1 hour. The product is crystallised from a mixture of tetrahydrofuran:diethyl ether (1:1), giving 2.22 g of 1,3-dimethyl-2-dimethylaminoimidazolidinium methylsulfate, corresponding to a yield of 85.7%.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][N:12]1[CH2:17][CH:16]=[C:15](B2OC(C)(C)C(C)(C)O2)[CH2:14][CH2:13]1.C([O-])([O-])=O.[Na+].[Na+].CC([O-])=O.[K+]>CC#N.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:11][N:12]1[CH2:13][CH:14]=[C:15]([C:2]2[N:6]([CH3:7])[N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:16][CH2:17]1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Reactant: CN1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: CN1CC=C(c2c([N+](=O)[O-])cnn2C)CC1
Temperature: 130 °C
Yield: 16 %

Procedure:
5-Chloro-1-methyl-4-nitro-1H-pyrazole (0.2 g, 1.24 mmol), 1-methyl-1,2,3,6 tetrahydropyridine-4-boronic acid pinacol ester (0.553 g, 2.48 mmol) and Pd(dppf)2Cl2 (0.02 g, 0.025 mmol) were suspended in degassed MeCN (5 mL). Aqueous Na2CO3/KOAc solution (1:1, 1.1 M, 1.5 mL) was added and the mixture was heated at 130° C. in a microwave for 40 min. A further portion of Pd(dppf)2Cl2 (0.1 g, 0.12 mmol) was added and the mixture was heated at 130° C. for a further 90 min. The solvents were removed under reduced pressure and the crude residue dissolved in EtOAc and water. The mixture was extracted with EtOAc and the combined organic layers passed through a phase separator cartridge. The solvent was removed under reduced pressure and the crude product was purified via silica gel column chromatography (0-10% MeOH/DCM) to give 1-methyl-4-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1,2,3,6-tetrahydropyridine as a brown oil (44 mg, 16%). 1H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 5.89-5.86 (m, 1H), 3.82 (s, 3H), 3.19 (q, J=3.0 Hz, 2H), 2.74 (q, J=5.5 Hz, 2H), 2.47-2.39 (m, 5H)
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH:10]([CH3:12])[CH3:11])[CH:3]=1.F[C:14]1[N:19]=[CH:18][C:17]([N:20]2[C:24](=[O:25])[C:23]([CH3:27])([CH3:26])[NH:22][C:21]2=[O:28])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)C>CN(C)C=O.O>[CH3:26][C:23]1([CH3:27])[C:24](=[O:25])[N:20]([C:17]2[CH:16]=[CH:15][C:14]([O:1][C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH:10]([CH3:12])[CH3:11])[CH:3]=3)=[N:19][CH:18]=2)[C:21](=[O:28])[NH:22]1
Reactant: CC(C)c1cc(O)ccc1C#N
Reactant: CC1(C)NC(=O)N(c2ccc(F)nc2)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)c1cc(Oc2ccc(N3C(=O)NC(C)(C)C3=O)cn2)ccc1C#N
Temperature: 120 °C
Reaction time: 40 h
Yield: 19.2 %

Procedure:
4-hydroxy-2-(1-methylethyl)benzonitrile (30 mg) was dissolved in 1 mL of dimethylformamide. 3-(6-fluoro-3-pyridinyl)-5,5-dimethyl-2,4-imidazolidinedione (Intermediate 106, 41.5 mg) and potassium carbonate (51.4 mg, 0.372 mmol) were added. The reaction mixture was stirred at 120° C. during 40 hours. Some diethylether (4 mL) and water (4 mL) were added. The aqueous layer was extracted 4 times with diethylether. The gathered organic layers were dried over sodium sulphate and evaporated giving a residue which was purified by mass directed purification (METHOD H). After evaporation of the fraction, addition of a solution of saturated NaHCO3 (3 mL) and extraction with dichloromethane (four times 4 mL), evaporation afforded the title compound (13 mg).
Reaction SMILES: C([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:29][C:30]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[C:34]([C:39]4[C:44]([F:45])=[CH:43][C:42]([O:46][CH:47]5[CH2:52][CH2:51][CH2:50][O:49][CH2:48]5)=[CH:41][C:40]=4[F:53])[N:33]=3)=[O:31])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=O)C.C1COCC1.[OH-].[Na+]>CO>[F:53][C:40]1[CH:41]=[C:42]([O:46][CH:47]2[CH2:52][CH2:51][CH2:50][O:49][CH2:48]2)[CH:43]=[C:44]([F:45])[C:39]=1[C:34]1[N:33]=[C:32]([C:30]([NH:29][C:12]2[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH:21][C:22](=[O:23])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:15]3)=[C:8]3[CH2:7][CH2:6][CH:5]([OH:4])[C:9]3=[N:10][CH:11]=2)=[O:31])[CH:37]=[CH:36][C:35]=1[F:38]
Reactant: CC(=O)OC1CCc2c1ncc(NC(=O)c1ccc(F)c(-c3c(F)cc(OC4CCCOC4)cc3F)n1)c2N1C[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2c(NC(=O)c3ccc(F)c(-c4c(F)cc(OC5CCCOC5)cc4F)n3)cnc3c2CCC3O)C1

Procedure:
The amide intermediate was treated with THF (0.7 mL), MeOH (0.7 mL) and 1.0 M aq. NaOH (0.74 mL, 0.74 mmol) at room temperature for 20 min. The volatile organic solvents were removed. The residue was extracted with EtOAc (2 times). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated to give an alcohol intermediate, tert-butyl ((3S,5R)-1-{3-[({6-[2,6-difluoro-4-(tetrahydro-2H-pyran-3-yloxy)phenyl]-5-fluoropyridin-2-yl}carbonyl)amino]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate.
Reaction SMILES: [C:1]1([C:7]([CH:9]2[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:10]2)=O)[CH:6]=[CH:5][CH:4]=[CH:3]C=1.B(F)(F)F.C[CH2:23][O:24]CC>CCOCC>[O:10]=[C:9]([C:7]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:1]=1)[CH:11]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH:23]=[O:24]
Reactant: CCOCC
Reactant: O=C(c1ccccc1)C1OC1c1ccccc1
Agent: FB(F)F
Product: O=CC(C(=O)c1ccccc1)c1ccccc1
Temperature: 50 °C

Procedure:
Phenyl(3-phenyloxiran-2-yl)methanone (5.0 g, 22.3 mmol) was suspended in dry Et2O (40 mL) under an argon balloon. Boron trifluoride diethyl etherate (3.00 mL, 23.7 mmol) was added slowly via syringe. The reaction was refluxed at 50° C. for an hour, then cooled and extracted with 60 mL each of H2O and Et2O/EtOAc. The aqueous layer was extracted again with EtOAc (60 mL). The combined organic layer was dried and concentrated to give 3-oxo-2,3-diphenylpropanal.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:13]2[CH:14]=[C:15]([CH:18]=O)[CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:20]1[CH2:24][C:23](=[O:25])[NH:22][C:21]1=[O:26]>>[C:1]([O:5][C:6]([N:8]1[C:13]2[CH:14]=[C:15]([CH:18]=[C:24]3[S:20][C:21](=[O:26])[NH:22][C:23]3=[O:25])[CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1CSC(=O)N1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(C=O)cc21
Product: CC(C)(C)OC(=O)N1CCOc2ccc(C=C3SC(=O)NC3=O)cc21

Procedure:
Following the general method as outlined in Example 1, starting from 6-Formyl-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester (intermediate 62) and 1,3-thiazolidine-2,4-dione, the title compound was obtained.
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[CH2:18]([O:20][C:21](=[O:39])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34](OC)OC)=[CH:30][CH:29]=1)[CH3:19].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>CN(C=O)C>[CH2:18]([O:20][C:21](=[O:39])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]2[O:5][CH:4]3[CH:6]([CH2:7][OH:8])[O:9][CH:1]([N:10]4[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]4=[O:12])[CH:2]3[O:3]2)=[CH:30][CH:29]=1)[CH3:19]
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: CCOC(=O)CCCCCOc1ccc(C(OC)OC)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCOc1ccc(C2OC3C(CO)OC(n4ccc(=O)[nH]c4=O)C3O2)cc1
Temperature: 50 °C
Reaction time: 15 h

Procedure:
Uridine 5 (7, 50 g, 0.21 mol) together with 4 (70 g, 0.23 mol) was dissolved in DMF (150 mL). p-Toluenesulfonic acid monohydrate (3.8 g, 20 mmol) was added, the mixture was placed on a Buechi R-134 rotavapor and agitated under reduced pressure (70 mbar) at 50° C. for 15 h. The mixture was then neutralized with triethylamine (2.8 ml, 20 mmol) and subsequently concentrated in vacuo. The resulting residue was suspended in EtOAc (400 mL), filtered and washed with 1:1 EtOAc/H2O (400 mL), H2O (2×200 mL), 1:1 H2O/Et2O (200 mL) and Et2O (2×200 mL) to give a colorless solid as a mixture of 2 diastereomers (6, 77 g, 0.16 mol, 76%). Upon recrystallisation from EtOH/EtOAc one of the diastereomers exclusively crystallized: M.p.: 176-178° C.; 1H-NMR (400 MHz, (CD3)2SO3) δ=11.38 (s, 1H), 7.82 (d, J=8.1, 1H), 7.42 (d, J8.6, 2H), 6.95 (d, J=8.6, 2H), 5.94 (s, 1H), 5.90 (s, 1H), 5.64 (d, J=8.1, 1H), 5.10 (t, J=5.2, 1H), 4.99 (m, 1H), 4.82 (m, 1H), 4.23 (m, 1H), 4.04 (q, J=7.1, 2H), 3.97 (t, J=6.3, 2H), 3.60 (m, 2H), 2.30 (t, J=7.4, 2H), 1.71 (m, 2H), 1.58 (m, 2H), 1.41 (m, 2H), 1.16 (t, J=7.1, 3H); 13C-NMR (400 MHz, (CD3)2SO) δ=172.8, 163.2, 159.7, 150.3, 142.1, 128.4 (2C), 128.0, 114.2 (2C), 106.5, 101.7, 91.3, 86.4, 84.2, 81.6, 67.4, 61.3, 59.6, 33.4, 28.3, 25.0, 24.2, 14.1; IR (film) ν=3467, 2933, 1692, 1677, 1248, 1116, 1077, 828; HRMS (MALDI-FTMS) m/z 513.1851 (513.1849 calculated for C24H30N2O9Na (M+Na)+).
Reaction SMILES: Cl.SC1C(N)=CC(C(O)=O)=CC=1C(O)=O.[N+:16]([C:19]1[CH:20]=[C:21]([C:29]([O:31][CH3:32])=[O:30])[CH:22]=[C:23]([CH:28]=1)[C:24]([O:26][CH3:27])=[O:25])([O-])=O>>[CH3:27][O:26][C:24](=[O:25])[C:23]1[CH:28]=[C:19]([NH2:16])[CH:20]=[C:21]([C:29]([O:31][CH3:32])=[O:30])[CH:22]=1
Reactant: COC(=O)c1cc(C(=O)OC)cc([N+](=O)[O-])c1
Agent: Cl
Agent: Nc1cc(C(=O)O)cc(C(=O)O)c1S
Product: COC(=O)c1cc(N)cc(C(=O)OC)c1

Procedure:
The AB2 monomer, 4-mercapto-5-aminoisophthalic acid hydrochloride, is synthesized in similar fashion, starting with catalytic hydrogenation of dimethyl 5-nitroisophthalate to form the corresponding amine, dimethyl-5-aminoisophthalate, which is then acetylated to protect the amino group. Dimethyl-5-aminoisophthalate is treated with thiocyanogen bromide (generated in-situ from bromine and ammonium thiocynate), and finally hydrolyzed to provide the desired monomer.
Reaction SMILES: Cl[CH:2]([O:4][C:5]([NH:7][CH2:8][CH:9]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:6])[CH3:3].CN1CCOCC1.[C:32]([OH:37])(=[O:36])[CH:33]([CH3:35])[CH3:34]>ClCCl>[C:32]([O:37][CH:2]([O:4][C:5]([NH:7][CH2:8][CH:9]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:6])[CH3:3])(=[O:36])[CH:33]([CH3:35])[CH3:34]
Reactant: CC(C)CC(CNC(=O)OC(C)Cl)CC(=O)OCc1ccccc1
Reactant: CC(C)C(=O)O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)CC(CNC(=O)OC(C)OC(=O)C(C)C)CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of (40) (0.53 g, 1.50 mmol) in isobutyric acid (1 mL) was added to a mixture of isobutyric acid (0.96 mL, 10.8 mmol) and N-methylmorpholine (1.14 mL, 10.4 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 48 h. The reaction mixture was diluted with dichloromethane, washed successively with water, 10% aqueous NaHCO3 solution and brine, then dried over anhydrous Na2SO4. After filtration and removal of the solvent in vacuo, the residue was purified by flash chromatography on silica gel, eluting with 5% ethyl acetate in hexane to afford the title compound (41) as a mixture of two diastereomers (400 mg, 66%). 1H-NMR (CDCl3, 400 MHz): δ 0.85 (m, 6H), 1.14 (m, 8H), 1.44 (m, 3H), 1.62 (m, 1H), 2.13 (m, 1H), 2.32 (m, 2H), 2.51 (m, 1H), 3.06 (m, 1H), 3.24 (m, 1H) 4.95 (m, 1H), 5.10 (s, 2H), 6.76 (q, 1H).
Reaction SMILES: [C:1]([NH:6][C:7]1[O:8][C:9]([CH3:12])=[CH:10][N:11]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].[H-].[Na+].I[CH2:16][CH2:17][CH2:18][CH3:19]>CN(C)C=O>[CH2:16]([N:6]([C:7]1[O:8][C:9]([CH3:12])=[CH:10][N:11]=1)[C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[CH2:17][CH2:18][CH3:19]
Reactant: Cc1cnc(NC(=O)C(C)C)o1
Reactant: CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCN(C(=O)C(C)C)c1ncc(C)o1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
2-isobutyramido-5-methyloxazole (2.10 g., 0.0124 mol), prepared as above, was dissolved in dry dimethylformamide (10 mls.) and cooled to below 5° C. To this was added sodium hydride (0.70 g., 0.0145 mol.) portionwise, keeping the temperature below 5° C. After the addition, the mixture was stirred for a further 30 minutes at 5° C. and then allowed to warm to room temperature. The iodobutane (5.0 g., 0.0271 mol.) was added. The mixture was stirred overnight, the solvent was evaporated under reduced pressure and the residue was partitioned between water (50 mls.) and ether (50 mls.). The organic phase was then washed with 2N HCl (2× 25 mls.), water (1× 25 mls.), 10% aqueous sodium carbonate (3× 25 mls.) and water (3× 25 mls.). The organic phase was then dried over magnesium sulphate and evaporated under reduced pressure. The residue was distilled from a Kugelrohr, air bath temperature 100° C./0.1 mm. Yield= 1.74 g. (62%).
Reaction SMILES: C[O:2][C:3]([C:5]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][C:13]2([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=3)[CH2:17][CH2:16][N:15]([C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14]2)[CH2:7][CH2:6]1)=[O:4].[OH-].[Na+]>C(O)C>[C:18]([N:15]1[CH2:16][CH2:17][C:13]([CH2:12][CH2:11][N:8]2[CH2:7][CH2:6][C:5]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:3]([OH:4])=[O:2])[CH2:10][CH2:9]2)([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[CH2:14]1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)C1(c2ccccc2)CCN(CCC2(c3ccc(Cl)c(Cl)c3)CCN(C(=O)c3ccccc3)C2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(c1ccccc1)N1CCC(CCN2CCC(C(=O)O)(c3ccccc3)CC2)(c2ccc(Cl)c(Cl)c2)C1
Yield: 42.4 %

Procedure:
1-[2-[1-Benzoyl-3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylic acid methyl ester (0.2850 g, 0.5 mmol) was dissolved in ethanol (10 mL) and treated with 1M sodium hydroxide (5 mL, 5 mmol) at 20° C. for 2 hours. The aqueous phase was washed with ethyl acetate. The aqueous phase was acidified with 1N hydrochloric acid, and then extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo to give 0.117 g (43%) of the title compound.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10]>C(Cl)Cl>[CH3:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[CH:22][N:23]=2)=[CH:14][CH:13]=1)(=[O:10])=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)nc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCNCC3)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
TFA (2 mL) was added to a solution of 1,1-dimethylethyl 4-[({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate (705 mg, 1.58 mmol) in CH2Cl2 (50 mL) at ambient temperature. The mixture was stirred at ambient temperature overnight. The mixture was concentrated, and the crude product was purified by chromatography on a silica gel column using 0 to 10% MeOH/CH2Cl2 give 460 mg (84%) of 2-[4-(methylsulfonyl)phenyl]-5-[(4-piperidinylmethyl)oxy]pyridine as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.44 (d, 1H, J=2.9 Hz), 8.29 (d, 2H, J=8.6 Hz), 8.08 (d, 1H, J=8.8 Hz), 8.00 (d, 2H, J=8.6 Hz), 7.55 (dd, 1H, Ja=8.8 Hz, Jb=3.0 Hz), 4.04 (d, 2H, J=6.2 Hz), 3.40-3.25 (m, 2H), 3.25 (s, 3H), 3.01-2.83 (m, 2H), 2.22-2.02 (m, 1H), 2.00-1.90 (m, 2H), 1.60-1.37 (m, 2H); LRMS (ESI), m/z 347 (M+H).
Reaction SMILES: [F:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:6][C:5]([NH2:15])=[C:4]([NH2:16])[CH:3]=1.[C:17](=S)=[S:18].[OH-].[K+].[K+].[Br-]>O.C(O)C>[F:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:6][C:5]2[N:15]=[C:17]([SH:18])[NH:16][C:4]=2[CH:3]=1
Reactant: CN1CCN(c2cc(N)c(N)cc2F)CC1
Reactant: S=C=S
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN1CCN(c2cc3nc(S)[nH]c3cc2F)CC1
Yield: 93.9 %

Procedure:
6-Fluoro-5-(4-methylpiperazin-1-yl)-2-mercapto-1H-benzimidazole (15.0 g, 94%) was prepared by a similar procedure to that described in preparation 1 (step 5) using the diamine (14.0 g, 0.06 mol) (obtained in step 3 above), carbon disulfide (6.1 g, 0.08 mol), potassium hydroxide (4.49 g, 0.08 mol), ethanol (70 mL) and water (10 mL). mp 290° C. (decomp.); IR (KBr) 3088, 1481 cm-1 ; 1H NMR (DMSO-d6) δ 2.24 (s, 3H, CH3), 2.50 (t, J=4.3 Hz, 4H, N(CH2)2), 3.00 (t, J=4.4 Hz, 4H, N(CH2)2), 6.78 (d, J=7.3 Hz, 1H), 7.00 (d, J=11.9 Hz, 1H); Mass (m/z) 266 (M+.).
Reaction SMILES: [CH2:1]([N:5]([CH2:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([CH3:17])[CH:16]=1)[C:11]([OH:13])=O)[CH3:6])[CH:2]([CH3:4])[CH3:3].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C.[NH2:61][C@@H:62]([CH2:76][C:77]1[CH:82]=[C:81]([F:83])[CH:80]=[C:79]([F:84])[CH:78]=1)[C@H:63]([OH:75])[CH2:64][NH:65][CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[C:69]([CH2:73][CH3:74])[CH:68]=1.[ClH:85]>C(Cl)Cl.CO.C(OCC)C>[ClH:85].[F:83][C:81]1[CH:82]=[C:77]([CH:78]=[C:79]([F:84])[CH:80]=1)[CH2:76][C@H:62]([NH:61][C:11](=[O:13])[C:10]1[CH:14]=[C:15]([CH3:17])[CH:16]=[C:8]([CH2:7][N:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[CH3:6])[CH:9]=1)[C@H:63]([OH:75])[CH2:64][NH:65][CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[C:69]([CH2:73][CH3:74])[CH:68]=1
Reactant: Cc1cc(CN(C)CC(C)C)cc(C(=O)O)c1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CCc1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(C)cc(CN(C)CC(C)C)c2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 3-{[isobutyl(methyl)amino]methyl}-5-methylbenzoic acid (110 mg, 0.48 mmol) in methylene chloride (3 mL) is added HBTU (273 mg, 0.72 mmol), HOBt (97 mg, 0.72 mmol), and N,N -diisopropylethylamine (0.243 mL, 1.44 mmol), followed by (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol prepared by the method of Example SP-272 (196 mg, 0.48 mmol), and the reaction mixture is stirred for 12 h at room temperature. The reaction mixture is diluted with methylene chloride, washed with water, and saturated sodium bicarbonate, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 10% methanol/chloroform) affords a clear oil, which is dissolved in methanol (2 mL). To this solution is added hydrochloric acid (5 mL, 4 N dioxane, 20 mmol), and the reaction mixture is stirred for 1 h at room temperature. The reaction mixture is then diluted with ethyl ether (10 mL). The precipitate that is formed is collected by filtration to provide the title compound. ESI MS m/z 552.5 [M+H]+.