Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[F:8][C:9]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:10]=1[O:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:19]=[C:20]3[CH2:31][CH2:30][NH:29][CH:28]([CH3:32])[C:21]3=[N:22][C:23]=2[NH:24][CH:25]([CH3:27])[CH3:26])[CH2:14][CH2:13]1.[CH3:38][N:39]([CH3:43])[C:40](Cl)=[O:41].CCN(C(C)C)C(C)C>C(Cl)Cl>[F:8][C:9]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:10]=1[O:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[N:19]=[C:20]3[CH2:31][CH2:30][N:29]([C:40]([N:39]([CH3:43])[CH3:38])=[O:41])[CH:28]([CH3:32])[C:21]3=[N:22][C:23]=2[NH:24][CH:25]([CH3:27])[CH3:26])[CH2:16][CH2:17]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCNC2C
Reactant: CN(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCN(C(=O)N(C)C)C2C

Procedure:
A solution of 2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (15 mg, 0.028 mmol), dimethylcarbamic chloride (6.1 mg, 0.056 mmol), and DIPEA (10.9 mg, 0.085 mmol) in DCM (282 μL) was stirred at room temperature overnight. Purification by HPLC Method A afforded the title compound as a TFA salt (6.1 mg) as an off-white film. 1H NMR (500 MHz, methanol-d4) δ ppm 1.26 (dd, J=9.3, 6.4 Hz, 6H), 1.50 (d, J=6.8 Hz, 3H), 1.89-1.98 (m, 2H), 2.12 (dq, J=13.2, 3.6 Hz, 2H), 2.55-2.64 (m, 1H), 2.88 (s, 6H), 2.94-3.03 (m, 3H), 3.34-3.41 (m, 3H), 3.72-3.82 (m, 1H), 4.14 (quin, J=6.5 Hz, 1H), 4.45 (dt, J=7.4, 3.8 Hz, 1H), 4.67 (q, J=6.8 Hz, 1H), 6.83-6.91 (m, 1H), 6.98 (ddd, J=11.4, 8.4, 3.2 Hz, 1H), 7.17 (td, J=9.3, 5.4 Hz, 1H); ESI-MS m/z [M+H]+ 489.90.
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[NH2:16][C:17](=O)[CH2:18][C:19]([CH3:26])([CH3:25])[CH2:20][C:21]([O:23][CH3:24])=[O:22].C(N(CC)CC)C.O>C(Cl)Cl>[C:17]([CH2:18][C:19]([CH3:26])([CH3:25])[CH2:20][C:21]([O:23][CH3:24])=[O:22])#[N:16]
Reactant: COC(=O)CC(C)(C)CC(N)=O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)CC(C)(C)CC#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
Trifluoromethanesulfonic anhydride (5.4 mL; 31.8 mmoles) was added to an ice cooled solution of methyl 5-amino-3,3-dimethyl-5-oxopentanoate (5.00 g; 28.9 mmoles) in methylene chloride (250 mL) and triethylamine (8 mL; 57.8 mmoles), under nitrogen while keeping the temperature below 5° C. The reaction mixture was allowed to warm to room temperature and stirred for 30 minutes. Water (125 mL) was added and the phases were separated. The aqueous phase was extracted with methylene chloride (100 mL). The organic phases were combined, washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. The solution was filtered and the solvent was removed under vacuum to give the product, methyl 4-cyano-3,3-dimethylbutanoate (3.1 g; 69%). 1H NMR (400 MHz) DMSO-d6 δ 3.60 (3H, s), 2.61 (2H, s), 2.35 (2H, s), 1.07 (6H, s).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[CH:13][Cl:14])[CH2:10][C@H:9]1[C:15]([OH:17])=O)=[O:7])(C)(C)C.[C:18]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]=[CH:22][C:21](C(Cl)=O)=[CH:20][CH:19]=1.[C:33]([NH2:37])([CH3:36])([CH3:35])[CH3:34]>>[C:27]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:28]=[CH:29][C:30]([C:6]([N:8]2[CH2:12][C:11](=[CH:13][Cl:14])[CH2:10][C@H:9]2[C:15]([NH:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:17])=[O:7])=[CH:31][CH:32]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)N
Reactant: CC(C)(C)OC(=O)N1CC(=CCl)C[C@H]1C(=O)O
Product: CC(C)(C)NC(=O)[C@@H]1CC(=CCl)CN1C(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-carbo-nyl chloride, and tert-butylamine the title compound was obtained in 80% purity by LC/MS. MS(ESI+): m/z=397.6.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][C:13]=2[CH3:20])=[CH:8][CH:7]=1.[CH3:21][N:22]([CH3:28])[C@@H:23]1[CH2:27][CH2:26][NH:25][CH2:24]1>>[CH3:21][N:22]([CH3:28])[C@@H:23]1[CH2:27][CH2:26][N:25]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][C:13]=3[CH3:20])=[CH:8][CH:7]=2)[CH2:24]1
Reactant: CN(C)[C@@H]1CCNC1
Reactant: Cc1cc(C#N)ccc1-c1ccc(OCCCCl)cc1
Product: Cc1cc(C#N)ccc1-c1ccc(OCCCN2CC[C@@H](N(C)C)C2)cc1
Yield: 55 %

Procedure:
The product from Example 165C and (3R)-N,N-dimethyl-3-pyrrolidinamine were processed as described in Example 164D to provide the title compound (55% yield). 1HNMR (300 MHz, CDCl3) δ1.65 (m, 2H), 1.81 (bs, 2H), 2.00-2.85 (m, 15H), 3.0 (m, 1H), 4.13 (bs, 2H), 6.90-7.54 (m, 7H); MS (ESI) m/z 364 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])=[CH:5]2.[Li]CCCC.CON(C)[C:30](=[O:34])[CH2:31][CH2:32][CH3:33]>C1COCC1>[Si:15]([O:14][CH2:13][CH2:12][C:6]1[N:7]([CH3:11])[C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([C:30](=[O:34])[CH2:31][CH2:32][CH3:33])=[CH:10][CH:9]=2)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: Cn1c(CCO[Si](C)(C)C(C)(C)C)cc2cc(Br)ccc21
Reactant: CCCC(=O)N(C)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC(=O)c1ccc2c(c1)cc(CCO[Si](C)(C)C(C)(C)C)n2C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 68.1 %

Procedure:
To solution of 5-bromo-2-(2-(tert-butyldimethylsilyloxy)ethyl)-1-methyl-1H-indole (9.963 g, 27.04 mmol) in THF (100 mL) at −78° C. was added solution of n-BuLi (2.5M hexanes, 13.0 mL, 32.50 mmol) dropwise over 10 min. Reaction was stirred at −78° C. for 10 min before solution of N-methoxy-N-methylbutyramide (4.30 g, 32.78 mmol) in THF (10 mL) was added dropwise. Reaction was stirred at −78° C. for 15 min and then quenched with NH4Cl (aqueous saturated, 30 mL). Once ambient temperature was reached in the reaction mixture product was extracted with EtOAc (2×100 mL). Combined organics were washed with NaCl (aqueous saturated) and dried over Na2SO4. Upon solvent removal residue was purified by column chromatography using EtOAc/hexanes (gradient 0-30%) to afford 1-(2-(2-(tert-butyldimethylsilyloxy)ethyl)-1-methyl-1H-indol-5-yl)butan-1-one (6.620 g, 68%) as white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13]O)[CH2:11][O:10][C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[SH:17][C:18]1[S:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][S:17][C:18]2[S:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=3[N:22]=2)[CH2:11][O:10][C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1[C@H](CO)COC1(C)C
Reactant: Sc1nc2ccccc2s1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@H](CSc2nc3ccccc3s2)COC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.4 %

Procedure:
To a stirred, cooled (0° C.) solution of (R)-4-hydroxymethyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (1.36 g; CAS 108149-65-1), 2-mercaptobenzothiazole (1.48 g) and triphenylphosphine (2.32 g) in THF (80 ml) under an argon atmosphere was added diethyl azodicarboxylate (4.1 ml; 40% solution in toluene). The mixture (soon turning to a yellow suspension, slowly warming up to r.t.) was stirred for 18 h overnight, then diluted with EtOAc and washed with sat. aq. Na2CO3. The aqueous phase was back extracted with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (SiO2; gradient: cyclohexane ->cyclohexane/EtOAc 85:15) to give (S)-4-(benzothiazol-2-ylsulfanyl-methyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (2.0 g) as light yellow viscous oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH2:11][C@@H:12]4[N:18]([CH:19]=3)[C:17](=[O:20])[C:16]3[CH:21]=[C:22]([O:83][CH3:84])[C:23]([O:25][CH2:26][CH2:27][CH2:28][O:29][C:30]5[C:80]([O:81][CH3:82])=[CH:79][C:33]6[C:34](=[O:78])[N:35]7[CH:41]=[C:40]([C:42]8[CH:47]=[CH:46][C:45]([NH:48][C:49](=[O:77])[C@@H:50]([NH:52][C:53](=[O:76])[C@@H:54]([NH:58]C(=O)OCC9C%10C=CC=CC=%10C%10C9=CC=CC=%10)[CH:55]([CH3:57])[CH3:56])[CH3:51])=[CH:44][CH:43]=8)[CH2:39][C@H:36]7[CH:37]=[N:38][C:32]=6[CH:31]=5)=[CH:24][C:15]=3[N:14]=[CH:13]4)=[CH:9][C:4]=2[O:3][CH2:2]1.N1CCCCC1>CN(C=O)C>[NH2:58][C@@H:54]([CH:55]([CH3:57])[CH3:56])[C:53]([NH:52][C@@H:50]([CH3:51])[C:49]([NH:48][C:45]1[CH:44]=[CH:43][C:42]([C:40]2[CH2:39][C@@H:36]3[N:35]([CH:41]=2)[C:34](=[O:78])[C:33]2[CH:79]=[C:80]([O:81][CH3:82])[C:30]([O:29][CH2:28][CH2:27][CH2:26][O:25][C:23]4[C:22]([O:83][CH3:84])=[CH:21][C:16]5[C:17](=[O:20])[N:18]6[CH:19]=[C:10]([C:8]7[CH:7]=[CH:6][C:5]8[O:1][CH2:2][O:3][C:4]=8[CH:9]=7)[CH2:11][C@H:12]6[CH:13]=[N:14][C:15]=5[CH:24]=4)=[CH:31][C:32]=2[N:38]=[CH:37]3)=[CH:47][CH:46]=1)=[O:77])=[O:76]
Reactant: COc1cc2c(cc1OCCCOc1cc3c(cc1OC)C(=O)N1C=C(c4ccc5c(c4)OCO5)C[C@H]1C=N3)N=C[C@@H]1CC(c3ccc(NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)OCC4c5ccccc5-c5ccccc54)C(C)C)cc3)=CN1C2=O
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OCCCOc1cc3c(cc1OC)C(=O)N1C=C(c4ccc5c(c4)OCO5)C[C@H]1C=N3)N=C[C@@H]1CC(c3ccc(NC(=O)[C@H](C)NC(=O)[C@@H](N)C(C)C)cc3)=CN1C2=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
The imine 35 (82 mg, 0.07 mmol, 1 equiv.) was dissolved in DMF (1 mL) before piperidine (0.2 mL, 2 mmol, excess) was added slowly. This solution was left to stir at room temperature for 20 minutes until LC/MS analysis showed complete consumption of starting material. The reaction mixture was diluted with CH2Cl2 (50 mL), washed with water (50 mL×4), dried with MgSO4, filtered and the solvent removed in vacuo. The product 33 was used without further purification in the next step. LC/MS (1.15 min (ES+) m/z (relative intensity) 910.60 ([M+H]+, 58).
Reaction SMILES: FC1C=CC(C(C2C=CC(F)=CC=2)=O)=CC=1.CC(N(C)C)=O.C(=O)([O-])[O-].[K+].[K+].[N+]([C:32]1[CH:33]=[C:34]([C:40]#[N:41])[C:35](=[CH:38][CH:39]=1)[C:36]#[N:37])([O-])=O>O.C1(C)C=CC=CC=1>[C:40](#[N:41])[C:34]1[C:35](=[CH:38][CH:39]=[CH:32][CH:33]=1)[C:36]#[N:37]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Agent: O=C([O-])[O-]
Agent: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Solvent: O
Product: N#Cc1ccccc1C#N
Temperature: 160 °C
Reaction time: 16 h
Yield: 426.3 %

Procedure:
To a 100 ml, 3-necked flask equipped with a thermometer and a Dean-Stark trap was added 4.0 gm (18.4 mmol ) of 4,4 '-difluorobenzophenone, 12.33 gm (36.7 mmol) of bisphenol A6F, and 40 ml of dimethylacetamide (DMAC). After flushing the mixture for 30 minutes with dry nitrogen, 10.1 gm (73.4 mmol) of pulverized anhydrous potassium carbonate was added with stirring. The light pink reaction mixture was stirred at 90° C. for 1 hour. Toluene was added to the Dean-Stark trap and to the reaction vessel (4 ml). The reaction mixture was refluxed at 145°-150° C. for 26 hours. Water which formed as a by-product was removed by azeotropic distillation. The toluene was removed by distillation while heating to 160 ° C. Upon cooling to 50 ° C., 6.37 gm (36.8 mmol) of 4-nitrophthalonitrile was added. The reaction mixture was observed to be viscous. The temperature of reaction mixture was increased to 110° C. and held at this temperature for 16 hours (overnight). The room temperature mixture was poured into 200 ml of water with stirring. The solid precipitate was collected by suction filtration, washed exhaustively with water, and dried to afford 20.1 gm of oligomeric phthalonitrile monomer.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:18][CH2:19][CH:20]([CH2:22]O)[N:21]=3)=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.CS(Cl)(=O)=O.[NH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>O1CCCC1.N1CCCCC1>[N:36]1([CH2:22][CH:20]2[CH2:19][O:18][C:17]([C:14]3[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)=[CH:16][CH:15]=3)=[N:21]2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: C1CCNCC1
Reactant: OCC1COC(c2ccc(OCCCN3CCCCC3)cc2)=N1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: c1cc(C2=NC(CN3CCCCC3)CO2)ccc1OCCCN1CCCCC1
Temperature: -23 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
To a cold (−23° C.) solution of {2-[4-(3-piperidin-1-ylpropoxy)phenyl]-4,5-dihydro-1,3-oxazol-4-yl}methanol ax46 (0.27 g, 0.85 mmol, 1 eq) and triethylamine (0.413 ml, 2.98 mmol, 3.5 eq) in tetrahydrofuran (10 ml) is added methanesulfonyl chloride (0.23 ml, 2.98 mmol, 3.5 eq). The mixture is stirred for 2 h at −23° C., and then, concentrated under vacuum. The residual oil is treated with piperidine (0.08 ml, 0.8 nmol, 2 eq) and triethylamine (0.05 ml, 0.42 mmol, 1 eq) and stirred at 100° C. in a sealed tube overnight. After 24 h, piperidine (1 eq) and triethylamine (1 eq) are added and the mixture is stirred for another 48 h at 100° C. Concentration under vacuum gives 0.33 g of brown oil. The oil is purified on silicagel (eluent: dichloromethane/ethanol/ammonia 92:7.2:0.8) to give 45 mg of 1-(3-{4-[4-(piperidin-1-ylmethyl)-4,5-dihydro-1,3-oxazol-2-yl]phenoxy}propyl)piperidine 20.
Reaction SMILES: C1COCC1.Br[C:7]1[C:8]2[C:33]([CH3:40])([C:34]3[O:35][C:36]([CH3:39])=[N:37][N:38]=3)[C:32](=[O:41])[NH:31][C:9]=2[N:10]=[C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH2:22][CH2:23][C:24]([F:30])([F:29])[C:25]([F:28])([F:27])[F:26])[N:14]=2)[N:12]=1.[CH3:42][NH2:43]>CO>[CH3:40][C:33]1([C:34]2[O:35][C:36]([CH3:39])=[N:37][N:38]=2)[C:8]2[C:7]([NH:43][CH3:42])=[N:12][C:11]([C:13]3[C:21]4[C:16](=[N:17][CH:18]=[CH:19][CH:20]=4)[N:15]([CH2:22][CH2:23][C:24]([F:29])([F:30])[C:25]([F:26])([F:28])[F:27])[N:14]=3)=[N:10][C:9]=2[NH:31][C:32]1=[O:41]
Reactant: CN
Reactant: Cc1nnc(C2(C)C(=O)Nc3nc(-c4nn(CCC(F)(F)C(F)(F)F)c5ncccc45)nc(Br)c32)o1
Solvent: CO
Solvent: C1CCOC1
Product: CNc1nc(-c2nn(CCC(F)(F)C(F)(F)F)c3ncccc23)nc2c1C(C)(c1nnc(C)o1)C(=O)N2

Procedure:
To a THF solution (9 mL) of the intermediate from Step A above (116 mg, 0.202 mmol) was added a 2 M methanol solution of methylamine (0.809 mL, 1.619 mmol) and the resultant mixture heated at 140° C. under microwave irradiation for 1 hour. Purification by silica gel column chromatography using DCM/MeOH (with 0.5% NH4OH) gradient provided the title compound. Chiral separation using SFC on a Chiralcel OD column provided both enantiomers of the title compound. 1H NMR (500 MHz, DMSO-d6): δ 11.52 (1H, s), 8.90-8.86 (1H, m), 8.66-8.64 (1H, m), 7.42 (1H, dd, J=8.08, 4.49 Hz), 6.77 (1H, d, J=5.11 Hz), 4.90 (2H, t, J=6.81 Hz), 3.05-2.92 (5H, m), 1.86 (3H, s). 1H NMR δ (ppm) (DMSO-d6 with added D2O): 8.86 (1H, d, J=8.14 Hz), 8.60 (1H, d, J=4.35 Hz), 7.40 (1H, dd, J=8.09, 4.54 Hz), 4.88 (2H, t, J=6.46 Hz), 2.99-2.85 (5H, m), 2.45 (3H, s), 1.81 (3H, s). m/z=524.1 (M+H).
Reaction SMILES: [NH2:1][C@:2]1([CH2:14][OH:15])[CH2:6][CH2:5][C@H:4]([C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=2)[CH2:3]1.N1C=CC=CC=1.[C:22](N1C=CN=C1)(N1C=CN=C1)=[O:23]>O1CCOCC1.C(OCC)(=O)C>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([C@H:4]2[CH2:5][CH2:6][C@@:2]3([NH:1][C:22](=[O:23])[O:15][CH2:14]3)[CH2:3]2)=[CH:8][CH:9]=1
Reactant: N[C@]1(CO)CC[C@H](c2ccc(Br)cc2)C1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C1N[C@@]2(CC[C@H](c3ccc(Br)cc3)C2)CO1
Reaction time: 4 h
Yield: 87.1 %

Procedure:
To a mixture of ((1R,3S)-1-amino-3-(4-bromophenyl)cyclopentyl)methanol (11 g, 40.7 mmol) and pyridine (I-3A, 3.29 mL, 40.7 mmol) in dioxane (300 mL) was added 1,1′-carbonyldiimidazole (19.81 g, 122 mmol). The reaction mixture was stirred for 4 hours. The reaction mixture was diluted with ethyl acetate and washed with 1M HCl, brine and saturated NaHCO3. The mixture was back extracted several times. The organic layer was dried with MgSO4, filtered and concentrated to afford 10.5 g of desired product as an off-white solid. HPLC retention time=0.87 min (Condition G). LC/MS M+1=297.9; 1H NMR (400 MHz, chloroform-d) δ 7.45 (d, J=8.6 Hz, 2H), 7.12 (d, J=8.4 Hz, 2H), 6.42 (br. s., 1H), 4.41-4.21 (m, 2H), 3.17-2.91 (m, 1H), 2.34 (dd, J=13.3, 7.4 Hz, 1H), 2.23-2.11 (m, 2H), 2.01-1.90 (m, 2H), 1.88-1.74 (m, 1H).
Reaction SMILES: C(O[C:4]([CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([CH2:14][CH2:15][CH2:16][C:17]2=[O:20])=[CH:12][CH:11]=1)=[O:5])C.C(N(CC)C(C)C)(C)C.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>C(Cl)Cl>[N:30]1([C:4](=[O:5])[CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:19]=[C:18]3[C:13]([CH2:14][CH2:15][CH2:16][C:17]3=[O:20])=[CH:12][CH:11]=2)[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1
Reactant: CCOC(=O)CCCOc1ccc2c(c1)C(=O)CCC2
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCCc2ccc(OCCCC(=O)N3CCOCC3)cc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 86 %

Procedure:
To a suspension of 7-(3-ethoxycarbonylpropoxy)-1-tetralone (0.925 g, 3.7 mmol), HUBT (1.415 g, 3.7 mmol), N,N-diisopropylethyl amine (1.3 mL) in CH2Cl2 (20 mL) was added morpholine (0.330 mL, 3.7 mmol) at room temperature and under argon atmosphere. The reaction mixture was then stirred at room temperature for 24 h and then concentrated. The residue dissolved in ethyl acetate (50 mL) and the organic layer was washed with dil. HCl, water, brine, and dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified on the column of silica gel using ethyl acetate-hexane (8:2) as an eluent to give 7-(4-morpholin-4-yl-4-oxo-butoxy)-1-tetralone (1.010 g, 86%): mp 88-90° C., 1H NMR (500 MHz, CDCl3): δ 2.07-2.15 (m, 4H), 2.50 (t, J=7.5 Hz, 2H), 2.61 (T, J=7.5 Hz, 2H), 2.88 (t, J=6.0 Hz, 2H), 3.46 (t, J=5.0 Hz, 2H), 3.59-3.66 (m, 6H), 4.04 (t, J=6.0 Hz, 2H), 7.01-7.03 (dd, J=3.0 and 8.5 Hz, 1H), 7.15 (d, J=8.5 Hz, 1H), 7.48 (d, J=3.0 Hz, 1H). HFABMS m/z 318.1706 (calc for C18H23NO4, MH+, 318.1705).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1.[CH3:11][C:12]1([CH3:22])[O:16][C:15](=[CH:17][C:18](O)=[O:19])[C:14](=[O:21])[O:13]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:18](=[O:19])[CH:17]=[C:15]2[C:14](=[O:21])[O:13][C:12]([CH3:11])([CH3:22])[O:16]2)=[CH:4][CH:3]=1
Reactant: CC1(C)OC(=O)C(=CC(=O)O)O1
Reactant: NCCc1ccc(Cl)cc1
Product: CC1(C)OC(=O)C(=CC(=O)NCCc2ccc(Cl)cc2)O1

Procedure:
By appropriate application of method described in Intermediate 7, 2-(4-chlorophenyl)ethylamine (0.27 mL, 1.9 mmol) and 2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-ylidene)acetic acid (365 mg, 2.12 mmol) were converted to Example 241A (190 mg, 32%) as a white solid. HPLC/MS (Method L) RT=1.78 min, [M+1]+ 310.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13]O)[CH2:11][O:10][C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[SH:17][C:18]1[S:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][S:17][C:18]2[S:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=3[N:22]=2)[CH2:11][O:10][C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CO)COC1(C)C
Reactant: Sc1nc2ccccc2s1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H](CSc2nc3ccccc3s2)COC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
To a stirred, cooled (0° C.) solution of (S)-4-hydroxymethyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (1.36 g), 2-mercaptobenzothiazole (1.48 g) and triphenylphosphine (2.32 g) in THF (80 ml) under an argon atmosphere was added diethyl azodicarboxylate (4.1 ml; 40% solution in toluene). The mixture (soon turning to a yellow suspension, slowly warming up to r.t.) was stirred for 18 h overnight, then diluted with EtOAc and washed with sat. aq. Na2CO3. The aqueous phase was back extracted with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (SiO2; gradient: cyclohexane ->cyclohexane/EtOAc 85:15) to give (R)-4-(benzothiazol-2-ylsulfanyl-methyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (2.1 g) as light yellow viscous oil.
Reaction SMILES: [O:1]=[S:2]1(=[O:43])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[N:17]=[C:16]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[S:28]([CH3:31])(=[O:30])=[O:29])=[O:19])[C:15](C2C=C(C)C=CC=2S([O-])(=O)=O)=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2.C[O-:45].[Na+]>CO.O>[O:1]=[S:2]1(=[O:43])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[N:17]=[C:16]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[S:28]([CH3:31])(=[O:30])=[O:29])=[O:19])[C:15]([OH:45])=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2
Reactant: C[O-]
Reactant: Cc1ccc(S(=O)(=O)[O-])c(-c2c(C(=O)NCc3ccccc3S(C)(=O)=O)nc(N3CCCCS3(=O)=O)c3cccnc23)c1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)c1ccccc1CNC(=O)c1nc(N2CCCCS2(=O)=O)c2cccnc2c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(1,1-dioxido-1,2-thiazinan-2-yl)-7-({[2-(methylsulfonyl)benzyl]amino}carbonyl)-1,6-naphthyridin-8-yl-4-methylbenzenesulfonate (220 mg, 0.34 mmol) was dissolved in methanol (10 mL) and NaOMe (55 mg, 1.02 mmol) was added. The reaction was stirred overnight at room temperature. The crude reaction was diluted with water (10 mL) and extracted with CH2Cl2 (2×10 mL). The organic phase was dried (MgSO4), filtered and concentrated in vacuo to afford a yellow oily solid. The material was suspended in methanol and a yellow precipitate fell out of solution. Washing with fresh methanol (2×10 mL) gave the desired product as an off-white solid.
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][C:15]([NH:17][OH:18])=[NH:16])[CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:29]=[CH:28][C:24]([C:25]([Cl:27])=O)=[CH:23][CH:22]=1>>[ClH:27].[CH2:1]([CH:3]([N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][C:15]2[N:16]=[C:25]([C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:30])[F:31])=[CH:29][CH:28]=3)[O:18][N:17]=2)[CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)N1CCC(CCCC(=N)NO)CC1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Product: CCC(CC)N1CCC(CCCc2noc(-c3ccc(C(F)(F)F)cc3)n2)CC1
Product: Cl

Procedure:
The title compound was prepared by a similar procedure to that described in Example 3, starting from 4-(1-(1-ethyl-propyl)piperidin-4-yl)-N-hydroxybutyramidine and 4-trifluoromethylbenzoyl chloride.
Reaction SMILES: [OH:1][C@@H:2]([CH2:7][CH:8]([CH3:10])[CH3:9])[C:3]([O:5][CH3:6])=[O:4].ClC(Cl)(Cl)C(=N)O[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl>[CH2:15]([O:1][C@@H:2]([CH2:7][CH:8]([CH3:10])[CH3:9])[C:3]([O:5][CH3:6])=[O:4])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)[C@@H](O)CC(C)C
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)[C@H](CC(C)C)OCc1ccccc1
Yield: 74.7 %

Procedure:
To a stirred solution of methyl (2S)-2-hydroxy-4-methylpentanoate (0.5 g, 3.4 mmol) in anhydrous CH2Cl2 (10 mL) at R.T. under Ar was added benzyl 2,2,2-trichloroacetimidate (1.4 mL, 6.8 mmol) and trifluoromethylsulfonyl acid (25 μl). After 30 min the reaction mixture was taken up in CH2Cl2 (20 mL). The organic layer was washed with sat. NaCl (2×10 mL), 1N HCl (2×10 mL), sat. NaCl (2×10 mL), dried (MgSO4), filtered and concentrated. Purification by flash chromatography on silica gel (EA:H; 1:10) afforded methyl (2S)-2-benzoxy-4-methylpentanoate as an oil (0.6 g, 73.5%): 1 H NMR (CDCl3, 300 MHz) δ 0.80-0.98 (m, 6H), 1.40-1.58 (m, 1H), 1.69-1.87 (m, 2H), 3.74 (s, 3H), 3.93-4.06 (m, 1H), 4.42 (d, 1H, J=12.0 Hz), 4.68-4.80 (m, 1H), 7.14-7.32 (m, 5H) ppm.