Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)(OC([NH:7][C@H:8]([C:28]([O:30][CH3:31])=[O:29])[CH2:9][NH:10][C:11]([O:13][CH2:14][CH:15]1[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])=O)C>FC(F)(F)C(O)=O.ClCCl>[CH:17]1[C:16]2[CH:15]([CH2:14][O:13][C:11]([NH:10][CH2:9][C@@H:8]([C:28]([O:30][CH3:31])=[O:29])[NH2:7])=[O:12])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]=2[CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)[C@H](CNC(=O)OCC1c2ccccc2-c2ccccc21)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H](N)CNC(=O)OCC1c2ccccc2-c2ccccc21

Procedure:
A solution of N-[(1,1-dimethylethoxy)carbonyl]-3-[(9H-fluoren-9-ylmethoxy)carbonyl]amino-L-alanine, methyl ester (Example 62; 200 mg, 0.45 mmol) in trifluoroacetic acid/dichloromethane (1:1; 2 mL) was stirred at room temperature for 40 min. The solvent was evaporated and ethyl acetate (10 mL) was added. The solution was washed with saturated aqueous sodium hydrogen carbonate, dried (Na2SO4), filtered and evaporated to give 3-[(9H-fluoren-9-ylmethoxy)carbonyl]amino-L-alanine, methyl ester. HOAT (73 mg, 0.45 mmol), DCC (111 mg, 0.45 mmol), 2-chloro-4-[[(1H-indol-4-ylmethyl)amino]carbonyl]-benzoic acid (Example 36; 148 mg, 0.45 mmol) and N,N-dimethylformamide (5 mL) were added and the solution was stirred at room temperature for 1.5 h. Water was added and the solution was extracted three times with ethyl acetate. The combined extracts were washed with brine, dried (Na2SO4), filtered, evaporated, and chromatographed (40-80% ethyl acetate/hexanes) to give 3-[(9H-fluoren-9-ylmethoxy)carbonyl]amino-N-[2-chloro-4-[[(1H-indol-4-ylmethyl)amino]carbonyl]benzoyl]-L-alanine, methyl ester (116 mg, 40%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6](=O)[CH2:5][C:4](=[O:9])[CH2:3]1.[NH3:10]>C1C=CC=CC=1>[NH2:10][C:6]1[CH2:7][CH:2]([CH3:1])[CH2:3][C:4](=[O:9])[CH:5]=1
Reactant: CC1CC(=O)CC(=O)C1
Reactant: N
Solvent: c1ccccc1
Product: CC1CC(=O)C=C(N)C1
Temperature: 0 °C

Procedure:
5-Methyl-1,3-cyclohexanedione (40 g, 0.32 mol) was dissolved in 500 ml of benzene at 70° C. The solution was heated at reflux for 2 hours, during which NH3 was bubbled through the reaction mixture and formed H2O was collected in a Dean-Stark trap. The mixture was then cooled to 0° C. and title product recovered by filtration, 39.8 g, m.p. 165°-169° C. 1H-NMR(DMSO-d6)delta(ppm): 0.98 (s, 3H), 1.6-1.88 (2H), 2.14-2.38 (2H), 3.14-3.6 (1H), 4.93 (s, 1H), 6.2-7.2 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH2:10][N:9]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])[CH2:8]2)[O:4][N:3]=1.[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>C(O)C>[N:25]1([C:23]([N:9]2[CH2:10][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH2:12][CH:7]([C:5]3[O:4][N:3]=[C:2]([N:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)[N:6]=3)[CH2:8]2)=[O:24])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: C1CCNCC1
Reactant: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(Cl)no2)C1
Solvent: CCO
Product: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(N3CCCCC3)no2)C1
Reaction time: 2 h

Procedure:
To a solution of 100 mg (0.225 mmol) of the oxadiazole from Example 23A in 1.5 ml of ethanol were added 195 mg (2.25 mmol) of piperidine, and then the reaction mixture was stirred in the microwave at 80 for 2 h. The solvent was removed under reduced pressure and the crude product was purified by means of preparative HPLC. Yield: 90.0 mg (80% of theory)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([NH:30][C:20]([C:17]1[CH:16]=[CH:15][C:14]([C:3]2[CH:4]=[C:5]([C:8]3[O:9][C:10]([CH3:13])=[N:11][N:12]=3)[CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:19][CH:18]=1)=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCc1ccccc1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCc4ccccc4)cc3)c2)o1

Procedure:
N-Benzyl-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and benzylamine using method N. NMR; δH [2H6]—DMSO 9.14,(1H, t), 8.00,(2H, d), 7.90,(1H, dd), 7.77,(1H, d), 7.56-7.51,(3H, m), 7.34,(4H, m), 7.25,(1H, m), 4.51,(2H, d), 2.56,(3H, s), 2.31,(3H, s). LCMS; retention time 3.35 min, MH+ 384.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:12])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:13](Cl)(=O)[CH3:14]>>[CH3:13][C:14]1[O:1][N:2]=[C:3](/[CH:4]=[CH:5]/[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:12]=1
Reactant: N=C(/C=C/c1ccccc1)NO
Reactant: CC(=O)Cl
Product: Cc1nc(/C=C/c2ccccc2)no1
Yield: 27 %

Procedure:
(2E)-N-Hydroxy-3-phenyl-2-propenimidamide (1.6 g, 10 mmol) was mixed with excess acetyl chloride (30 mL), and heated to reflux. After 1 h the solution was cooled and the excess acetyl chloride was removed in vacuo. The resultant solids were triturated in hot ethyl acetate-hexane-acetone solution, and the supernatant was removed. The remaining solids were dried under high vacuum to afford 5-methyl-3-[(E)-2-phenylethenyl]-1,2,4-oxadiazole (0.50 g, 27% yield from cinnamonitrile) as a pale yellow powder. M.p. 166–168° C. 1H NMR (DMSO-d6, 300 MHz) δ 7.59 (m, 3H), 7.42 (m, 3H), 6.58 (d, J=16 Hz, 1H), 2.17 (s, 3H).
Reaction SMILES: [CH:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:19]=[C:18]([OH:20])[C:17]3[C:12](=[CH:13][C:14]([O:21][CH3:22])=[CH:15][CH:16]=3)[N:11]=2)[N:9]=1)([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:29]([O:31][C:32]([C:34]12[CH2:51][CH:50]1[CH:49]=[CH:48][CH2:47][CH2:46][CH2:45][CH2:44][N:43]([CH3:52])[C:42](=[O:53])[CH:41]1[CH:37]([CH2:38][CH:39](OS(C3C=CC(Br)=CC=3)(=O)=O)[CH2:40]1)[C:36](=[O:65])[NH:35]2)=[O:33])[CH3:30]>CN1C(=O)CCC1.C(Cl)(Cl)Cl>[CH2:29]([O:31][C:32]([C:34]12[CH2:51][CH:50]1[CH:49]=[CH:48][CH2:47][CH2:46][CH2:45][CH2:44][N:43]([CH3:52])[C:42](=[O:53])[CH:41]1[CH:37]([CH2:38][CH:39]([O:20][C:18]3[C:17]4[C:12](=[CH:13][C:14]([O:21][CH3:22])=[CH:15][CH:16]=4)[N:11]=[C:10]([C:8]4[N:9]=[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])[S:6][CH:7]=4)[CH:19]=3)[CH2:40]1)[C:36](=[O:65])[NH:35]2)=[O:33])[CH3:30]
Reactant: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)C1CC(OS(=O)(=O)c3ccc(Br)cc3)CC1C(=O)N2
Reactant: COc1ccc2c(O)cc(-c3csc(NC(C)C)n3)nc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClC(Cl)Cl
Solvent: CN1CCCC1=O
Product: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)C1CC(Oc3cc(-c4csc(NC(C)C)n4)nc4cc(OC)ccc34)CC1C(=O)N2
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 12.9 %

Procedure:
2-(Isopropylamino-thiazol-4-yl)-7-methoxy-quinolin-4-ol (220 mg, 0.7 mmol) (prepared as described in WO 00/59929) was dissolved in 7 ml of NMP (N-methyl pyrrolidinone), one spoon of Cs2CO3 was added, stirred at 60° C. for 1.5 h. Then compound 108 (150 mg, 0.24 mmol) was added. The reaction mixture was stirred at 80° C. overnight. Was diluted with chloroform and washed with sodium bicarbonate, brine. Water phases were back-extracted with chloroform. The combined organic layers were dried over sodium sulphate and evaporated. The crude product was purified by preparative HPLC (Gilson) (MeOH—H2O, 65%) to give 21 mg of product (yield 13%) as well as 12 mg of isomer.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][CH2:19][CH2:20][CH2:21][C:22](=[O:24])[NH2:23])=[CH:14][CH:13]=1)(C)(C)C>C(O)(C(F)(F)F)=O.ClCCl>[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][CH2:19][CH2:20][CH2:21][C:22]([NH2:23])=[O:24])=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)NCCCCc1ccc(NCCCC(N)=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCCCc1ccc(NCCCC(N)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
{4-[4-(3-Carbamoylpropylamino)phenyl]butyl}carbamic acid tert-butyl ester 430 (0.23 g, 0.66 mmol) was cooled to 0° C. in an ice bath. A cold solution of TFA/dichloromethane (10 mL) was added. The reaction was slowly warmed to room temperature and stirred for 30 minutes. The solvent was evaporated in vacuo to provide 440. 1H NMR (300 MHz, CD3OD) δ 1.69 (m, 4H), 1.95 (m, 2H), 2.47 (m, 2H), 2.71 (m, 2H), 2.93 (m, 2H), 3.39 (m, 2H), 7.39 (s, 4H). m/z (ESI) 250.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][N:15]=[C:14]([C:17]3[C:18]([O:26][CH3:27])=[C:19]([CH2:23][CH:24]=O)[CH:20]=[CH:21][CH:22]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[NH:28]1[CH2:33][CH2:32][CH:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CC(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][N:15]=[C:14]([C:17]3[C:18]([O:26][CH3:27])=[C:19]([CH2:23][CH2:24][N:28]4[CH2:33][CH2:32][CH:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:30][CH2:29]4)[CH:20]=[CH:21][CH:22]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)C1CCNCC1
Reactant: COc1c(CC=O)cccc1-c1nsc(-c2ccc(OC(C)C)c(Cl)c2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)C1CCN(CCc2cccc(-c3nsc(-c4ccc(OC(C)C)c(Cl)c4)n3)c2OC)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 32.8 %

Procedure:
To a mixture of [3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-(methyloxy)phenyl]acetaldehyde (D103) (87.6 mg, 0.217 mmol) and ethyl 4-piperidinecarboxylate (137 mg, 0.870 mmol) in Dichloromethane (DCM) (5 mL) was added 3 drops of HOAc. The mixture was stirred at room temperature for 20 min. Then sodium triacetoxyborohydride (92 mg, 0.435 mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature overnight (16 h). The reaction was quenched with water. DCM was removed. The residue was extracted with EA (10 mL×3). The combined organic layers were dried over anhydrous sodium sulphate. After filtration and concentration, the residue was purified by column chromatography to afford ethyl 1-{2-[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-(methyloxy)phenyl]ethyl}-4-piperidinecarboxylate (D104) (38.7 mg). MS (ES): C28H34ClN3O4S requires 513.2. found 514.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([O:11][CH3:12])[CH:4]=1.[Cl:13][S:14](O)(=[O:16])=[O:15].P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:11][CH3:12])[C:6]([O:9][CH3:10])=[CH:7][C:8]=1[S:14]([Cl:13])(=[O:16])=[O:15]
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccc(OC)c(OC)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COc1cc(OC)c(S(=O)(=O)Cl)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 11.4 %

Procedure:
To a solution of 10.0 g of 1,3,4-trimethoxy benzene in CHCl3 (100 ml) was added dropwise 6.90 g of chlorosulfonic acid over 10 minutes under ice cooling. After stirring at room temperature for two hours, the solution was poured into ice water and the resulting mixture was extracted with CHCl3. The aqueous layer was filtered with celite, the filtrate was neutralized with an aqueous solution of 2 mol/L KOH (pH=9), and the solvent was evaporated under reduced pressure to obtain 7.81 g. Phosphorus oxychloride (30 ml) was added to the obtained residue and the reaction mixture was stirred at an external temperature of 100° C. for one hour. The solution was poured into ice water and the resulting mixture was extracted with Et2O; the organic layer was washed with water and with saturated brine and then dried over MgSO4; the drying agent was separated by filtration, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silicagel 60N; mobile phase: EtOAc/n-hexane=1/10 to 1/2; v/v) to obtain 1.80 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:17]2[S:18][CH:19]=[C:20](C)[C:21]=2[Br:22])=[N:15][OH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24](OC(N1CCC(C(C2SC(C)=CC=2Br)=O)CC1)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:17]2[S:18][C:19]([CH3:24])=[CH:20][C:21]=2[Br:22])=[N:15][OH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(Br)c(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)s1
Reactant: Cc1csc(C(=NO)C2CCN(C(=O)OC(C)(C)C)CC2)c1Br
Product: Cc1cc(Br)c(C(=NO)C2CCN(C(=O)OC(C)(C)C)CC2)s1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
Prepared essentially as 29b except that 4-[1-(3-Bromo-5-methyl-thiophen-2-yl)-methanoyl]-piperidine-1-carboxylic acid tert-butyl ester is used as the starting material and the reaction mixture was stirred at 70° C. for 6 hours. LC/MS (ESI), m/e 347 (M-56) and 403 (MH+), retention time 2.03 minutes. Condition II.
Reaction SMILES: [Br:1]Br.[C:3]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].C(Cl)(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[Br:1][C:11]1[CH:12]=[C:7]([C:3]([CH3:6])([CH3:4])[CH3:5])[CH:8]=[CH:9][C:10]=1[OH:13]
Reactant: BrBr
Reactant: CC(C)(C)c1ccc(O)cc1
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1ccc(O)c(Br)c1
Yield: 100.1 %

Procedure:
A solution of bromine (7.18 mL, 0.14 mol) in chloroform (25 mL) was added dropwise over 2 hours to a solution of 4-tert-butyl-phenol (20 g, 0.133 mol) in 1:1 v/v chloroform:carbon tetrachloride (64 mL) at 0° C. under nitrogen until a slight red coloration persisted (approximately 1 mL of bromine solution remained). The reaction mixture was then purged with nitrogen overnight. The resulting tan solution was diluted with dichloromethane (50 mL), washed with 1% aqueous sodium thiosulfate solution (100 mL) and saturated brine (100 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give 2-bromo-4-(tert-butyl)phenol (30.5 g, quantitative yield) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17](S(CC)(=O)=O)[C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)[CH2:10][CH2:9]2)=[CH:6][C:5](=[O:32])[N:4]([CH3:33])[C:3]1=[O:34].[Cl:35]C1C=C([N+]([O-])=O)C=CC=1Cl.C(N(CC)CC)C>CN(C)C=O>[CH3:1][N:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:19]=3[Cl:35])[CH2:10][CH2:9]2)=[CH:6][C:5](=[O:32])[N:4]([CH3:33])[C:3]1=[O:34]
Reactant: CCS(=O)(=O)N(CCCN1CCN(c2cc(=O)n(C)c(=O)n2C)CC1)c1ccc([N+](=O)[O-])cc1
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1c(N2CCN(CCCNc3ccc([N+](=O)[O-])cc3Cl)CC2)cc(=O)n(C)c1=O
Yield: 155.7 %

Procedure:
A mixture consisting of 0.4 g of Compound 158 obtained in Example 99-(1), 0.4 g of 3,4-dichloro-nitrobenzene, 0.43 ml of triethylamine and 6 ml of dimethylformamide was treated in a manner similar to Example 99-(2), thereby obtaining 0.55 g of 1,3-dimethyl-6-{4-[3-(2-chloro-4-nitroanilino)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: [C:1]([C:5]1[CH:42]=[CH:41][C:8]([C:9]([NH:11][C:12]2[C:13]([CH3:40])=[C:14]([C:18]3[N:23]=[C:22]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([CH2:31][CH2:32]OS(C)(=O)=O)=[CH:27][CH:26]=4)[C:21](=[O:38])[N:20]([CH3:39])[CH:19]=3)[CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:43][CH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1.O>C(#N)C>[C:1]([C:5]1[CH:42]=[CH:41][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[N:23]=[C:22]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][NH:43][CH:44]5[CH2:49][CH2:48][O:47][CH2:46][CH2:45]5)=[CH:27][CH:26]=4)[C:21](=[O:38])[N:20]([CH3:39])[CH:19]=3)[C:13]=2[CH3:40])=[O:10])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: NC1CCOCC1
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cn(C)c(=O)c(Nc2ccc(CCOS(C)(=O)=O)cc2)n1
Solvent: CC#N
Solvent: O
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cn(C)c(=O)c(Nc2ccc(CCNC3CCOCC3)cc2)n1
Temperature: 90 °C

Procedure:
Methanesulfonic acid 2-(4-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-ethyl ester (3) (0.2 g; 0.34 mmol) was dissolved in acetonitrile (2 mL) and excess 4-aminotetrahydropyran (0.25 mL) was added. The reaction vessel was sealed and heated to 90° C. for 4 hr. Water (10 mL) was added to the reaction vessel and the reaction was extracted with EtOAc (3×25 mL). The EtOAc layers were pooled, washed with brine, dried over solid sodium sulfate and filtered. The filtrate was then adsorbed directly onto silica and chromatographed using methanol/CH2Cl2 (1:9) as eluent to provide 75 mg of 4-tert-butyl-N-[2-methyl-3-(4-methyl-5-oxo-6-{4-[2-(tetrahydro-pyran-4-ylamino)-ethyl]-phenylamino}-4,5-dihydro-pyrazin-2-yl)-phenyl]-benzamide (4) as a light tan solid. MS 594.33 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl:32][CH2:33][C:34]([CH3:39])([CH3:38])[C:35](Cl)=[O:36]>ClCCl>[Cl:32][CH2:33][C:34]([CH3:39])([CH3:38])[C:35]([N:8]([C@H:9]1[CH2:10][CH2:11][C@H:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:19])[CH3:20])[CH2:13][CH2:14]1)[CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:24][CH:23]=1)=[O:36]
Reactant: COc1ccc(CN[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)cc1
Reactant: CC(C)(CCl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CN(C(=O)C(C)(C)CCl)[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)cc1
Reaction time: 2 h

Procedure:
A stirred solution of 15A (200 mg, 0.598 mmol) in dichloromethane (5 mL) was treated with triethylamine (0.208 mL, 1.495 mmol), followed by slow addition of 3-chloro-2,2-dimethyl propanoyl chloride (0.155 mL, 1.196 mmol) at room temperature. After stirring for 2 h, reaction was judged complete by LCMS. It was washed with water, and the organics were dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was purified by Isco silica column (24 g) eluted with ethyl acetate:hexane, 0%-100%. Concentration of the appropriate fractions yielded 15B (226 mg, 83% yield) as a white foam. MS (ES): m/z=453.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.02 (d, 2H, J=8.5 Hz); 6.75 (d, 2H, J=8.5 Hz); 4.41 (s, 2H); 4.22-4.30 (m, 1H); 3.88-3.98 (m, 1H); 3.72 (s, 3H); 3.69 (s, 2H); 3.19-3.30 (m, 1H); 1.92-2.02 (m, 2H); 1.01-1.69 (m, 23H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=O.[CH2:13]([OH:16])[CH2:14][OH:15].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[O:15]1[CH2:14][CH2:13][O:16][CH:1]1[C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: OCCO
Reactant: COC(=O)c1cccc(C=O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(C2OCCO2)c1

Procedure:
A stirred solution of methyl 3-formylbenzoate (10.0 g., 61 mmol), ethylene glycol (5.0 ml, 91 mmol) and p-toluene sulphonic acid (10 mb) in toluene (100 ml) was refluxed under a Dean and Stark water trap for 4 hours. The cooled solution was washed with sodium bicarbonate solution, dried and evaporated to a pale oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[CH2:10][CH2:9][NH:8]2)[CH:2]=1.C=O.[CH:13](O)=O.C(=O)(O)[O-].[Na+]>O>[CH3:13][N:8]1[CH2:9][CH2:10][CH:7]1[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: c1cncc(C2CCN2)c1
Reactant: O=CO
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CN1CCC1c1cccnc1
Temperature: 0 °C

Procedure:
To a solution of 920 mg (6.88 mmoles) of the 2-(3-pyridyl)azetidine produced in Example 2 in 9 ml of water was added a solution of 660 mg (8.83 mmoles) of formaldehyde (40% w/w) in 9 ml of water and 755 mg (14.5 mmoles) of 88% formic acid in 9 ml of water. After heating on a steam bath for 2 hours, cooling to 0° C. and adding 1.21 g (14.4 mmoles) of sodium bicarbonate, the colored solution was concentrated under reduced pressure to 7 ml. It was then dried by azeotroping in benzene and ethyl alcohol to give a dry benzene solution containing insolubles. These insolubles were then filtered off to yield a solution of N-methyl-2-(3-pyridyl)azetidine.
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH2:5][C@@:6]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:11][C:10](=[O:12])[N:9]([C@H:13]([C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[CH:17][CH:16]=2)[CH3:14])[CH2:8][CH2:7]1)[C:3]#[N:4].Br[C:38]1[S:39][C:40]([C:43]([NH:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[CH:41][N:42]=1>>[C:46]([NH:45][C:43]([C:40]1[S:39][C:38]([C:18]2[CH:19]=[CH:20][C:15]([C@@H:13]([N:9]3[CH2:8][CH2:7][C@:6]([CH2:5][C:2]([C:3]#[N:4])([CH3:36])[CH3:1])([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[O:11][C:10]3=[O:12])[CH3:14])=[CH:16][CH:17]=2)=[N:42][CH:41]=1)=[O:44])([CH3:49])([CH3:47])[CH3:48]
Reactant: CC(C)(C)NC(=O)c1cnc(Br)s1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ncc(C(=O)NC(C)(C)C)s2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from 2,2-dimethyl-3-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanenitrile and 2-bromo-N-tert-butylthiazole-5-carboxamide following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.292 min, m/z=545.4; 1H NMR (CDCl3) 1.25 (s, 3H), 1.40 (s, 3H), 1.49 (d, 3H), 2.11 (s, 2H), 2.26 (m, 1H), 2.42 (m, 2H), 2.88 (m, 1H), 5.61 (m, 1H), 5.73 (s, 1H), 6.85 (m, 2H), 7.31 (m, 5H), 7.60 (m, 2H), 8.00 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([CH2:21][CH2:22][S:23]([NH2:26])(=[O:25])=[O:24])[O:12]1.[NH2:27][C@@H:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29]1.C(N(CC)C(C)C)(C)C.C(O)C>>[CH:28]1([NH:27][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[C@H:11]2[C@@H:15]3[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]3[C@@H:13]([CH2:21][CH2:22][S:23]([NH2:26])(=[O:25])=[O:24])[O:12]2)[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29]1
Reactant: N[C@H]1CCc2ccccc21
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CCS(N)(=O)=O)O[C@H]2n1cnc2c(Cl)ncnc21
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CCS(N)(=O)=O)O[C@H]2n1cnc2c(NC3CCc4ccccc43)ncnc21

Procedure:
2-[(3aR,4R,6R,6aR)-6-(6-Chloro-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-ethanesulfonamide (45.0 mg, 0.000111 mol), (S)-(+)-1-aminoindane (20.0 μL, 0.000156 mol) and N,N-diisopropylethylamine (24.0 μL, 0.000138 mol) were dissolved in ethanol (1.25 mL, 0.0214 mol) and reacted in a microwave at 140° C. for 10 minutes. The mixture was then concentrated in vacuo and used crude in the next step.