Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30](O)=[O:31])[C:25]=1[CH3:33])(=[O:12])=[O:11].C1C=C[C:37]2[N:42](O)N=N[C:38]=2[CH:39]=1.CCN=C=NCCCN(C)C.Cl.[N:56]1(C(C)CN)[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1>CN(C=O)C>[N:56]1([CH2:39][CH2:38][CH2:37][NH:42][C:30]([C:26]2[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])(=[O:12])=[O:11])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])=[O:31])[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Reactant: On1nnc2ccccc21
Reactant: CC(CN)N1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)NCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
To a mixture of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (100 mg, 0.19 mmol), HOBt (31 mg, 1.2 eq.), EDAC.HCl (44 mg, 1.2 eq.) and 2-morpholin-4-yl-propylamine (69 mg, 2.5 eq.) in DMF (2 mL) was added TEA (0.066 mL, 2.5 eq.). After stirring at rt for 6 days, the reaction was concentrated, diluted with DCM, washed with sat. NaHCO3 and water, dried, concentrated and purified on a silica gel column to give the titled compound as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][N:25]([CH3:37])[C:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)=[O:27]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:31]5[CH:32]=[CH:33][C:28]([C:26]([N:25]([CH3:37])[CH3:24])=[O:27])=[CH:29][CH:30]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CN(C)C(=O)c1ccc(B(O)O)cc1
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4ccc(C(=O)N(C)C)cc4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.106 mmol) and 4-(N,N-dimethylaminocarbonyl)phenylboronic acid (Combi-Blocks, San Diego, USA, 25 mg, 0.126 mmol) to give the title compound as a white solid. (HPLC: tR 2.51 min (Method A); M+H=441 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.97 (s, 1H), 8.17 (s, 1H), 8.12-8.10 (m, 1H), 7.96-7.93 (m, 1H), 7.59-7.58 (m, 1H), 7.55-7.50 (m, 4H), 3.93 (s, 3H), 3.58 (s, 3H), 2.99 (s, 3H), 2.94 (s, 3H), 1.95 (s, 3H))
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[N:13][CH:14]=2)=[CH:5][CH:4]=1.[Cl:23][CH2:24][C:25]([N:27]([CH3:29])[CH3:28])=[O:26]>>[ClH:23].[CH3:28][N:27]([CH3:29])[C:25](=[O:26])[CH2:24][N:18]1[CH2:19][CH2:20][N:15]([C:12]2[CH:11]=[CH:10][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:21])[F:22])=[CH:8][CH:7]=3)=[CH:14][N:13]=2)[CH2:16][CH2:17]1
Reactant: CN(C)C(=O)CCl
Reactant: FC(F)(F)c1ccc(-c2ccc(N3CCNCC3)nc2)cc1
Product: CN(C)C(=O)CN1CCN(c2ccc(-c3ccc(C(F)(F)F)cc3)cn2)CC1
Product: Cl

Procedure:
The title compound was prepared by a similar procedure to that described in Example 55, starting from 4-(5-(4-trifluoromethylphenyl)pyridin-2-yl)piperazine and 2-chloro-N,N-dimethylacetamide.
Reaction SMILES: O.NN.[F:4][C:5]1[CH:6]=[CH:7][C:8]2[N:14]3[C:15](CON4C(=O)C5=CC=CC=C5C4=O)=[N:16][N:17]=[C:13]3[CH2:12][N:11]=[C:10]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:9]=2[CH:37]=1>C(O)C>[F:4][C:5]1[CH:6]=[CH:7][C:8]2[N:14]3[CH:15]=[N:16][N:17]=[C:13]3[CH2:12][N:11]=[C:10]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:9]=2[CH:37]=1
Reactant: O=C1c2ccccc2C(=O)N1OCc1nnc2n1-c1ccc(F)cc1C(c1ccccc1)=NC2
Agent: NN
Solvent: CCO
Solvent: O
Product: Fc1ccc2c(c1)C(c1ccccc1)=NCc1nncn1-2

Procedure:
In the manner given in Example 2, solution of hydrazine hydrate in ethanol is reacted at 65° C. with 8-fluoro-1-[(phthalimidooxy)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine to give 1-(aminooxy)methyl]-8-fluoro-6phenyl-4H-s-triazolo[4,3-a][1,4]-benzodiazepine.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([CH2:9][CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[S:8][C:4]=2[CH:3]=1.Cl[C:19]1[N:24]=[CH:23][C:22]([CH2:25][CH2:26][CH3:27])=[CH:21][N:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([CH2:9][CH:10]3[CH2:11][CH2:12][N:13]([C:19]4[N:24]=[CH:23][C:22]([CH2:25][CH2:26][CH3:27])=[CH:21][N:20]=4)[CH2:14][CH2:15]3)[S:8][C:4]=2[CH:3]=1
Reactant: Brc1ccc2nc(CC3CCNCC3)sc2c1
Reactant: CCCc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1cnc(N2CCC(Cc3nc4ccc(Br)cc4s3)CC2)nc1
Temperature: 110 °C
Reaction time: 3 h
Yield: 47.8 %

Procedure:
To a solution of 6-bromo-2-(piperidin-4-ylmethyl)benzo[d]thiazole (380 mg, 1.221 mmol) and 2-chloro-5-propylpyrimidine (249 mg, 1.587 mmol) in DMF (8 mL) was added potassium carbonate (675 mg, 4.88 mmol). The reaction mixture was stirred at 110° C. for 3 h. The reaction mixture was cooled to rt, diluted with water (15 mL), and extracted with EtOAc (3×10 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated. The crude product was purified by column chromatography (silica gel, hexanes-EtOAc gradient 0 to 50% EtOAc) to afford 6-bromo-2-((1-(5-propylpyrimidin-2-yl)piperidin-4-yl)methyl)benzo[d]thiazole (252 mg, 0.584 mmol, 48% yield) as a light brown solid. LCMS (m/z)=432 (M+H)+.
Reaction SMILES: [C:1](=[O:29])([O:3][CH2:4][C:5]1[N:6]([CH2:22][C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[C:7]([S:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=2)=[C:8]([CH:10]([CH3:12])[CH3:11])[N:9]=1)[NH2:2].[CH2:30]([NH:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[CH2:45]=O>C(OCC)(=O)C>[CH2:38]([N:37]([CH2:45][NH:2][C:1](=[O:29])[O:3][CH2:4][C:5]1[N:6]([CH2:22][C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[C:7]([S:13][C:14]2[CH:15]=[C:16]([Cl:21])[CH:17]=[C:18]([Cl:20])[CH:19]=2)=[C:8]([CH:10]([CH3:12])[CH3:11])[N:9]=1)[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: C=O
Reactant: CC(C)c1nc(COC(N)=O)n(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Solvent: CCOC(C)=O
Product: CC(C)c1nc(COC(=O)NCN(Cc2ccccc2)Cc2ccccc2)n(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Yield: 63.8 %

Procedure:
A mixture of the compound 111 (306 mg, 0.7 mmol), dibenzylamine (138 mg, 0.7 mmol) and paraformaldehyde (22.0 mg., 0.733 mmol) in ethyl acetate (4 mL) was heated under reflux in an atmosphere of nitrogen for 8 hours. After cooling down at room temperature, the reaction mixture was purified by chromatography on a silica gel column (eluate: ethyl acetate) to give the compound 114 (295 mg, 64%). Rf 0.70 (EtOAc). 1H-NMR (CDCl3): δH1.31 (6 H, d, J 6.6 Hz, (CH3)2CH), 3.18 (1 H, sep, J 6.6 Hz, (CH3)2CH), 3.57 (4H, s, 2 x benzyl-CH2), 4.04 (2 H, d, J 6.0 Hz, NCH2NH), 4.88 (1H, t, 6.0 Hz, NCH2NH), 5.19 (2 H, s, CH2O), 5.24 (2 H, s, NCH2), 6.68 (2 H, d, J 1.5 Hz, arom 2- and 6-H), 6.78 (2 H, d-like, 4-pyridyl 2- and 6-H), 7.03 (1 H, t, J 1.5 Hz, arom 4-H), 7.20-7.35 (10 H, m, 2 x benzyl), 8.43 (2 H, d-like, 4-pyridyl 3- and 5-H). Elementary analysis (for C35H35N5O2SCl2) Calcd.: C, 63.63% H, 5.34% N, 10.60% S, 4.85% Cl, 10.73% Found: C, 63.39% H, 5.44% N, 10.63% S, 4.88% Cl, 10.53% The above compounds are shown as follows. ##STR6##
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:7]=[CH:8][CH2:9]CCCCC.C=C>CCCCCC>[CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:7]=[CH:8][CH3:9]
Reactant: C=CCCCCCC
Agent: C=C
Solvent: CCCCCC
Solvent: C=CCCCC
Product: C=CC

Procedure:
The procedure used for the preparation of copolymer S-2 was repeated except that 1-hexene was replaced with 1 -octene. A tacky amorphous polymer was obtained in 56% conversion having an inherent viscosity of 4.2 dL/g in n-hexane and a Tg of -51° C. It contained 89 mole percent of 1-octene and 11 mole percent of ethylene.
Reaction SMILES: [NH3:1].CN.[Cl:4][C:5]1([Cl:14])[CH2:10][CH2:9][CH2:8][C:7]([Cl:12])([Cl:11])[C:6]1=O>[Ti](Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[Cl:4][C:5]1([Cl:14])[CH2:10][CH2:9][CH2:8][C:7]([Cl:12])([Cl:11])[C:6]1=[NH:1]
Reactant: O=C1C(Cl)(Cl)CCCC1(Cl)Cl
Reactant: N
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CN
Solvent: Cc1ccccc1
Product: N=C1C(Cl)(Cl)CCCC1(Cl)Cl

Procedure:
The procedure of Example 1 was repeated except that 1.56 moles of each amine and ammonia shown in Table 1 was used instead of aniline to give oily 2,2,6,6-tetrachlorocyclohexaneimine derivative. In Examples 4 and 5, gaseous ammonia and methylamine were introduced into the mixture of 2,2,6,6-tetrachlorocyclohexanone, toluene and titanium tetrachloride, respectively. The structural formulae, yields and results of IR analysis of the obtained 2,2,6,6-tetrachlorocyclohexaneimine derivatives (I) are shown in Table 1.
Reaction SMILES: [CH3:1][CH:2]1[CH:6]([CH2:7][CH:8]=[CH2:9])[NH:5][C:4](=[O:10])[CH2:3]1.F[B-](F)(F)F.[CH3:16][O+](C)C>>[CH3:16][O:10][C:4]1[CH2:3][CH:2]([CH3:1])[CH:6]([CH2:7][CH:8]=[CH2:9])[N:5]=1
Reactant: C=CCC1NC(=O)CC1C
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Product: C=CCC1N=C(OC)CC1C

Procedure:
The product of EXAMPLE 265 is reacted with trimethyloxonium tetrafluoroborate by the method of EXAMPLE 26 to produce the title material.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@H:5]([CH2:7][C:8]([OH:10])=O)[C:4](=[O:11])[O:3]1.[CH2:13]([SH:15])[CH3:14].C1CCC(N=C=NC2CCCCC2)CC1.C(O)(=O)C>C(Cl)Cl.CN(C)C1C=CN=CC=1.CCOCC>[CH3:12][C:2]1([CH3:1])[O:6][C@H:5]([CH2:7][C:8](=[O:10])[S:15][CH2:13][CH3:14])[C:4](=[O:11])[O:3]1
Reactant: CCS
Reactant: CC1(C)OC(=O)[C@@H](CC(=O)O)O1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCSC(=O)C[C@H]1OC(C)(C)OC1=O
Reaction time: 1 h
Yield: 71.5 %

Procedure:
(R)-2-(2,2-Dimethyl-5-oxo-1,3-dioxolan-4-yl)acetic acid (25 g, 144 mmol) was dissolved in CH2Cl2 (500 mL) and cooled in an ice bath. Ethanethiol (21.2 mL, 287 mmol) and N,N-dimethylpyridin-4-amine (0.351 g, 2.87 mmol) were added followed by DCC (35.5 g, 172 mmol). This mixture was stirred in ice bath for 1 hour, and then 2 hours at ambient temperature. Acetic acid (45 mL) was added and then stirred the mixture for 10 minutes. The reaction mixture was then poured into vigorously stirred ether (400 mL) and filtered. The filtrate was washed with 10% sodium carbonate, water, 0.5 N HCl, water and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified over silica gel (1-5-10% EtOAc in hexanes) to afford (R)—S-ethyl 2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)ethanethioate (22.5 g, 103 mmol, 71.8% yield) as a clear colorless oil that solidified to a white solid.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH3:14])[O:13][CH2:12][CH2:11][O:10]2)=[CH:5][CH:4]=1)=[O:2].S([CH2:25][N+:26]#[C-:27])(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CO.O>[O:2]1[C:1]([C:3]2[CH:4]=[CH:5][C:6]([C:9]3([CH3:14])[O:10][CH2:11][CH2:12][O:13]3)=[CH:7][CH:8]=2)=[CH:27][N:26]=[CH:25]1
Reactant: CC1(c2ccc(C=O)cc2)OCCO1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC1(c2ccc(-c3cnco3)cc2)OCCO1
Yield: 37.4 %

Procedure:
To a stirred solution of 2-(4-formylphenyl)-2-methyl-1,3-dioxolane (1.58 g, 8.23 mmol) in methanol (10 ml) was added tosylmethyl isocyanide (2.0 g, 10.3 mmol), potassium carbonate (1.42 g, 10.3 mmol), and the mixture was heated at reflux temperature for 2 hours. The reaction mixture was diluted with water and the whole was extracted with CH2Cl2. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate-hexane (1:4) to give the title compound (711 mg, 37% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][N:11]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:5]=[N:6][CH:7]=1.[NH2:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[NH2:21][C:22]1[CH:27]=[C:26]([C:2]2[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]3[CH2:13][CH2:12][N:11]3[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:5]=[N:6][CH:7]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(Br)c1
Reactant: Nc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(-c2cccc(N)c2)c1
Yield: 41.7 %

Procedure:
The 5-bromo-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine from Example 54b (400 mg, 1.2 mmol), 3-aminophenylboronic acid (361 mg, 2.3 mmol, Aldrich Chem. Co.), Pd(0) (35 mg) and Na2CO3 (1.5 mL of a 2M solution) were mixed in 8 mL of toluene, and the mixture was stirred at reflux for 16 hours. The solvent was removed under vacuum, and the residue was purified by chromatography on silica gel, eluting with exane:ether 1:1, to afford 178 mg of the title compound. MS (CI/NH3) m/z 356 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ1.42 (s, 9H), 2.33 (m, 2H), 3.92 (m, 2H), 4.20 (m, 1H), 4.38 (m, 1H), 4.55 (m, 1H), 6.72 (m, 1H), 6.88 (s, 1H), 6.97 (m, 1H), 7.44 (m, 2H), 8.31 (m, 1H), 8.44 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[C:13]([CH3:14])=[CH:12][C:10]([NH2:11])=[C:9]([CH3:15])[CH:8]=2)=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>C(O)CCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:17]=[CH:16][C:5]([O:6][C:7]3[C:13]([CH3:14])=[CH:12][C:10]([NH2:11])=[C:9]([CH3:15])[CH:8]=3)=[CH:4][CH:3]=2)=[CH:22][CH:21]=1
Reactant: Cc1cc(Oc2ccc(Br)cc2)c(C)cc1N
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCO
Solvent: O
Product: COc1ccc(-c2ccc(Oc3cc(C)c(N)cc3C)cc2)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 79.7 %

Procedure:
Under argon, 0.50 g (1.7 mmol) of 4-(4-bromophenoxy)-2,5-dimethylaniline and 0.34 g (2.2 mmol) of 4-methoxyphenylboronic acid are dissolved in 10 ml of 1-butanol and the solution is admixed with 2.23 g (6.8 mmol) of cesium carbonate, 39.5 mg (0.03 mmol) of tetrakis(triphenylphosphine)palladium(0) and 2.5 ml of water. The reaction mixture is stirred at 80° C. for 16 h, poured into water and extracted repeatedly with ethyl acetate. The combined organic phases are dried over Na2SO4 and filtered and the solvent is removed under reduced pressure. This is followed by purification by column chromatography (0.44 g, purity 99.0%, yield 79.7%, log P (pH 2.3)=3.06).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[CH3:8][C:9]([NH2:17])([CH3:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH3:8][C:9]([NH:17][CH2:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])([CH3:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C=CC(=O)OCC
Reactant: CC(C)(N)c1ccccc1
Product: CCOC(=O)CCNC(C)(C)c1ccccc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 76.8 %

Procedure:
100 g (1 mol) of ethyl acrylate was added to 135.2 g (1 mol) of α,α-dimethylbenzylamine, and the mixture was stirred at 100° C. for 18 hours. The reaction product was subjected to distillation to obtain 180.7 g (yield: 77.8%) of the desired compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][C:8]2([CH2:14][NH2:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1.Cl[C:19]1[C:20]2[CH:27]=[CH:26][NH:25][C:21]=2[N:22]=[CH:23][N:24]=1.C(N(CC)CC)C>C(O)CCC>[Cl:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][C:8]2([CH2:14][NH2:15])[CH2:13][CH2:12][N:11]([C:19]3[C:20]4[CH:27]=[CH:26][NH:25][C:21]=4[N:22]=[CH:23][N:24]=3)[CH2:10][CH2:9]2)=[CH:5][CH:4]=1
Reactant: NCC1(Cc2ccc(Cl)cc2)CCNCC1
Reactant: Clc1ncnc2[nH]ccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: NCC1(Cc2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Yield: 55.8 %

Procedure:
A solution of C-[4-(4-chlorobenzyl)piperidin-4-yl]methyl amine hydrochloride (0.063 g, 0.2016 mmol), 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.031 g, 0.2016 mmol) and triethylamine (0.140 ml, 1.0079 mmol) in n-butanol (2.0 ml) was heated to 100° C. for 24 hours. Concentration and purification by SCX-2 Isolute column (2 g), eluting with 1M NH3/MeOH, followed by silica column chromatography (15% methanol in DCM) gave a white solid (0.040 g, 56%). LC-MS (LCT2) m/z 356 [M+H+], Rt 2.97 min.
Reaction SMILES: [C:1]([S:26]([NH:29][CH2:30][CH3:31])(=[O:28])=[O:27])([C:4]([C:7]([C:10]([C:13]([C:16]([C:19]([C:22]([F:25])([F:24])[F:23])([F:21])[F:20])([F:18])[F:17])([F:15])[F:14])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].C(N(CC)CC)C.C1C2NC3C(=CC=CC=3)SC=2C=CC=1.[C:53]([O:57][CH2:58][CH3:59])(=[O:56])[CH:54]=[CH2:55]>C1(C)C=CC=CC=1>[C:1]([S:26]([N:29]([CH2:55][CH2:54][C:53]([O:57][CH2:58][CH3:59])=[O:56])[CH2:30][CH3:31])(=[O:27])=[O:28])([C:4]([C:7]([C:10]([C:13]([C:16]([C:19]([C:22]([F:24])([F:25])[F:23])([F:21])[F:20])([F:18])[F:17])([F:15])[F:14])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: CCNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: C=CC(=O)OCC
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CCN(CC)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 97 °C
Yield: 97 %

Procedure:
In a 1-L, three-necked flask, fitted with a condenser, stirrer, and thermometer were placed 263 g (0.5 mole) of C8F17SO2N(C2H5)H, 15 g of triethylamine, 3 g of phenothiazine, 150 g toluene and 90 g (0.9 mole) of ethyl acrylate. The reaction mixture was stirred and heated at reflux (about 97° C.) for 16 hours to yield the known adduct C8F17SO2N(C2H5)C2H4COOC2H5 in 97% yield as shown by H-NMR analysis. The adduct was isolated by stripping off the toluene solvent, triethyl amine and excess ethyl acrylate under water aspirator pressure.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][CH2:10][CH2:11][O:12][CH3:13])[N:3]=1.[Cl:14][C:15]1[CH:16]=[C:17](B(O)O)[C:18]([F:21])=[N:19][CH:20]=1.C([O-])(=O)C.[K+]>O1CCOCC1.Cl[Pd]Cl>[Cl:14][C:15]1[CH:16]=[C:17]([C:2]2[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][CH2:10][CH2:11][O:12][CH3:13])[N:3]=2)[C:18]([F:21])=[N:19][CH:20]=1
Reactant: OB(O)c1cc(Cl)cnc1F
Reactant: COCCNc1nc(C)nc(Cl)n1
Agent: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COCCNc1nc(C)nc(-c2cc(Cl)cnc2F)n1
Temperature: 100 °C
Reaction time: 6 h
Yield: 29.5 %

Procedure:
A mixture of 4-chloro-N-(2-methoxyethyl)-6-methyl-1,3,5-triazin-2-amine (300 mg, 1.480 mmol), 5-chloro-2-fluoropyridin-3-ylboronic acid (320 mg, 1.825 mmol), potassium acetate (298 mg, 3.04 mmol), and Am-phos PdCl2 (47 mg, 0.066 mmol) in dioxane (10 mL) was heated at 100° C. under nitrogen. After 6 h, the mixture was cooled to rt and partitioned between water (10 mL) and EtOAc (20 mL). The organic layer was dried over Na2SO4 and concentrated. The oil was purified on silica using EtOAc in hexane (10-80%) to give the product as a yellow solid (130 mg). LCMS (ES, pos.): calcd for C12H13ClFN5O: 297.1. found: 298.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.55 (ddd, J=16.24, 7.92, 2.64 Hz, 1H); 8.27 (br. s., 1H); 5.91 (br. s., 1H); 3.72 (quin, J=5.62 Hz, 2H); 3.59 (t, J=5.09 Hz, 2H); 3.40 (2s, 3H); 2.51 (2s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.C(N(CC)CC)C.N[CH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C(O)C>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: NC1CCOCC1
Solvent: CCO
Solvent: O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cc(Br)ccc1C1CCOCC1
Reaction time: 2 h
Yield: 91.2 %

Procedure:
An eggplant flask was charged with 5-bromo-2-fluoronitrobenzene (3.0 g, 13.6 mmol), triethylamine (1.66 g, 16.3 mmol), 4-aminotetrahydropyran (1.52 g, 15.0 mmol), and ethanol (60 mL), and this was heated to reflux with stirring for 2 hours. After concentration of the reaction mixture under reduced pressure, water (60 mL) was added and this was stirred as is at room temperature for 30 minutes. The precipitated crystals were filtered off and washed with water. The crystals obtained were dried at reduced pressure with heating to yield the title compound (3.55 g, 86% yield) as a reddish-orange solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([NH:11][C@H:12]([C:20]([NH:22][C@H:23]2[C@H:26](OC(=O)C)[NH:25][C:24]2=[O:31])=[O:21])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:32][CH2:33][CH:34]([OH:37])[CH2:35][Br:36].O>C1C=CC=CC=1.C1(C)C=CC=CC=1.O.O.C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[C:1]1([CH2:7][CH2:8][C:9]([NH:11][C@H:12]([C:20]([NH:22][C@H:23]2[C@H:26]([O:37][CH:34]([CH2:35][Br:36])[CH2:33][Br:32])[NH:25][C:24]2=[O:31])=[O:21])[CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)O[C@@H]1NC(=O)[C@H]1NC(=O)[C@H](Cc1ccccc1)NC(=O)CCc1ccccc1
Reactant: OC(CBr)CBr
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Solvent: O
Solvent: c1ccccc1
Product: O=C(CCc1ccccc1)N[C@@H](Cc1ccccc1)C(=O)N[C@@H]1C(=O)N[C@H]1OC(CBr)CBr
Yield: 7 %

Procedure:
A mixture of (3S,4S)-3-{N-(3-phenylpropionoyl)-L-phenylalanyl}amino-4-acetoxy-azetidin-2-one (1.67 g, 3.95 mmole), 1,3-dibromo-2-propanol (689 mg, 3.16 mmole), and zinc acetate dihydrate (435 mg, 1.98 mmole) in a mixture of benzene (25 ml) and toluene (25 ml) was refluxed overnight using Dean-Stark water separator. After cooling, the reaction mixture was partitioned between ethyl acetate (200 ml), acetone (40 ml) and water (150 ml). The organic layer was washed with water, brine and dried over sodium sulfate. After removal of the solvent, the residue was purified by silica gel column chromatography using ethyl acetate-hexane (4:3) as eluent and (3S,4S)-3-{N-(3-phenylpropionoyl)-L-phenylalanyl}amino-4-(1,3-dibromoprop-2-yl)oxy-azetidin-2-one was obtained (170 mg, 7% yield).
Reaction SMILES: [CH2:1]([N:8]1[C@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH2:11][CH:10]([N:21]2C(=O)C3C(=CC=CC=3)C2=O)[C:9]1=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>CO.CCOCC>[NH2:21][C@@H:10]1[CH2:11][CH:12]=[CH:13][C@@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]1=[O:32].[NH2:21][C@H:10]1[CH2:11][CH:12]=[CH:13][C@@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]1=[O:32]
Reactant: O=C1c2ccccc2C(=O)N1C1CC=C[C@@H](c2ccccc2)N(Cc2ccccc2)C1=O
Agent: NN
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: N[C@@H]1CC=C[C@@H](c2ccccc2)N(Cc2ccccc2)C1=O
Product: N[C@H]1CC=C[C@@H](c2ccccc2)N(Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To 2-[(7S)-1-benzyl-2-oxo-7-phenyl-2,3,4,7-tetrahydro-1H-azepin-3-yl]-1H-isoindole-1,3(2H)-dione (5c) (126 mg) dissolved in MeOH (4 mL) was added hydrazine hydrate (0.036 mL) and the mixture was stirred overnight at RT. A white precipitate formed in solution. The reaction mixture was diluted with ether and the precipitate was filtered and washed with ether. The etheral filtrate was concentrated and the resulting residue dissolved in DCM. The DCM solution was washed with H2O and brine, dried (Na2SO4) and concentrated. The diastereomeric mixture was separated via preparative plate chromatography (eluent 10% MeOH/DCM) to give (3R,7S)-3-amino-1-benzyl-7-phenyl-1,3,4,7-tetrahydro-2H-azepin-2-one (5e) and (3S,7S)-3-amino-1-benzyl-7-phenyl-1,3,4,7-tetrahydro-2H-azepin-2-one (5d) (combined yield of 72%).