Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:24])[C:5]1=[O:34].C(N(C(C)C)CC)(C)C.Cl[C:45]([O:47][CH3:48])=[O:46]>CN(C=O)C>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][C:11]2[CH:12]=[C:13]3[C:8]([C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][N:28]4[CH2:29][CH2:30][O:31][CH2:32][CH2:33]4)=[O:24])[C:5](=[O:34])[N:4]3[CH2:3][CH2:2][NH:1][C:45](=[O:46])[O:47][CH3:48])=[N:9][CH:10]=2)=[CH:20][CH:19]=1
Reactant: NCCn1c(=O)c(C(=O)NCCN2CCOCC2)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Reactant: COC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)NCCn1c(=O)c(C(=O)NCCN2CCOCC2)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
A solution of 1-(2-aminoethyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-[2-(4-morpholinyl)ethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (0.025 g, 0.052 mmol) and diisopropyl ethylamine (0.05 mL, 0.29 mmol) in DMF (5 mL) under nitrogen was treated with methyl chloroformate (0.0087 mL, 0.11 mmol) at 40° C. for 1 h then 3½ h at ambient temperature. The reaction was concentrated in vacuo and the resulting residue was triturated with Et2O:MeOH, filtered, washed with 2:1 Et2O:MeOH, and dried in vacuo to provide the title compound as a pale yellow solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.23 (s, 1 H), 3.06-3.20 (m, 2 H), 3.25-3.32 (m, 2 H), 3.36-3.43 (m, 2 H), 3.45 (s, 3 H), 3.55 (d, J=10.95 Hz, 2 H), 3.69 (t, J=12.2 Hz, 2 H), 3.78 (d, J=6.74 Hz, 2 H), 4.00 (d, J=12.35 Hz, 2 H), 4.15 (s, 2 H), 4.31 (t, J=5.76 Hz, 2 H), 7.12-7.19 (m, 2 H), 7.38-7.45 (m, 2 H), 8.16 (s, 1 H), 8.55 (s, 1 H), 9.91 (br. s., 1 H), 10.39 (t, J=6.60 Hz, 1 H); ES+ MS: 528 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[C:4]([CH3:11])[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:45][C@@H:46]1[NH:51][CH2:50][CH2:49][N:48]([S:52]([C:55]2[CH:60]=[CH:59][C:58]([C:61]([F:64])([F:63])[F:62])=[CH:57][CH:56]=2)(=[O:54])=[O:53])[CH2:47]1>CN(C=O)C>[CH3:1][C:2]1[C:7]([C:8]([N:51]2[CH2:50][CH2:49][N:48]([S:52]([C:55]3[CH:56]=[CH:57][C:58]([C:61]([F:64])([F:62])[F:63])=[CH:59][CH:60]=3)(=[O:53])=[O:54])[CH2:47][C@@H:46]2[CH3:45])=[O:10])=[CH:6][CH:5]=[C:4]([CH3:11])[N:3]=1
Reactant: Cc1ccc(C(=O)O)c(C)n1
Reactant: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)N2CCN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@@H]2C)c(C)n1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 65.1 %

Procedure:
2,6-Dimethyl-3-pyridinecarboxylic acid (GSK1770624A, Atlantic) (98 mg, 0.65 mmol) and HATU (247 mg, 0.65 mmol) were suspended in DMF (2 ml) and DIPEA (0.170 ml, 0.97 mmol) was added. This mixture was stirred for 40 min at ambient temperature. (3S)-3-Methyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (may be prepared as described in Description 2) (100 mg, 0.32 mmol) was added and stirring continued for 3 h. The reaction mixture was partitioned between DCM and sat aq. NaHCO3 solution (10 ml each). The layers were separated and the aqueous was washed with further DCM (2×5 ml). The combined organic layers were concentrated to leave a brown oil. This was purified by MDAP to give the title compound (92 mg) as an orange solid.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10](/[CH:12]=[CH:13]/[C:14]2[CH:19]=[C:18]([CH3:20])[C:17]([O:21][CH2:22][O:23][CH3:24])=[C:16]([CH3:25])[CH:15]=2)[CH:11]=1)[C:6]([OH:8])=O.C1CCC(N=C=NC2CCCCC2)CC1.[F:42][C:43]1[CH:48]=[CH:47][C:46]([SH:49])=[CH:45][CH:44]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][N:2]([CH3:26])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10](/[CH:12]=[CH:13]/[C:14]2[CH:15]=[C:16]([CH3:25])[C:17]([O:21][CH2:22][O:23][CH3:24])=[C:18]([CH3:20])[CH:19]=2)[CH:11]=1)[C:6](=[O:8])[S:49][C:46]1[CH:47]=[CH:48][C:43]([F:42])=[CH:44][CH:45]=1
Reactant: Fc1ccc(S)cc1
Reactant: COCOc1c(C)cc(/C=C/c2cc(C(=O)O)cc(N(C)C)c2)cc1C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COCOc1c(C)cc(/C=C/c2cc(C(=O)Sc3ccc(F)cc3)cc(N(C)C)c2)cc1C
Reaction time: 18 h

Procedure:
To a solution of Compound 5 (80 mg, 0.225 mmol) in DCM (3 mL) were added DCC (70 mg, 0.338 mmol), DMAP (5.5 mg, 0.045 mmol), and 4-fluorobenzenethiol (37 μL, 0.338 mmol) at room temperature. The reaction mixture was stirred overnight (about 18 hours) and filtered through Celite. The filtrate was washed with brine, and dried with Na2SO4. The solution was filtered and concentrated. The residue was subjected to chromatography over silica gel (Hexanes/EtOAc=8/1) to give (E)-S-4-fluorophenyl 3-(dimethylamino)-5-(4-(methoxymethoxy)-3,5-dimethylstyryl)benzothioate.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.N12CCCN=C1CCCCC2>CS(C)=O.O>[N:14]1([C:2]2[N:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C1CCNC1
Reactant: CCOC(=O)Cc1ccc(Cl)nc1
Solvent: O
Solvent: CS(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)Cc1ccc(N2CCCC2)nc1
Temperature: 150 °C
Reaction time: 8 h
Yield: 28.4 %

Procedure:
A reaction mixture of ethyl (6-chloropyridin-3-yl)acetate (0.30 g, 1.5 mmol) (Asymchem, Cat. #110112), pyrrolidine (0.14 mL, 1.6 mmol and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.25 mL, 1.6 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 150° C. overnight. The mixture was diluted with water, and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-40%) to afford the desired product (0.10 g, 28.4%). Analytic LCMS (M+H)+: m/z=235.2.
Reaction SMILES: [CH3:1][N:2]([CH3:36])[CH2:3][CH2:4][N:5](C)[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([Cl:20])[C:17]([CH2:21][CH:22]3[CH2:26][CH2:25][N:24]([CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)[C:23]3=[O:33])=[C:16]([Cl:34])[CH:15]=2)=[CH:10][CH:9]=1)=[O:7].ClC1C=C(C=CC=1)C(OO)=[O:42]>ClCCl>[CH3:1][N:2]([CH3:36])[CH2:3][CH2:4][NH+:5]([O-:42])[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([Cl:20])[C:17]([CH2:21][CH:22]3[CH2:26][CH2:25][N:24]([CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)[C:23]3=[O:33])=[C:16]([Cl:34])[CH:15]=2)=[CH:10][CH:9]=1)=[O:7]
Reactant: CN(C)CCN(C)C(=O)c1ccc(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CN(C)CC[NH+]([O-])C(=O)c1ccc(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)cc1
Yield: 88.3 %

Procedure:
Dissolve racemic 3′,5′-dichloro-4′-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-4-carboxylic acid (2-dimethylamino-ethyl)-methyl-amide (0.097 g, 0.183 mmol) in dichloromethane (5 mL) under argon atmosphere. Add 3-chloroperoxybenzoic acid (0.045 g, 0.200 mmol) and stir at room temperature for 1 hour. Concentrate under reduced pressure and purify via flash chromatography by eluding with gradient (100%) dichloromethane to 25% methanol/75% dichloromethane to obtain 0.086 g (87%) of a white solid: MS (m/z): 546 (M+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[CH2:10][C:11]([OH:13])=[O:12].C1(C(=CC(=CC=1)C)C)C.C(O)(=O)C=[O:25]>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[CH:10]([OH:25])[C:11]([OH:13])=[O:12]
Reactant: O=CC(=O)O
Reactant: Cc1cc(C)c(CC(=O)O)cc1C
Agent: Cc1ccc(C)c(C)c1
Product: Cc1cc(C)c(C(O)C(=O)O)cc1C

Procedure:
Finally, a further possibility for preparing 2,4,5-trimethylphenylacetic acid is to initially react pseudocumene with glyoxylic acid to give 2,4,5-trimethylmandelic acid (Atti Accad., Lettere Arti Palermo, Pt. I24 (1965) 19–33) and then to reduce it to 2,4,5-trimethylphenylacetic acid (J. Amer. Chem. Soc. 58 (1936) 629–35). However, the preparation of 2,4,5-trimethylmandelic acid by the process specified has the disadvantage that the 2,4,5-trimethylmandelic acid which has already formed reacts with further pseudocumene under the customary reaction conditions and thus forms considerable proportions of 2,2′,4,4′,5,5′-hexamethyldiphenylacetic acid (Atti Accad., Lettere Arti Palermo, Pt. I24 (1965) 19–33), which of course reduce the yield and make necessary additional purification steps.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[NH:11][C:10](=O)[N:9]=2)=[CH:4][C:3]=1[CH3:16].O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:10]1[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:16])[CH:4]=2)[CH:13]=[C:12]([CH3:14])[N:11]=1
Reactant: Cc1cc(-c2ccc(Cl)c(C)c2)nc(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(-c2ccc(Cl)c(C)c2)nc(Cl)n1

Procedure:
The title compound was prepared from 4-(4-chloro-3-methyl-phenyl)-6-methyl-1H-pyrimidin-2-one (9.78 g, 41.7 mmol) and phosphoroxychloride (98 mL) according to the general procedure I. Obtained as an off-white solid (7.38 g, 70%). MS (ISP) 253.1 [(M+H)+]; mp 131° C.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:30][CH:29]=1>CC#N>[Br-:23].[C:31]1([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:30]=[CH:29][C:28]([O:27][CH2:26][CH2:25][CH2:24][N+:1]23[CH2:6][CH2:5][C:4]([C:9]([OH:10])([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)([CH2:3][CH2:2]2)[CH2:7][CH2:8]3)=[CH:33][CH:32]=1
Reactant: BrCCCOc1ccc(-c2ccccc2)cc1
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Solvent: CC#N
Product: OC(c1ccccc1)(c1ccccc1)C12CC[N+](CCCOc3ccc(-c4ccccc4)cc3)(CC1)CC2
Product: [Br-]
Yield: 77.8 %

Procedure:
Following the general procedure outlined in Example 3, 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0437 g, 0.144 mmol) and 4-biphenylyl 3-bromopropyl ether (0.0562 g, 0.194 mmol) in 2 CH3CN/3 CHCl3 (4.0 mL) were reacted to give the desired product (0.0655 g, 75.2%). EI-MS m/z 504 (M+) Rt (2.24 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:18][CH:17]([C:19](O)=[O:20])[N:8]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]([F:16])[C:14]=4[CH:15]=[C:7]3[C:6]=2[N:22]=1.[NH4+].[Cl-].C1C=CC2N(O)N=[N:31]C=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:18][CH:17]([C:19]([NH2:31])=[O:20])[N:8]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]([F:16])[C:14]=4[CH:15]=[C:7]3[C:6]=2[N:22]=1
Reactant: O=C(O)C1Oc2ccc(Cl)nc2-c2cc3c(F)cccc3n21
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)C1Oc2ccc(Cl)nc2-c2cc3c(F)cccc3n21
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.1 %

Procedure:
A mixture of 2-chloro-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole-6-carboxylic acid (60 mg, 0.19 mmol), NH4Cl (20 mg, 0.38 mmol), HOBT (38 mg, 0.28 mmol), EDCI (54 mg, 0.28 mmol) and triethylamine (76 mg, 0.75 mmol) in DMF (1 mL) was stirred at room temperature overnight under N2 atmosphere. The mixture was then diluted with water (30 mL) and extracted with EtOAc (20 mL×3). The organic layer was washed with brine (30 mL×3), dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using column chromatography (dichloromethane:MeOH=30:1) to provide 2-chloro-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole-6-carboxamide (20 mg, yield: 33.3%). 1H-NMR (Methanol-d4, 400 MHz) δ 7.54 (d, J=8.4 Hz, 1H), 7.28˜7.31 (m, 2H), 7.20˜7.24 (m, 2H), 6.90 (s, 1H), 6.82˜6.84 (m, 1H). MS (M+H)+: 318.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][OH:11])[C:5]([N+:12]([O-])=O)=[CH:4][N:3]=1.[CH2:15](OCC)C>C(O)(=O)C.[Fe]>[NH2:1][C:2]1[N:7]=[C:6]2[C:5]([N:12]=[CH:15][N:8]2[CH2:9][CH2:10][OH:11])=[CH:4][N:3]=1
Reactant: CCOCC
Reactant: Nc1ncc([N+](=O)[O-])c(NCCO)n1
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1ncc2ncn(CCO)c2n1
Temperature: 35 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
19.92 g (0.1 mole) of 2-amino-4-(2-hydroxyethylamino)-5-nitropyrimidine was suspended in 400 ml of acetic acid, to which 20 g of iron powder was then added. The mixture was stirred at a temperature of 30-40° C. for 3 hours. After completion of the reaction, the reaction product was filtered through nitrocellulose, followed by washing. The filtrate was concentrated under reduced pressure. To the resulting concentrate, 100 ml of triethylorthoformate and 10 ml of concentrated hydrochloric acid were added, and the mixture was stirred under reflux for 9 hours at a temperature of 80-90° C. After completion of the reaction, the crude product was cooled to room temperature, and 200 ml of ethylether was added thereto. The resulting crystal was filtered, washed and dried, thereby giving 10.75 g (60% yield) of yellowish brown-colored 2-amino-9-(2-hydroxyethyl)purine.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH2:13]([O:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(#N)C>[ClH:1].[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([NH:25][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:26][CH:27]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Clc1ncnc2ccc(I)cc12
Reactant: Nc1ccc(OCc2ccccc2)cc1
Solvent: CC#N
Product: Cl
Product: Ic1ccc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2c1
Yield: 97.4 %

Procedure:
4-Chloro-6-iodoquinazoline (8 g) was treated with 4-benzyloxyaniline (5.5 g) in acetonitrile (500 ml) at reflux under N2 for 18 hours. Subsequent cooling and filtration gave the title compound (13.13 g); δH [2H6]-DMSO 11.45 (1H, b, NH), 9.22 (1H, s, 5-H), 8.89 (1H, s, 2-H), 8.36 (1H, d, 7-H), 7.69 (1H, d, 8-H), 7.63 (2H, d, 2′-H, 6′-H), 7.52-7.29 (5H, m, Ph-H), 7.14 (2H, d, 3′-H, 5′-H), 5.18 (2H, s, CH2); m/z (M+1)+454.
Reaction SMILES: O(CCN(C)C)CCN(C)C.[CH2:12]([Mg]Br)[CH3:13].[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[Cl:26])[C:20](Cl)=[O:21]>C1COCC1>[Cl:16][C:17]1[CH:18]=[C:19]([C:20](=[O:21])[CH2:12][CH3:13])[CH:23]=[CH:24][C:25]=1[Cl:26]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CC[Mg]Br
Agent: CN(C)CCOCCN(C)C
Solvent: C1CCOC1
Product: CCC(=O)c1ccc(Cl)c(Cl)c1
Temperature: -60 °C
Reaction time: 0.17 h
Yield: 61.9 %

Procedure:
To a solution of THF (100 mL) and 2,2′-oxybis(N,N-dimethylethanamine) (9.18 g, 57.3 mmol) cooled to 0° C. was added ethylmagnesium bromide (19.1 mL, 57.3 mmol, 3N in THF) and stirred for 10 min. The solution was cooled to −60° C. and a solution of 3,4-dichlorobenzoyl chloride (10.0 g, 47.7 mmol) in THF (20 mL) was added dropwise over 10 min. The reaction was stirred for 1 h, quenched by adding sat'd. NH4Cl sat. and extracted with EtOAc. The combined extracts were dried with (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography (Biotage 40M) eluting an EtOAc/hexane gradient (2 to 10% EtOAc) to afford 6.0 g (85%, 53% pure) 1-(3,4-dichlorophenyl)propan-1-one (156) as clear oil which was used without additional purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][C:10]2[C:11]([NH2:16])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.N1C=CC=CC=1.[CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][C:26]=1[C:35](Cl)=[O:36].Cl>C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:35]([C:26]3[CH:27]=[CH:28][C:29]4[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:25]=3)=[O:36])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:17][CH:18]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2N)cc1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)c2ccc3ccccc3c2)cc1
Reaction time: 20 h
Yield: 64.4 %

Procedure:
A solution of N1-(4-methoxybenzoyl)-1,2-benzenediamine (200 mg, 0.826 mmol) and pyridine (0.25 mL) in chloroform (5 mL) was treated with 2-naphthoyl chloride (158 mg, 0.826 mmol). After 20 h, the mixture was poured into a mixture of ethyl acetate and 1 N aqueous hydrochloric acid. The organic layer was washed with water, saturated sodium chloride solution, and dried (potassium carbonate), filtered, and concentrated in vacuo. Recrystallization from hexanes/ethyl acetate yielded 211 mg (65%) of the title compound.
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]([CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:10]=1.[Cl-:20].[NH4+:21]>CO>[ClH:20].[C:14]1([CH2:13][CH2:12][CH2:11][CH:9]2[NH:10][C:3](=[NH:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC1=NC(CCCc2ccccc2)CCCCC1
Reactant: [NH4+]
Reactant: [Cl-]
Solvent: CO
Product: Cl
Product: N=C1CCCCCC(CCCc2ccccc2)N1

Procedure:
The title product of Example 72 in MeOH is reacted with ammonium chloride by the method of Example 5 to generate the title material.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([NH:11][S:12]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:14])=[O:13])([CH3:10])([CH3:9])[CH3:8].[C:22](OCC)(=[O:28])[C:23](OCC)=[O:24].Cl>C1COCC1>[C:7]([N:11]1[C:23](=[O:24])[C:22]([OH:28])=[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:12]1(=[O:14])=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)NS(=O)(=O)Cc1ccccc1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)N1C(=O)C(O)=C(c2ccccc2)S1(=O)=O
Temperature: 150 °C
Yield: 471.3 %

Procedure:
Potassium tert-butoxide (0.845 g, 10.56 mmol) was added to a solution of N-(tert-butyl)-1-phenylmethanesulfonamide (1.2 g, 5.28 mmol) and diethyl oxalate (0.85 mL, 6.33 mmol) in THF (8 mL) and the mixture was heated at 150° C. for 15 mins in a microwave reactor. The reaction mixture was acidified with 1M HCl, the THF was evaporated and the residue was Example tracted with DCM. Evaporation and trituration of the residue with petroleum ether gave the title compound (7 g, 63%) as a solid; 1H NMR (500 MHz, CDCl3): δ 7.44-7.32 (m, 5H), 3.90 (br s, 1H), 1.36 (s, 9H); Mass Spectrum: M−H+ 280
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][C:48]([F:51])([F:50])[F:49])=[CH:43][CH:42]=3)[CH:34]=2)([O:31]C)[O:11][C:10]1([CH2:54]O)[CH2:52][OH:53])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@:12]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:42]=[CH:43][C:44]([O:47][C:48]([F:50])([F:51])[F:49])=[CH:45][CH:46]=4)[CH:34]=3)[O:11][C@@:10]1([CH2:52][OH:53])[CH2:54][O:31]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OC(F)(F)F)cc3)c2)OC(CO)(CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OC(F)(F)F)cc4)c3)(O1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Reaction time: 1.5 h
Yield: 76.1 %

Procedure:
[(3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(trifluoromethoxy)phenyl]methyl-]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol 6q (400 mg, 0.51 mmol) was dissolved in 10 mL dichloromethane, followed by addition of trifluoroacetic acid (0.15 mL, 2.05 mmol). The reaction mixture was stirred for 1.5 hours. Thereafter, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system B to obtain the title compound [(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[[4-(trifluoromethoxy)phenyl]methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]methanol 6r (290 mg, white solid), yield: 76.1%. 1H NMR (400 MHz, DMSO-d6): δ 7.59 (dd, 1H), 7.50-7.44 (m, 2H), 7.34-7.15 (m, 17H), 6.83 (d, 2H), 5.22 (t, 1H), 4.81-4.74 (m, 4H), 4.32 (d, 1H), 4.11-4.08 (m, 3H), 4.07-4.04 (m, 1H), 3.93 (d, 1H), 3.87 (t, 1H), 3.79-3.71 (m, 3H), 3.59 (dd, 1H), 3.52 (d, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C@H:8]([CH2:13][N:14]([C:27]1[CH:32]=[CH:31][C:30](Br)=[CH:29][CH:28]=1)[C:15]([C@@H:17]1[CH2:19][C@H:18]1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=1)=[O:16])[C@@H:9]([CH3:12])[CH2:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].B(O)O.[C:38]([O-:41])([O-])=O.[K+].[K+].[CH3:44][C:45]#N>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[C:1]([O:5][C:6](=[O:34])[NH:7][C@H:8]([CH2:13][N:14]([C:15]([C@@H:17]1[CH2:19][C@H:18]1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=1)=[O:16])[C:27]1[CH:32]=[CH:31][C:30]([C:9]2[CH:10]=[CH:11][C:45]([CH2:44][O:41][CH3:38])=[CH:13][CH:8]=2)=[CH:29][CH:28]=1)[C@@H:9]([CH3:12])[CH2:10][CH3:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC#N
Reactant: CC[C@H](C)[C@@H](CN(C(=O)[C@@H]1C[C@H]1c1ccc(F)cn1)c1ccc(Br)cc1)NC(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: OBO
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC[C@H](C)[C@@H](CN(C(=O)[C@@H]1C[C@H]1c1ccc(F)cn1)c1ccc(-c2ccc(COC)cc2)cc1)NC(=O)OC(C)(C)C
Yield: 72 %

Procedure:
To 80 mg (0.15 mmol) of the aryl bromide, [(1S,2S)-1-({(4-bromo-phenyl)-[(trans)-2-(5-fluoro-pyridin-2-yl)-cyclopropanecarbonyl]-amino}-methyl)-2-methyl-butyl]-carbamic acid tert-butyl ester, in a microwave vial was added boronic acid (26 mg, 0.158 mmol), K2CO3 (41.5 mg, 0.301 mmol), PdCl2(PPh3)2 (5.3 mg, 0.008 mmol), 6 mL of MeCN, and 1 mL of water. The resulting mixture was microwaved at 140° C. for 30 min. It was then diluted with EtOAc, washed with water, brine and concentrated, and then purified in the neutral PREP HPLC to give 62 mg (72%) of the desired product.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[C:21]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=O)#[N:22].C([O-])(=O)C.[NH4+]>>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:26]([C:25]3[CH:28]=[CH:29][CH:30]=[C:23]([C:21]#[N:22])[CH:24]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: N#Cc1cccc(C=O)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: N#Cc1cccc(-c2nc3c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)c(Cl)cnc3[nH]2)c1
Yield: 70.3 %

Procedure:
In a similar fashion to Compound CXXV, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (75.00 mg, 0.2553 mmol), 3-cyanobenzaldehyde (36.8 mg, 0.281 mmol), and Ammonium acetate (39.4 mg, 0.511 mmol) were reacted to produce 72.70 mg (63%) of the title compound. (300 MHz, DMSO-d6) 13.44 (s, 1H), 8.49 (s, 1H), 8.43 (d, J=8 Hz, 1H), 7.99 (s, 1H), 7.95 (d, J=8 Hz, 1H), 7.77 (m, 2H), 7.35 (d, J=9 Hz, 1H) 7.25 (s, 1H), 6.41 (m, 2H), 5.14 (t, J=17 Hz, 8.5 Hz, 1H), 2.91 (s, 1H), 2.81 (s, 1H), 2.63 (d, J=8 Hz, 1H), 2.23 (d, J=8 Hz, 1H), 1.39 (d, J=8 Hz, 1H). MS=405 (M+H), HPLC: 2.39 min. (G Method)
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=[O:7].[CH3:13]I>>[Br:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([O:8][CH3:13])=[O:7]
Reactant: CI
Reactant: O=C(O)C=Cc1ccccc1Br
Product: COC(=O)C=Cc1ccccc1Br

Procedure:
Esterification of 2-bromocinnamic acid (10.0 g) with methyl iodide (9.4 g) as described in Example 1 gave the title compound as an oil which was purified by chromatography on silica eluting with chloroform in quantitative yield. υmax (film) 1725, 1640, 1470, 1440 cm-1, δ(CDCl3) 3.79 (3H, s, CH3), 6.30 (1H, d, J 16 Hz, C=CHCO2), 7.19 (2H, complex m), 7.50 (2H, complex m), 7.97 (1H, d, J 16 Hz, ArCH=C).