Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[N:13]=[C:12]([CH2:14][OH:15])[CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:16]/[C:17](/[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)=[CH:18]\[C@H:19]1[C@H:21]([C:22](Cl)=[O:23])[C:20]1([CH3:26])[CH3:25].N1C=CC=CC=1.O>C1(C)C=CC=CC=1>[Cl:16]/[C:17](/[C:27]1[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=1)=[CH:18]\[C@H:19]1[C@H:21]([C:22]([O:15][CH2:14][C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[N:13]=2)=[O:23])[C:20]1([CH3:26])[CH3:25]
Reactant: CC1(C)[C@@H](/C=C(\Cl)c2ccc(Cl)cc2)[C@@H]1C(=O)Cl
Reactant: OCc1cccc(Oc2ccccc2)n1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: CC1(C)[C@@H](/C=C(\Cl)c2ccc(Cl)cc2)[C@@H]1C(=O)OCc1cccc(Oc2ccccc2)n1
Yield: 91.8 %

Procedure:
4.02 g (0.02 mol) of (6-phenoxy-2-pyridinyl)-methanol and 6.07 g (0.02 mol) of (±)-trans-Z-3-(2-chloro-2-(4-chloro-phenyl)-vinyl)-2,2-dimethyl-1-cyclopropanecarboxylic acid-chloride were dissolved in 100 ml of anhydrous toluene, and 2 g of pyridine, dissolved in 10 ml of anhydrous toluene, were added dropwise to the solution at 20°-25° C., while stirring. The mixture was then stirred for a further 3 hours at 25° C. The reaction mixture was poured into 150 ml of water, and the organic phase was separated off and again washed with 100 ml of water. The toluene phase was then dried over sodium sulphate and the solvent was distilled off in a water jet vacuum. The last solvent residues were removed by incipient distillation for a short time at a bath temperature of 60° C./1 mm Hg. 8.6 g (92% of theory) of (6-phenoxy-2-pyridinyl)-methyl (±)-trans-Z-3-(2-chloro-2-(4-chlorophenyl)-vinyl)-2,2-dimethyl-1-cyclopropanecarboxylate were obtained as a yellow viscous oil. The structure was established by the 1H-NMR spectrum.
Reaction SMILES: [Cl-].[C:2]([C:5]1[CH:10]=[CH:9][N+:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])[NH2:3].[H][H]>CO.[Pd]>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([N:8]2[CH2:9][CH2:10][CH:5]([C:2]([NH2:3])=[O:4])[CH2:6][CH2:7]2)=[CH:16][CH:15]=1
Reactant: [H][H]
Reactant: COc1ccc(-[n+]2ccc(C(N)=O)cc2)cc1
Agent: [Pd]
Agent: [Cl-]
Solvent: CO
Product: COc1ccc(N2CCC(C(N)=O)CC2)cc1
Yield: 51.4 %

Procedure:
A suspension of 4-carbamoyl-1-(4-methoxyphenyl)-pyridinium chloride (22.0 g) in methanol (250 ml) was hydrogenated at ambient temperature and pressure in the presence of 10% palladium-on-carbon catalyst (1.0 g) for 2 days. Further catalyst (0.75 g) was added, and when no more hydrogen was taken up, the catalyst was removed by filtration. The filtrate was basified by the addition of an excess of triethylamine and the solvent removed in vacua. The residue was partitioned between water and a 19:1 mixture of chloroform and methanol. The solvent was removed in vacuo from the organic layer and the residue dried in vacuo over phosphorus pentoxide to give 1-(4-methoxyphenyl)piperidine-4-carboxamide as a white solid (10 g), m.p. 178°-181° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][O:13][C:14]2[CH:21]=[CH:20][CH:19]=[C:18](F)[C:15]=2[C:16]#[N:17])[CH2:8][CH2:7]1.C(=O)(O)O.[NH2:30][C:31]([NH2:33])=[NH:32].O>CC(N(C)C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][O:13][C:14]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:15]=2[C:16]([NH2:17])=[N:32][C:31]([NH2:33])=[N:30]3)[CH2:8][CH2:7]1
Reactant: N#Cc1c(F)cccc1OCC1CCC(Cc2cccc(Cl)c2)CC1
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: CC(=O)N(C)C
Solvent: O
Product: Nc1nc(N)c2c(OCC3CCC(Cc4cccc(Cl)c4)CC3)cccc2n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 76 %

Procedure:
2-[4-(3-Chlorobenzyl)cyclohexylmethoxy]-6-fluorobenzonitrile (150 mg; 0.42 mmol) was heated to 135° C. in the presence of guanidine carbonate (76 mg; 0.42 mmol) in 1.5 mLs of dimethylacetamide. After 6 hours, mixture was cooled to room temperature and 2 mLs of water added. After 30 minutes solids were collected by filtration. Solids were purified by trituration using a 3:1 mixture of ethyl alcohol and water. Solids collected by filtration to give title compound as a white solid. (128 mgs; 76% yield).
Reaction SMILES: [OH:1]O.[CH2:3]([S:6][C:7]1[N:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1)[CH:4]=[CH2:5]>C(O)(=O)C>[CH2:3]([S:6]([C:7]1[N:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1)=[O:1])[CH:4]=[CH2:5]
Reactant: OO
Reactant: C=CCSc1ncc(Cl)cn1
Solvent: CC(=O)O
Product: C=CCS(=O)c1ncc(Cl)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78 %

Procedure:
30% Hydrogen peroxide (50 mmol) was added to a solution of 2-allylthio-5-chloropyrimidine (10 mmol) in acetic acid (15 ml) and the mixture stirred at room temperature for 24 h. The resultant solution was concentrated at reduced pressure to a small volume, water (20 ml) added and the mixture extracted with chloroform, the chloroform solution washed with potassium carbonate solution, the dried (MgSO4) solution evaporated and the residue crystallized from chloroform: pet. ether; yield 78%, m.p. 82° C. 1H NMR (CDCl3): δ3.7-4.0 (CH2, 5.0-6.2 (3H, CH2 =CH), 8.86 (H-4, H-6).
Reaction SMILES: [OH:1][CH:2]([C:5]1[C:26]([CH3:27])=[CH:25][C:8]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2/[C:17](=[CH:22]\[O:23][CH3:24])/[C:18]([O:20][CH3:21])=[O:19])=[C:7]([CH3:28])[CH:6]=1)[CH2:3][CH3:4].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl>[CH3:28][C:7]1[CH:6]=[C:5]([C:2](=[O:1])[CH2:3][CH3:4])[C:26]([CH3:27])=[CH:25][C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1/[C:17](=[CH:22]\[O:23][CH3:24])/[C:18]([O:20][CH3:21])=[O:19]
Reactant: CCC(O)c1cc(C)c(OCc2ccccc2/C(=C\OC)C(=O)OC)cc1C
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCC(=O)c1cc(C)c(OCc2ccccc2/C(=C\OC)C(=O)OC)cc1C
Yield: 73.7 %

Procedure:
A solution of 0.15 g (0.39 mmol) of (E)-methyl 2-(2-((4-(1-hydroxypropyl)-2,5-dimethylphenoxy)methyl)phenyl)-3-methoxyacrylate obtained in Step 2 in 10 mL of dichloromethane was reacted with 0.29 g (0.78 mmol) of pyridinium dichromate at room temperature for 2 hours with stirring, followed by filtration through celite. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in a vacuum to afford (E)-methyl 2-(2-((2,5-dimethyl-4-propionylphenoxy)methyl)phenyl)-3-methoxyacrylate as a brown oil (0.11 g, yield: 71%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@@H:11]1[CH2:14][C@H:13]([O:15][C:16]2[C:21]([C:22]3[CH2:27][CH2:26][N:25]([C:28](=[O:30])[CH3:29])[CH2:24][CH:23]=3)=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:12]1.CC1C=C2N=C3C(=NC(NC3=O)=O)N(C[C@H](O)[C@H](O)[C@H](O)CO)C2=CC=1C>C(O)C.[OH-].[Pd+2].[OH-].[Pd]>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@@H:11]1[CH2:12][C@H:13]([O:15][C:16]2[C:21]([CH:22]3[CH2:23][CH2:24][N:25]([C:28](=[O:30])[CH3:29])[CH2:26][CH2:27]3)=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:14]1
Reactant: CC(=O)N1CC=C(c2cccnc2O[C@H]2C[C@@H](Nc3nc4ccccc4s3)C2)CC1
Agent: [Pd+2]
Agent: [Pd]
Agent: Cc1cc2nc3c(=O)[nH]c(=O)nc-3n(C[C@H](O)[C@H](O)[C@H](O)CO)c2cc1C
Solvent: CCO
Product: CC(=O)N1CCC(c2cccnc2O[C@H]2C[C@@H](Nc3nc4ccccc4s3)C2)CC1

Procedure:
A solution of 1-(4-(2-(cis-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone (0.12 g, 0.28 mmol) in ethanol (2 mL) was added palladium hydroxide, 20 wt. % Pd (dry basis) on carbon, wet, Degussa type E101 NE/W (0.039 g, 0.056 mmol) and hydrogenated (double-walled balloon pressure) at 50° C. for 3 days. The cooled reaction was filtered via a pad of Celite®, and the filtrate was concentrated in vacuo and purified via flash column chromatography (20% EtOAc/Hexanes to 100% EtOAc) to afford 1-(4-(2-(cis-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyridin-3-yl)piperidin-1-yl)ethanone as a white solid. [M+1]=423.0. IC50 (uM): 0.001566.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[O:11][C:12]2[C:18]([C:19]([O:21]C)=O)=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1.O.[NH4+:24]>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[O:11][C:12]2[C:18]([C:19]([NH2:24])=[O:21])=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1
Reactant: COC(=O)c1cccc2nc(-c3cc4ccccc4[nH]3)oc12
Reactant: [NH4+]
Solvent: O
Product: NC(=O)c1cccc2nc(-c3cc4ccccc4[nH]3)oc12
Yield: 51 %

Procedure:
Methyl 2-(1H-indol-2-yl)benzo[d]oxazole-7-carboxylate (70 mg, 0.24 mmol) in ammonium water (10 mL) was stirred at 35° C. overnight. Then the suspension was filtered, and the solid was purified by column chromatography (silica gel, petroleum ether:ethyl acetate 1:1) to obtain 2-(1H-indol-2-yl)benzo[d]oxazole-7-carboxamide as a solid (32 mg, yield 51%). 1H-NMR (400 MHz, DMSO-d6) δ 6.54 (s, 1H), 7.11-7.13 (t, J=8 Hz, 1H), 7.26-7.30 (t, J=8 Hz, 1H), 7.48-7.54 (dd, J1=16 Hz, J2=8 Hz, 2H), 7.70-7.72 (d, J=8 Hz, 1H), 7.84-7.86 (d, 1H), 7.88 (brs, 1H), 7.93-7.95 (d, J=8 Hz, 1H), 8.01 (brs, 1H), 12.47 (brs, 1H); LC-MS (ESI) m/z 278 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[N:5]=[C:4]([SH:9])[N:3]=1.[CH2:10](I)[CH2:11][CH2:12][CH2:13][CH3:14]>[OH-].[Na+].C(O)C>[CH2:10]([S:9][C:4]1[NH:3][C:2](=[O:1])[CH2:7][C:6](=[O:8])[N:5]=1)[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCI
Reactant: Oc1cc(O)nc(S)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCSC1=NC(=O)CC(=O)N1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of 4,6-dihydroxy-2-mercaptopyrimidine (14.4 g) in 2N sodium hydroxide solution (100 ml) was added pentyl iodide (15.6 ml) in ethanol (25 ml) and the resulting reaction mixture stirred at room temperature for four days. The ethanol was removed at reduced pressure and N,N-dimethylformamide (80 ml) and pentyl iodide (1.56 ml) added then the reaction mixture stirred for an additional 16 hours. The solution was made acidic by addition of 2N HCl solution and the aqueous layer decanted. The remaining gum was dissolved in methanol and evaporated to dryness then azeotroped with toluene (×2). The solid was triturated with ether, filtered and dried to give the subtitle compound as a white solid (11.9 g).
Reaction SMILES: FC(F)(F)OC1C=C2C(=CC=1)C(=O)CC2.[F:16][C:17]([F:32])([F:31])[O:18][C:19]1[CH:20]=[C:21]([CH2:25][CH2:26][C:27]([O:29]C)=[O:28])[CH:22]=[CH:23][CH:24]=1.[OH-].[K+]>C(O)C.O>[F:16][C:17]([F:31])([F:32])[O:18][C:19]1[CH:20]=[C:21]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)CCc1cccc(OC(F)(F)F)c1
Agent: O=C1CCc2cc(OC(F)(F)F)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCc1cccc(OC(F)(F)F)c1

Procedure:
5-Trifluoromethoxyindan-1-one: 9.37 g of methyl 3-(3-trifluoromethoxyphenyl)propionate are dissolved in 50 ml of ethanol with 25 ml of water. 3.74 g of potassium hydroxide are added and the mixture is refluxed for 45 minutes. The cooled solution is concentrated, the residue is treated with 25 ml of water, and conc. hydrochloric acid is added with stirring until the pH is 1. The aqueous reaction mixture is extracted twice by shaking with 75 ml of dichloromethane in each case. The organic phase is washed with water, dried over magnesium sulfate, concentrated and dried in vacuo. 3-(3-trifluoromethoxy-phenyl) propionic acid is obtained as a colorless oil. 6.24 g of the acid are dissolved in 40 ml of toluene, and the solution is treated with 2.1 ml of thionyl chloride and refluxed for 1 hour. The cooled reaction mixture is concentrated, and the residue is taken up in 5 ml of toluene and concentrated again. 3-(3-Trifluoromethoxyphenyl)propionyl chloride is obtained, which is dissolved in 30 ml of dichloromethane without further purification and added dropwise at 0-5° C. with stirring in the course of 15 minutes to a suspension of 5.49 g of anhydrous aluminum trichloride in 40 ml of dichloromethane. The reaction mixture is stirred at 0° C. for one hour and then added to 40 ml of ice water. The organic phase is separated off and the aqueous phase is again extracted by shaking with 40 ml of dichloromethane. The combined organic phases are washed with 40 ml of satd. sodium hydrogencarbonate solution and water, dried over magnesium sulfate, concentrated in vacuo and, for purification, purified by chromatography on silica gel using toluene/ethyl acetate 20/1. 5-Trifluoromethoxyindan-1-one is obtained as a pale yellow oil.
Reaction SMILES: [C:1]([N:9]1[C:13]([CH3:15])([CH3:14])[CH2:12][N:11](CC2C=CC(OC)=CC=2)[C:10]1=[O:25])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)S(O)(=O)=O.C(=O)([O-])O.[Na+]>ClCCl>[C:1]([N:9]1[C:13]([CH3:14])([CH3:15])[CH2:12][NH:11][C:10]1=[O:25])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CN2CC(C)(C)N(C(=O)c3ccccc3)C2=O)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)CNC(=O)N1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.3 %

Procedure:
3-Benzoyl-1-(4-methoxybenzyl)-4,4-dimethylimidazolidin-2-one (500 mg) described in Preparation Example 57 was dissolved in dichloromethane (5 mL), trifluoromethanesulfonic acid (0.39 mL) was added, and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added 5% aqueous sodium hydrogen carbonate solution, the solvent was evaporated, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (146 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([C:21]3[N:30]([CH3:31])[C:29](=[O:32])[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)[CH3:20])[CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C=O.[CH3:35]N(C=O)C.C([BH3-])#N>CC#N>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]2[CH2:13][CH2:14][CH:15]([N:18]([CH3:35])[CH:19]([C:21]3[N:30]([CH3:31])[C:29](=[O:32])[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)[CH3:20])[CH2:16][CH2:17]2)(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(S(=O)(=O)N2CCC(NC(C)c3nc4ccccc4c(=O)n3C)CC2)cc1
Agent: C=O
Agent: [BH3-]C#N
Solvent: CC#N
Product: COc1ccc(S(=O)(=O)N2CCC(N(C)C(C)c3nc4ccccc4c(=O)n3C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-{1-[1-(4-methoxy-benzenesulfonyl)-piperidin-4-ylamino]-ethyl}-3-methyl-3H-quinazolin-4-one (183 mg, 0.4 mmol), formaldehyde (39 μL, 0.48 mmol, 37% wt. solution in water) and DMF (1 mL) was added MP-Cyanoborohydride (300 mg, 2-3 mmol/g) and the reaction was stirred overnight at room temperature. The reaction mixture was then filtered and purified by HPLC to yield the product. HPLC ret. time 2.41 min, 10-99% CH3CN, 5 min run; 1H NMR (400 MHz, CDCl3) δ 8.28 (d, J=8.0 Hz, 1H), 7.93 (t, J=7.2 Hz, 1H), 7.68 (m, 4H), 7.03 (d, J=8.6 Hz, 2H), 4.93 (m, 1H), 3.98 (s, 1H), 3.89 (s, 3H), 3.69 (s, 3H), 3.10 (s, 3H), 2.58 (m, 2H), 2.21 (m, 2H), 1.78 (d, J=6.6 Hz, 3H), 1.31 (m, 4H); ESI-MS m/z 471.3 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:16]=1.B([O-])([O-])O[C:19]1[CH:23]=[CH:22][S:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O>[S:21]1[CH:22]=[CH:23][C:19]([C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=3[CH:16]=2)=[CH:20]1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2OCC1
Reactant: [O-]B([O-])Oc1ccsc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)C1=Cc2cc(-c3ccsc3)ccc2OCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.2 %

Procedure:
In toluene/ethanol/water (10/1/1) (12 ml) was dissolved methyl 7-bromo-2,3-dihydro-1-benzoxepine-4-carboxylate (700 mg), and to the mixture were added 3-thienyl borate (422 mg) and potassium carbonate (0.98 g). The mixture was stirred at room temperature for 30 minutes, and to the mixture was added tetrakistriphenylphosphine palladium (136 mg). The mixture was stirred at 100° C. for 13 hours and cooled to room temperature, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was removed, and the resulting residue was purified with silica gel column chromatography (hexane/acetone=3/1) to give methyl 7-(3-thienyl)-2,3-dihydro-1-benzoxepine-4-carboxylate (610 mg).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=1)[N:15]([CH3:19])[C:16](=[O:18])[CH3:17].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH3:19][N:15]([C:14]1[CH:13]=[C:12]([NH:11][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:22]=[CH:21][CH:20]=1)[C:16](=[O:18])[CH3:17]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CC(=O)N(C)c1cccc(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)N(C)c1cccc(Nc2ncccc2[N+](=O)[O-])c1
Yield: 24.6 %

Procedure:
A mixture of 2-chloro-3-nitropyridine (1.96 g) and 3′-amino-N-methylacetanilide (2.03 g) in toluene (20 ml) was refluxed for 7 hours. The mixture was poured into a mixture of ethyl acetate and aqueous sodium bicarbonate solution. The organic phase was separated, washed with brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give 2-[3-(N-methylacetamido)phenylamino]-3-nitropyridine (872 mg).
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:42][C@@H:43]1[C:50](=[O:51])[N:49]2[CH2:52][CH2:53][CH2:54][CH2:55][C@@H:48]2[CH2:47][CH2:46][CH2:45][CH2:44]1>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9](=[O:10])[NH:42][C@@H:43]1[C:50](=[O:51])[N:49]2[CH2:52][CH2:53][CH2:54][CH2:55][C@@H:48]2[CH2:47][CH2:46][CH2:45][CH2:44]1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Reactant: N[C@H]1CCCC[C@H]2CCCCN2C1=O
Agent: Cl
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCCC[C@H]4CCCCN4C3=O)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-oxo-6-((7S,11aS)-6-oxodecahydro-1H-pyrido[1,2-a]azocin-7-ylamino)hexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (11 mg, 0.019 mmol) and Intermediate 56 (5.0 mg, 0.021 mmol) to give a white solid (11 mg, 80% yield). Anal. Calcd. for C42H56N4O6S m/z 744.4. found: 745.3 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.28-7.08 (11H, m), 7.05 (1H, d, J=7.1 Hz), 5.33 (1H, t, J=4.7 Hz), 5.15-5.09 (1H, m), 5.04-4.95 (1H, m), 4.82-4.73 (1H, m), 4.39 (1H, d, J=13.2 Hz), 4.16 (1H, d, J=12.6 Hz), 3.68 (3H, s), 3.16 (1H, t, J=11.5 Hz), 2.87-2.69 (5H, m), 2.52 (1H, td, J=13.2, 2.7 Hz), 2.46-2.34 (3H, m), 2.15 (1H, t, J=13.5 Hz), 2.07-1.99 (2H, m), 1.94-1.77 (2H, m), 1.76-1.37 (16H, m), 1.36-1.19 (2H, m), 1.08-0.94 (1H, m), 0.89-0.76 (1H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[C:10]([C:12]1[S:16][C:15]([C:17]([OH:19])=[O:18])=[CH:14][CH:13]=1)=O.[NH2:20][C:21]([NH2:23])=[O:22].CC(C)([O-])C.[Na+].Cl>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:23][C:21](=[O:22])[N:20]=[C:10]([C:12]2[S:16][C:15]([C:17]([OH:19])=[O:18])=[CH:14][CH:13]=2)[CH:9]=1
Reactant: NC(N)=O
Reactant: O=C(O)c1ccc(C(=O)/C=C/c2ccccc2Cl)s1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(O)c1ccc(-c2cc(-c3ccccc3Cl)[nH]c(=O)n2)s1
Temperature: 80 °C
Reaction time: 8 h
Yield: 65.4 %

Procedure:
(E)-5-(3-(2-chlorophenyl)acryloyl)thiophene-2-carboxylic acid (1.0 g, 3.4 mmol), urea (1.0 g, 16.6 mmol), and sodium t-butoxide (1.6 g, 16.6 mmol) were suspended in 17 mL of 1,4-dioxane. The reaction mixture was stirred overnight at 80° C. After cooling, the suspension was neutralized by the addition of 1M HCl. The precipitate was filtered, washed with water and air dried to give 740 mg of product. 1H NMR (400 MHz, d6-DMSO): δ 7.89 (s, 1H), 7.63 (m, 2H), 7.56 (t, 1H), 7.50 (t, 1H), 7.24 (d, 1H), 7.07 (s, 1H); MS (EI) for C15H9ClN2O3S: 332 (MH+).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([Cl:15])=[N:12][O:13][CH3:14])(=[O:4])=[O:3].C1([O:22][C:23](=O)[NH:24][C:25]2[N:30]=[C:29]([O:31][CH3:32])[CH:28]=[C:27]([CH3:33])[N:26]=2)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C(#N)C.O>[CH3:32][O:31][C:29]1[CH:28]=[C:27]([CH3:33])[N:26]=[C:25]([NH:24][C:23]([NH:1][S:2]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:11]([Cl:15])=[N:12][O:13][CH3:14])(=[O:3])=[O:4])=[O:22])[N:30]=1
Reactant: COc1cc(C)nc(NC(=O)Oc2ccccc2)n1
Reactant: CON=C(Cl)c1ccccc1S(N)(=O)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CC#N
Product: CON=C(Cl)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)cc(OC)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.6 %

Procedure:
To a suspension of 0.4 g of the product of Example 4 and 0.46 g of phenyl(4-methoxy-6-methylpyrimidin-2-yl)carbamate in 10 ml of dry acetonitrile was added 0.25 g of DBU. The suspension was stirred for about two hours at room temperature, then diluted with excess water and filtered. The filtrate was acidified with concentrated hydrochloric acid to yield a precipitate. After filtration, the residue was washed with excess water and suction-dried to yield 0.35 g of the subject compound, m.p. 178° to 179° C.;
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH2:9]O)=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2].S(Cl)([Cl:13])=O>C(Cl)Cl>[CH2:1]([C:3]1[C:8]([CH2:9][Cl:13])=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCc1ncccc1CO
Solvent: ClCCl
Product: CCc1ncccc1CCl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
The 2-ethyl-3-hydroxymethylpyridine (2.3 g, 16.8 mmol) was dissolved in CH2Cl2 (100 mL) and cooled under nitrogen to 0° C. and thionyl chloride (7.0 mL) was slowly added and the reaction was stirred for 3 hours. The solvent was removed under reduced pressure and the residue was partitioned between CH2Cl2 (100 mL) and saturated aqueous sodium bicarbonate (100 mL). The organic layer was dried with MgSO4, filtered, and the solvent removed under reduced pressure to give the desired 2-ethyl-3-chloromethylpyridine.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[C:40]([F:48])[CH:39]=2)[C:35](O)=[O:36])[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=1>C(Cl)Cl>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:46])([F:45])[F:47])=[C:40]([F:48])[CH:39]=2)[C:35]([NH:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=2)=[O:36])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: Nc1ccccn1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(C(F)(F)F)c(F)c1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1ccccn1)C(CC1CCCC1)c1ccc(C(F)(F)F)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45.4 %

Procedure:
A solution of triphenylphosphine (312 mg, 1.19 mmol) in methylene chloride (5 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (212 mg, 1.19 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with 3-cyclopentyl-2-(3-fluoro-4-trifluoromethyl-phenyl)-propionic acid (prepared as in Example 70, 300 mg, 0.99 mmol). The resulting reaction mixture was stirred at 0° C. for 15 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-aminopyridine (205 mg, 2.18 mmol). The resulting reaction mixture was stirred at 25° C. for 3 d. The crude reaction mixture was then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 2/1 hexanes/ethyl acetate) to afford 3-cyclopentyl-2-(3-fluoro-4-trifluoromethyl-phenyl)-N-pyridin-2-yl-propionamide (171 mg, 45%) as a pale yellow foam: mp 40-44° C. (foam to gel); EI-HRMS m/e calcd for C20H20F4N2O (M+) 380.1512, found 380.1519.