Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[C:6](=[O:10])[NH:7][CH2:8][CH2:9][C:4]=2[CH:3]=[CH:2]1.I[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1[CH3:18].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:18][C:17]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[N:7]1[CH2:8][CH2:9][C:4]2[CH:3]=[CH:2][S:1][C:5]=2[C:6]1=[O:10]
Reactant: Cc1ccncc1I
Reactant: O=C1NCCc2ccsc21
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCc2ccsc2C1=O
Yield: 50.6 %

Procedure:
Using analogous reaction conditions as described in example 1, 5,6-dihydro-4H-thieno[2,3-c]pyridin-7-one (I-5d: 130 mg, 0.849 mmol) was reacted with 3-iodo-4-methyl-pyridine (185 mg, 0.849 mmol), 1,4-dioxane (5 mL), copper iodide (16 mg, 0.0849 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (0.04 mL, 0.254 mmol) and potassium phosphate (538 mg, 2.54 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% methanol in CHCl3) afforded 105 mg of the product (51.4% yield).
Reaction SMILES: [CH2:1]([C:3]1([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH3:10])[C:4]1=O)[CH3:2].[H-].[Li+].[Al+3].[H-].[H-].[H-].O>O1CCCC1>[CH2:1]([C:3]1([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH3:10])[CH2:4]1)[CH3:2]
Reactant: CCC1(c2cccc(O)c2)CCCCN(C)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCC1(c2cccc(O)c2)CCCCN(C)C1
Yield: 64.3 %

Procedure:
A solution of 3-ethylhexahydro-3-(3-hydroxyphenyl)-1-methyl-2H-azepin-2-one (1.5 g) in dry tetrahydrofuran was added to a stirred suspension of aluminium lithium hydride (0.48 g) and heated under reflux for 5 hours. The reaction mixture was cooled and decomposed by the addition of water and the precipitate filtered. The precipitate was washed with tetrahydrofuran and the combined filtrate and washings evaporated to a solid. The solid was dissolved in water and ammonium chloride added. The precipitated oil was extracted with dichloromethane, dried over anhydrous magnesium sulphate and evaporated to leave a solid which was recrystallised from acetonitrile to give 0.91 g of the title compound, m.p. 127.5°-133° C., identical with material prepared by an alternative route described in U.K. specification No. 1,285,025.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[N+:12]([O-])([O-:14])=[O:13].[K+].O>OS(O)(=O)=O>[F:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([N+:12]([O-:14])=[O:13])=[C:4]([CH:3]=1)[C:5]([OH:7])=[O:6]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1cc(F)cc(C(=O)O)c1
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: Cc1cc(F)cc(C(=O)O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Fluoro-5-methylbenzoic acid (4 g, 25.96 mmol) and KNO3 (2.884 g, 28.556 mmol) were dissolved in conc. H2SO4 (32 mL) at 0° C. The mixture was stirred at rt for 1 h. Water (60 mL) was added, and the resulting precipitate was filtered and dried to provide the title compound, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=3)=[CH:9][CH:8]=[N:7][C:6]=12.C([BH3-])#N.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[N:4][N:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=3)=[CH:9][CH2:8][NH:7][C:6]=12
Reactant: FC(F)(F)c1cccc(-c2ccnc3c(Cl)cnn23)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: FC(F)(F)c1cccc(C2=CCNc3c(Cl)cnn32)c1

Procedure:
A 13.3 g portion of 3-chloro-7-[3-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyrimidine and 7 g of sodium cyanoborohydride in 150 ml of acetic acid, were reacted as described in Example 1, giving 6.7 g of 3-chloro-4,5-dihydro-7-[3-(trifluoromethyl) phenyl]pyrazolo[1,5-a]pyrimidine.
Reaction SMILES: [CH3:1][C:2]1([C:8]([NH:10][CH:11]([C:17](=[O:19])[CH3:18])[CH2:12][C:13]([O:15][CH3:16])=[O:14])=O)[CH2:7][CH2:6][CH:5]=[CH:4][CH2:3]1.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:18][C:17]1[O:19][C:8]([C:2]2([CH3:1])[CH2:7][CH2:6][CH:5]=[CH:4][CH2:3]2)=[N:10][C:11]=1[CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)CC(NC(=O)C1(C)CC=CCC1)C(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)Cc1nc(C2(C)CC=CCC2)oc1C

Procedure:
A mixture of methyl 3-(1-methyl-3-cyclohexen-1-ylcarbonylamino)-4-oxovalerate (3.4 g), toluene (50 ml) and phosphorus oxychloride (3.5 ml) was refluxed for 3 hours and the solvent was distilled off. Aqueous sodium hydrogen carbonate was added, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off and the oily residue was further distilled under reduced pressure to give methyl 5-methyl-2-(1-methyl-3-cyclohexen-1-yl)-4-oxazoleacetate as an oil; yield 2.5 g (78.1%). Bp 120°-123° C. (0.3 mmHg).
Reaction SMILES: Br[C:2]1[N:18]([CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([CH3:26])[CH2:22][CH2:21]2)[C:5]2[C:6]([O:11][CH:12]([CH:14]3[CH2:17][CH2:16][CH2:15]3)[CH3:13])=[N:7][C:8]([Cl:10])=[CH:9][C:4]=2[N:3]=1.[C:27]1([C@@H:33]2[CH2:38][O:37][CH2:36][CH2:35][NH:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[F-].[Cs+]>CS(C)=O.O>[Cl:10][C:8]1[N:7]=[C:6]([O:11][CH:12]([CH:14]2[CH2:17][CH2:16][CH2:15]2)[CH3:13])[C:5]2[N:18]([CH2:19][C@H:20]3[CH2:25][CH2:24][C@H:23]([CH3:26])[CH2:22][CH2:21]3)[C:2]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][C@H:33]3[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:3][C:4]=2[CH:9]=1
Reactant: CC(Oc1nc(Cl)cc2nc(Br)n(C[C@H]3CC[C@H](C)CC3)c12)C1CCC1
Reactant: c1ccc([C@@H]2COCCN2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CS(C)=O
Product: CC(Oc1nc(Cl)cc2nc(N3CCOC[C@H]3c3ccccc3)n(C[C@H]3CC[C@H](C)CC3)c12)C1CCC1
Temperature: 125 °C

Procedure:
To a solution of 2-bromo-6-chloro-4-(1-cyclobutylethoxy)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine (1.5 g, 3.40 mmol) in DMSO (15 mL), in a microwave tube was added (R)-3-phenylmorpholine (797 mg, 4.77 mmol) and cesium fluoride (3.6 g, 23.8 mmol). The reaction was heated at 125° C. in a microwave for 45 mins. The reaction was then diluted with water (50 mL) and extracted with ethyl acetate (2×30 mL). The combined organic extracts were washed with water (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (eluting with 8-10% EtOAc/petroleum ether) to yield (3R)-4-(6-chloro-4-(1-cyclobutylethoxy)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-2-yl)-3-phenylmorpholine. MS ES/APCI calc'd. for C30H39ClN4O2 [M+H]+ 523. found 523.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[Cl:7][C:8]1[C:13](B(O)O)=[CH:12][CH:11]=[CH:10][N:9]=1.Cl[C:18]1[C:19]([CH3:38])=[N:20][C:21]2[C:26]([N:27]=1)=[C:25]([C:28]1[NH:36][C:35]3[CH2:34][CH2:33][NH:32][C:31](=[O:37])[C:30]=3[CH:29]=1)[CH:24]=[CH:23][CH:22]=2>>[Cl:7][C:8]1[C:13]([C:18]2[C:19]([CH3:38])=[N:20][C:21]3[C:26]([N:27]=2)=[C:25]([C:28]2[NH:36][C:35]4[CH2:34][CH2:33][NH:32][C:31](=[O:37])[C:30]=4[CH:29]=2)[CH:24]=[CH:23][CH:22]=3)=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1Cl
Reactant: OB(O)c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1-c1cccnc1Cl
Temperature: 100 °C
Yield: 4 %

Procedure:
A mixture of Na2CO3 (102 mg, 0.959 mmol), Pd(Ph3)4 (18.47 mg, 0.016 mmol; Strem Chemicals), (2-chloropyridin-3-yl)boronic acid (75 mg, 0.480 mmol; Alfa Aesar, Ward Hil, Mass.), and 2-(3-chloro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (100 mg, 0.320 mmol, 254c) was added to a conical vessel, sealed, and evacuated and backfilled with nitrogen three times. 1,4-dioxane (2.4 mL) and water (0.8 mL) were added via syringe, and the reaction was heated to 100° C. overnight. The reaction was cooled to RT and concentrated under reduced pressure to a residue. The residue was taken up in 2 mL DMSO, filtered through a syringe filter, and purified by reverse-phase preparative HPLC using a Xbridge C18 column (150 mm×30 mm, 10 mm), 40 mL min with 0.1% TFA in CH3CN/H2O, gradient 25% to 75% over 12 min. The product fractions were concentrated in a Genevac EZ-2 evaporator. The resulting solids were taken up in MeOH and eluted through a Si-carbonate cartridge (Silicycle, pre-washed with MeOH). The eluent was concentrated under reduced pressure to give 2-(3-(2-chloro-3-pyridinyl)-2-methyl-5-quinoxalinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (5 mg, 4%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.72 (1H, s) 8.84-8.98 (1H, m) 8.79 (1H, d, J=4.89 Hz) 8.08 (1H, dd, J=5.97, 2.64 Hz) 7.89-7.95 (2H, m) 7.82 (1H, d, J=4.89 Hz) 7.16-7.23 (1H, m) 7.01 (1H, br. s.) 3.33-3.43 (2H, m) 2.83 (2H, t, J=6.94 Hz) 2.54 (3H, s) m/z (ESI, +ve) 390.8 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](Cl)=[CH:7][C:6]=1[F:12].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:51]([C:53]([OH:86])([CH2:84][CH3:85])/[CH:54]=[CH:55]/[C:56]1[CH:61]=[CH:60][C:59]([C:62]([CH2:81][CH3:82])([C:65]2[CH:70]=[CH:69][C:68](B3OC(C)(C)C(C)(C)O3)=[C:67]([CH3:80])[CH:66]=2)[CH2:63][CH3:64])=[CH:58][C:57]=1[CH3:83])[CH3:52].C(=O)(O)[O-].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[CH2:63]([C:62]([C:65]1[CH:70]=[CH:69][C:68]([C:8]2[CH:9]=[CH:10][C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:13])=[C:6]([F:12])[CH:7]=2)=[C:67]([CH3:80])[CH:66]=1)([C:59]1[CH:60]=[CH:61][C:56](/[CH:55]=[CH:54]/[C:53]([CH2:51][CH3:52])([OH:86])[CH2:84][CH3:85])=[C:57]([CH3:83])[CH:58]=1)[CH2:81][CH3:82])[CH3:64]
Reactant: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(B3OC(C)(C)C(C)(C)O3)c(C)c2)cc1C)CC
Reactant: COC(=O)Cc1ccc(Cl)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(-c3ccc(CC(=O)OC)c(F)c3)c(C)c2)cc1C)CC
Temperature: 100 °C
Reaction time: 1 h
Yield: 46.6 %

Procedure:
(4-Chloro-2-fluoro-phenyl)acetic acid methyl ester (Example 40; 52 mg, 0.256 mmol), toluene (2.8 mL), palladium acetate (3.8 mg, 0.017 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (14 mg, 0.034 mmol), potassium phosphate (108 mg, 0.510 mmol) and water (0.28 mL) were added to (E)-3-ethyl-1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl-2-methyl-phenyl)-1-penten-3-ol (Example 28; 83.6 mg, 0.170 mmol), and the mixture was stirred in a nitrogen atmosphere at 100° C. for one hour. The reaction solution was poured into a saturated aqueous sodium bicarbonate solution, and then the aqueous layer was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (17% ethyl acetate/hexane) to give the title compound (42 mg, 47%).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[CH2:20][CH2:19][CH2:18][C@H:7]1[C:8]([N:10]1[CH2:17][CH2:16][CH2:15][C@H:11]1[C:12]([OH:14])=[O:13])=[O:9])=[O:5])[CH3:3].[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>[OH-].[Na+]>[C:21]1([NH:27][C:28]([NH:1][C@H:2]([C:4]([N:6]2[CH2:20][CH2:19][CH2:18][C@H:7]2[C:8]([N:10]2[CH2:17][CH2:16][CH2:15][C@H:11]2[C:12]([OH:14])=[O:13])=[O:9])=[O:5])[CH3:3])=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C=Nc1ccccc1
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: C[C@H](NC(=O)Nc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Yield: 58.7 %

Procedure:
L-alanyl-L-prolyl-L-proline (3.00 g, 10.6 m mole) was dissolved in 1N aqueous sodium hydroxide (10.6 ml, 10.6 m mole), and phenylisocyanate (1.89 g, 15.9 m mole) was gradually added thereto while stirring and coating with ice. After that, the reaction solution was stirred overnight at room temperature. The pH value of the solution was about 7 and white crystals were given in the solution. The solution was adjusted to pH 12 with 1N aqueous sodium hydroxide and the insoluble matters were filtered off. The filtrate was washed with two 50 ml portions of ether and 6N hydrochloric acid was added thereto to adjust the pH value to 1.0. The solution was extracted with two 100 ml portions of ethyl acetate in order to separate the products. The ethyl acetate layer was washed with 10% aqueous sodium chloride, dried over anhydrous sodium sufate, and concentrated under reduced pressure. To the thus concentrated matter with crystals, ether was added to effect further crystallization. The crystals were obtained by filtration and dried to give N-phenylcarbamoyl-L-alanyl-L-prolyl-L-proline (2.50 g).
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[Br:9].[F-].[K+].[CH2:12](Br)Br>CN(C=O)C>[CH2:12]1[O:8][C:7]2[C:2](=[C:3]([Br:9])[CH:4]=[CH:5][CH:6]=2)[O:1]1
Reactant: Oc1cccc(Br)c1O
Reactant: BrCBr
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1cccc2c1OCO2
Temperature: 135 °C
Yield: 30.1 %

Procedure:
To 2,3-dihydroxy-bromobenzene (3.0 g, 0.16 mole), KF (4.63 g, 0.080 mole), DMF (15 mL was added CH2Br2 (4.13 g, 0.024 moles). This suspension was heated to 135° C. for 3 hours, cooled and filtered. The filtrate was poured into 200 mL of ether and washed with water, 1 N KOH and brine. The organic layer was dried over magnesium sulfate, filtered and the solvent removed under vacuum, to yield 2,3-Methylenedioxy-bromobenzene (1.45 g, 45 % yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[NH:17][N:18]=[CH:19][CH:20]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:23][C:24]4[CH:25]=[CH:26][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][CH:29]=4)[N:17]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1
Reactant: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1cccnc1
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Product: Cc1nc(-c2ccn(Cc3ccc(S(C)(=O)=O)cc3)n2)sc1C(=O)NCc1cccnc1

Procedure:
The title compound was prepared from 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide and 1-bromomethyl-4-methanesulfonyl-benzene as described in Example 49 and isolated as a white solid (0.058 mg, 45% yield). 1HNMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 8.57 (d, J=4 Hz, 1H), 7.91 (d, J=8 Hz, 2H), 7.70 (d, J=8 Hz, 1H), 7.48 (d, J=2 Hz, 1H), 7.40 (d, J=8 Hz, 2H), 7.26-7.32 (m, 1H), 6.89 (d, J=4 Hz, 1H), 6.03-6.12 (m, 1H), 5.44 (s, 2H), 4.63 (d, J=4 Hz, 2H), 3.03 (s, 3H), 2.75 (s, 3H); MS (M+H)+=468.1; Rt=0.99 min; HRMS (M+H)+=468.12.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:14]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:15]=1.C(O)C.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:10]=1)[NH:7][CH:6]=[CH:5]2
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(O)c1cc(Cl)cc2cc[nH]c12
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1cc(Cl)cc2cc[nH]c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
To a mixture of 5-chloro-1H-indole-7-carboxylic acid (500 mg), triphenylphosphine (1.01 g), ethanol (235 mg) and toluene (20 mL) was added dropwise diethyl azodicarboxylate (2.2 M toluene solution, 1.74 mL) at room temperature. After stirring for 2 hours at room temperature, the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain ethyl 5-chloro-1H-indole-7-carboxylate (550 mg) as a white solid.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[N:26]1([S:32](Cl)(=[O:34])=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][S:32]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)(=[O:34])=[O:33])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: O=S(=O)(Cl)N1CCOCC1
Agent: Cl
Product: O=S(=O)(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1)N1CCOCC1

Procedure:
The title compound, white solid (5.4 mg, 13.2%), MS (ISP) m/z=480.2 [(M+H)+], was prepared in accordance with the general method of example 78 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (31.2 mg, 85 mmol) and morpholine-4-sulfonyl chloride.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C@:9]12[C:15]([CH3:17])([CH3:16])[C@H:12]([CH2:13][CH2:14]1)[CH:11]([C:18](Cl)=[O:19])[C:10]2=[O:21].[C:22]([O:26][C:27]([NH:29][NH:30][C:31]1[CH:36]=[C:35]([Cl:37])[CH:34]=[C:33]([Cl:38])[CH:32]=1)=[O:28])([CH3:25])([CH3:24])[CH3:23].O>ClCCl>[C:22]([O:26][C:27]([NH:29][N:30]([C:31]1[CH:32]=[C:33]([Cl:38])[CH:34]=[C:35]([Cl:37])[CH:36]=1)[C:18]([CH:11]1[C:10](=[O:21])[C@@:9]2([CH3:8])[C:15]([CH3:17])([CH3:16])[C@@H:12]1[CH2:13][CH2:14]2)=[O:19])=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)C(=O)C2C(=O)Cl
Reactant: CC(C)(C)OC(=O)NNc1cc(Cl)cc(Cl)c1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NN(C(=O)C1C(=O)[C@]2(C)CC[C@H]1C2(C)C)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Triethylamine (10.75 mL, 77 mmol) was added in two portions to a cooled (0° C.) solution of (1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 20; 5.5 g, 25.6 mmol) in dichloromethane (55 mL), giving a thick precipitate. N′-(3,5-dichloro-phenyl)-hydrazinecarboxylic acid tert-butyl ester (Intermediate 35; 5.5 g, 19.8 mmol) was added, along with dichloromethane (25-30 mL). The reaction mixture was placed in an oil-bath at 50° C., heated at this temperature overnight and then allowed to cool to room temperature and stir for 20 min. The reaction mixture was poured into water (100 mL) and two layers were separated. The organic layer was washed with water (100 mL) and brine (100 mL), dried (magnesium sulfate), filtered, evaporated, and then dried under high vacuum to give N′-(3,5-dichloro-phenyl)-N′-((1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl)-hydrazinecarboxylic acid tert-butyl ester (10 g, 111% of the expected amount) as an orange foam, which was used directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([OH:15])=O)=[CH:4][C:3]=1[F:22].[F:23][C:24]([F:33])([F:32])[C:25]1[N:29]=[C:28]([CH2:30][NH2:31])[O:27][N:26]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([NH:31][CH2:30][C:28]2[O:27][N:26]=[C:25]([C:24]([F:33])([F:32])[F:23])[N:29]=2)=[O:15])=[CH:4][C:3]=1[F:22]
Reactant: COCCOc1ncc(C(=O)O)cc1-c1ccc(Cl)c(F)c1
Reactant: NCc1nc(C(F)(F)F)no1
Product: COCCOc1ncc(C(=O)NCc2nc(C(F)(F)F)no2)cc1-c1ccc(Cl)c(F)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(4-chloro-3-fluorophenyl)-6-(2-methoxyethoxy)-nicotinic acid (example CF) and 3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine (example AK) as starting materials; LC-MS (UV peak area/ESI) 100%, 473.0662 (M−H)−.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][C:30]1[C:31]2[CH:40]=[CH:39][CH:38]=[CH:37][C:32]=2[S:33][C:34]=1[CH:35]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:35][C:34]3[S:33][C:32]4[CH:37]=[CH:38][CH:39]=[CH:40][C:31]=4[C:30]=3[CH3:29])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(C=O)sc2ccccc12
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: Cc1c(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)sc2ccccc12

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 3-methyl benzo[b]thiophene-2-carbaldehyde. MS (ESI) m/z 539.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[C:5]([O:7][CH3:8])=[O:6].C1COCC1.CCN(C(C)C)C(C)C.O([CH2:38][C:39]([F:42])([F:41])[F:40])S(C(F)(F)F)(=O)=O>CN(C=O)C>[Cl:15][C:12]1[CH:11]=[CH:10][C:9]([CH:4]([CH2:3][NH:2][CH2:38][C:39]([F:42])([F:41])[F:40])[C:5]([O:7][CH3:8])=[O:6])=[CH:14][CH:13]=1
Reactant: COC(=O)C(CN)c1ccc(Cl)cc1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(CNCC(F)(F)F)c1ccc(Cl)cc1
Reaction time: 20 h
Yield: 92.4 %

Procedure:
A solution of methyl 3-amino-2-(4-chlorophenyl)propanoate hydrochloride (215 mg, 0.86 mmol) in 1:1 THF:DMF (3.0 mL) was treated with DIEA (389 uL, 2.23 mmol) at room temperature. Trifluoroethyl triflate (299 mg, 1.29 mmol) was added to the mixture, and the reaction was stirred for 20 hours to completion. The mixture was partitioned between ethyl acetate and diluted NaHCO3 solution. The aqueous portion was extracted twice, and the combined organic portions were washed with water (3×). The organic portion was washed with brine, separated, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by chromatography (silica gel eluted with 4:1 hexanes:ethyl acetate, Rf=0.18) to afford the pure methyl 2-(4-chlorophenyl)-3-(2,2,2-trifluoroethylamino)propanoate (235 mg, 93%) as a colorless oil. LCMS (APCI+) m/z 296.0 [M+H]+.
Reaction SMILES: [CH:1]1([NH:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH2:18])(=[O:17])=[O:16])=[CH:11][C:10]=2[N+:19]([O-:21])=[O:20])[CH2:3][CH2:2]1.[C:22]1(=O)[CH2:25][CH2:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH:22]1([N:4]([CH:1]2[CH2:3][CH2:2]2)[CH2:5][CH2:6][CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH2:18])(=[O:16])=[O:17])=[CH:11][C:10]=2[N+:19]([O-:21])=[O:20])[CH2:25][CH2:24][CH2:23]1
Reactant: O=C1CCC1
Reactant: NS(=O)(=O)c1ccc(NCCCNC2CC2)c([N+](=O)[O-])c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(NCCCN(C2CCC2)C2CC2)c([N+](=O)[O-])c1
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 308A (314 mg) in dichloromethane (5 mL) was added cyclobutanone (70 mg) followed by sodium triacetoxyborohydride (318 mg). The mixture was stirred overnight. The mixture was diluted with dichloromethane (300 mL) and washed with aqueous NaHCO3, water and brine and dried over Na2SO4. After filtration, evaporation of solvent gave the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][S:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27](=[O:45])[CH:28]([C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=1)[CH3:29])[CH3:25]>>[CH2:24]([O:26][C:27](=[O:45])[CH:28]([C:30]1[CH:35]=[CH:34][C:33]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[CH2:14][S:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:4][CH:3]=2)=[CH:32][CH:31]=1)[CH3:29])[CH3:25]
Reactant: CCOC(=O)C(C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CSCCc1ccccc1
Product: CCOC(=O)C(C)c1ccc(-c2ccc(-c3onc(C)c3CSCCc3ccccc3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 108, Step 2, using 5-(4-bromo-phenyl)-3-methyl-4-phenethylsulfanylmethyl-isoxazole and 2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propionic acid ethyl ester.