Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH2:12].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=S)=[CH:16][CH:15]=1.C1(N=C=NC2CCCCC2)CCCCC1>C1(C)C=CC=CC=1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[NH:1][C:2]3[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=3[N:12]=2)=[CH:16][CH:15]=1
Reactant: Nc1ccc(C(F)(F)F)cc1N
Reactant: S=C=Nc1ccc(Br)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc2nc(Nc3ccc(Br)cc3)[nH]c2c1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
1,2-Diamino-5-trifluoromethylbenzene (0.25 g, 1.42 mmol) was diluted in toluene (5 mL) and treated with 4-bromophenylisothiocyanate (0.30 g, 1.42 mmol). The dark solution was stirred at 100° C. for 15 minutes, then treated with 1,3-dicyclohexylcarbodiimide (0.44 g, 2.13 mmol). The reaction was maintained at 100° C. for 5 h. The reaction was concentrated and partitioned between ethyl acetate and water. The organic layer was separated, dried (MgSO4), and concentrated under reduced pressure. The dark brown oil was purified by flash chromatography on silica gel, eluting with a gradient from 9:1 hexanes/ethyl acetate to 100% ethyl acetate. The title compound was obtained as a light pink solid (0.50 g, 30%). 1H NMR (300 MHz, DMSO-d6) δ 11.3 (broad d, 1H), 9.87 (d, 1H), 7.50 (d, 2H), 7.61 (d, 1H), 7.55-7.42 (m, 3H), 7.35-7.30 (m, 1H); LC/MS m/z 356.2 (MH+), retention time 2.33 minutes.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[NH:14][CH3:15])[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[CH3:16][O:17][CH2:18][CH2:19][NH:20][CH3:21]>>[CH3:16][O:17][CH2:18][CH2:19][N:20]([CH3:21])[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[NH:14][CH3:15])[C:8]([OH:10])=[O:9])(=[O:4])=[O:3]
Reactant: CNc1ccc(C(=O)O)cc1S(=O)(=O)Cl
Reactant: CNCCOC
Product: CNc1ccc(C(=O)O)cc1S(=O)(=O)N(C)CCOC

Procedure:
3-(Chlorosulfonyl)-4-(methylamino)benzoic acid 1.2 was reacted with 2-methoxy-N-methylethanamine Ac following the procedure described in Example 1A to provide 1.3.Ac. MS analysis (m−1)=301.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].C(OP([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])(OCC)=O)C>O1CCCC1.C(OCC)(=O)C>[CH2:29]([O:28][C:26](=[O:27])[CH:25]=[C:13]1[CH2:14][CH2:15][N:10]([C:8]([O:7][C:3]([CH3:6])([CH3:5])[CH3:4])=[O:9])[CH2:11][CH2:12]1)[CH3:30]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C=C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.33 h

Procedure:
To a solution of 9.1 g of 60% oily sodium hydride in 200 ml of tetrahydrofuran, 38.0 ml of ethyl diethylphosphonoacetate was added dropwise under cooling with ice, stirred for 20 minutes, and thereafter a solution of 31.4 g of 1-t-butoxycarbonyl-4-piperidone in 500 ml of tetrahydrofuran was added dropwise, followed by 40 minutes' stirring at the same temperature. The reaction liquid was diluted with ethyl acetate, washed successively with aqueous ammonium chloride solution, water and saturated brine, and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, the residue was recrystallized from methanol to provide 33.5 g of the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:13](Br)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[H][H]>CC(C)=O>[CH2:24]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH3:13]
Reactant: C1COCCN1
Reactant: CCCCCCCCCCCCBr
Reactant: [H][H]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCN1CCOCC1

Procedure:
174.2 g of morpholine (1 mole), 69 g of potassium carbonate (0.5 mole) and 300 mL of acetone were heated to reflux. To the above solution 124.5 g (0.5 mole) of dodecylbromide were added dropwise. After the addition was complete, the reaction mixture was heated at reflux for four hours. The reaction mixture was filtered, and the solvent evaporated in vacuo to leave an oil, which was distilled under vacuum to give a colorless liquid. Yield is 112.9 g (90% of the theory). Proton NMR δ0.8 (S,3Hz), 1.2 (M, 22Hz), 2.3 (M,4Hz) and 3.5 (M,4Hz). Elemental analysis, observed (theory) is carbon 74.96 (75.25), hydrogen 13.21 (13.02), and nitrogen 5.38 (5.48). Close proximity between the observed and theoretical values indicates the positive identification of this compound. Similarly prepared compounds are shown in Table I:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([OH:20])=[CH:14][C:15](=[O:19])[O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C1(C)C=CC(S([N:37]=[N+:38]=[N-])(=O)=O)=CC=1>C1COCC1>[N+:37](=[C:14]1[C:13](=[O:20])[C:12]2[C:17](=[CH:18][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)[O:16][C:15]1=[O:19])=[N-:38]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: O=c1cc(O)c2ccc(OCc3ccccc3)cc2o1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: [N-]=[N+]=C1C(=O)Oc2cc(OCc3ccccc3)ccc2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
A solution of7-benzyloxy-4-hydroxy coumarin (2.5 g, 9.3 mmol; prepared in accordance with Example 5) in anhydrous THF (40 mL) was mixed with triethylamine (0.9 g, 9 mmol) taken in a 100 mL 3-neck round-bottom flask under an atmosphere of N2. A solution of p-toluenesulfonyl azide (2.8 g, 14 mmol) in dry THF (20 mL) was added dropwise through an addition funnel. The mixture was stirred at room temperature for 3 hrs. The color of the solution turned orange. The solvent was rotary evaporated and the product was taken in CH2Cl2 and washed with water (3 times). Petroleum ether (twice the volume) was added to the solution and the solid precipitate was filtered with a frit and dried at 45° C. The product was recrystallized using CH2Cl2 ; yield 90%. The product was characterized by NMR: 13C NMR (100 MHz, CD2 Cl2): 173.3, 165.4, 158.7, 156.0, 136.0, 129.1, 128.8, 128.0, 127.6, 113.9, 113.0, 103.0, 75.7, 71.2; DSC - m. pt. 191° C. followed by decomposition; IR (KBr): 2182, 2154, 1717, 1647, 1605 cm-1 ; MS(APCI): (M+H), 295 (base peak).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH2:12]([C:14]1[CH:15]=[C:16]([CH3:26])[C:17]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:18][CH:19]=1)[CH3:13]>>[CH2:12]([C:14]1[CH:15]=[C:16]([CH3:26])[C:17]([N:20]2[CH2:21][CH2:22][N:23]([C:6]([C:5]3[CH:4]=[N:3][C:2]([F:1])=[CH:10][C:9]=3[CH3:11])=[O:8])[CH2:24][CH2:25]2)=[N:18][CH:19]=1)[CH3:13]
Reactant: CCc1cnc(N2CCNCC2)c(C)c1
Reactant: Cc1cc(F)ncc1C(=O)O
Product: CCc1cnc(N2CCN(C(=O)c3cnc(F)cc3C)CC2)c(C)c1
Yield: 59.1 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 60 and using 6-fluoro-4-methylnicotinic acid (500 mg) and 1-(5-ethyl-3-methylpyridin-2-yl)piperazine (649 mg) described in Preparation Example 53, the title compound (640 mg) was obtained.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[CH3:7][O:8][C:9](=[O:30])[CH:10]([O:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[C:16]([CH3:29])[N:17]2[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:11].[NH3:31]>CCOC(C)=O>[NH2:31][C:1](=[O:5])[C:2]([C:15]1[C:14]2[C:18](=[CH:19][CH:20]=[CH:21][C:13]=2[O:12][CH:10]([CH3:11])[C:9]([O:8][CH3:7])=[O:30])[N:17]([CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:16]=1[CH3:29])=[O:3]
Reactant: N
Reactant: COC(=O)C(C)Oc1cccc2c1cc(C)n2Cc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Product: COC(=O)C(C)Oc1cccc2c1c(C(=O)C(N)=O)c(C)n2Cc1ccccc1
Yield: 90 %

Procedure:
Oxalyl chloride (0.16 mL, 1.9 mmol) was reacted with 480 mg (1.5 mmol) of dl-2-[[2-methyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]propanoic acid methyl ester and then reacted with anhydrous ammonia as in Example 1, Part F and the reaction product was dissolved in EtOAc, washed with water, dried (MgSO4) and concentrated. The residue was chromatographed on silica gel (eluted with EtOAc) to give 531 mg (90% yield) of dl-2-[[3-(2-amino-1,2-dioxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]propanoic acid, methyl ester, melting at approximately 175° C.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1/[CH:8]=[C:9]1\[C:10](=[O:18])[NH:11][C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH:19]1[N:23]=[CH:22][N:21]([C:24](N2C=NC=C2)=[O:25])[CH:20]=1>CN(C=O)C>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1/[CH:8]=[C:9]1\[C:10](=[O:18])[N:11]([C:24]([N:21]2[CH:20]=[CH:19][N:23]=[CH:22]2)=[O:25])[C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: Cc1cc(C)c(/C=C2\C(=O)Nc3ccccc32)[nH]1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)n3ccnc3)c3ccccc32)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.5 %

Procedure:
A reaction mixture of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole (1.0 gram, 4.2 mmol) and CDI (1.36 gram 8.4 mmol) in DMF was stirred at room temperature for 2 h and filtered. The precipitate was washed with DMF and dried in a high vacuum oven to give 1.25 gram (89%) of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-1-(imidazol-1-ylcarbonyl)-1,3-dihydro-indol-2-one as an orange solid. 1HNMR (400 MHz, DMSO-d6) δ 12.23 (s, 1H, NH-1′), 8.45 (s, 1H), 7.94 (m, 1H), 7.79 (m, 1H), 7.73 (s, 1H, H-vinyl), 7.46 (m, 1H), 7.25 (m, 2H), 7.13 (m, 1H), 6.14 (d, J=1.95 Hz, 1H, H-4′), 2.36 (s, 3H, CH3), and 2.32 (s, 3H, CH3). MS m/z (relative intensity, %) 332 (100, M+.)
Reaction SMILES: [CH:1]([C:3]1[CH:23]=[CH:22][C:6]([CH2:7][N:8]([CH2:16][C:17]2[NH:18][CH:19]=[CH:20][N:21]=2)[C:9]([C:11]2[NH:12][CH:13]=[CH:14][N:15]=2)=[O:10])=[CH:5][CH:4]=1)=O.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH2:29][N:30]1[CH2:34][CH2:33][C:32]2([CH2:38][CH2:37][NH:36][CH2:35]2)[CH2:31]1>>[NH:21]1[CH:20]=[CH:19][N:18]=[C:17]1[CH2:16][N:8]([CH2:7][C:6]1[CH:22]=[CH:23][C:3]([CH2:1][N:36]2[CH2:37][CH2:38][C:32]3([CH2:33][CH2:34][N:30]([CH2:29][C:25]4[S:24][CH:28]=[CH:27][CH:26]=4)[CH2:31]3)[CH2:35]2)=[CH:4][CH:5]=1)[C:9]([C:11]1[NH:12][CH:13]=[CH:14][N:15]=1)=[O:10]
Reactant: O=Cc1ccc(CN(Cc2ncc[nH]2)C(=O)c2ncc[nH]2)cc1
Reactant: c1csc(CN2CCC3(CCNC3)C2)c1
Product: O=C(c1ncc[nH]1)N(Cc1ccc(CN2CCC3(CCN(Cc4cccs4)C3)C2)cc1)Cc1ncc[nH]1
Yield: 54.4 %

Procedure:
The same operation as in Example 2 was performed, except for using the compound (107 mg) obtained in Example 38 in place of 2-formyl-N,N-dimethyl-1H-imidazole-1-sulfonamide, and 2-(2-thienylmethyl)-2,7-diazaspiro[4.4]nonane (86 mg) in place of benzylamine, to obtain the title compound (97 mg) having the following physical properties.
Reaction SMILES: [Br:1][C:2]1[C:3]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][S:5][CH:6]=1.[CH3:11][O:12][C:13]1[C:18]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]([NH2:27])[CH3:26])=[CH:21][CH:20]=2)=[CH:17][CH:16]=[CH:15][N:14]=1>>[CH3:11][O:12][C:13]1[C:18]([C:19]2[CH:24]=[CH:23][C:22]([C@H:25]([NH:27][S:7]([C:3]3[C:2]([Br:1])=[CH:6][S:5][CH:4]=3)(=[O:9])=[O:8])[CH3:26])=[CH:21][CH:20]=2)=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: O=S(=O)(Cl)c1cscc1Br
Reactant: COc1ncccc1-c1ccc(C(C)N)cc1
Product: COc1ncccc1-c1ccc([C@@H](C)NS(=O)(=O)c2cscc2Br)cc1

Procedure:
2M Aqueous sodium carbonate solution (3.25 ml, 6.50 mmol) was added to a mixture of 2-methoxypyridine-3-boronic acid (994 mg, 6.50 mmol), (R)-[1-(4-bromo-phenyl)-ethyl]-carbamic acid tert-butyl ester (650 mg, 2.16 mmol) and tetrakis(triphenylphosphine)palladium (0) (125 mg, 0.108 mmol) in 1,2 dimethoxyethane (27 ml). The mixture was heated at 95° C. for 16 h under nitrogen atmosphere. The solvent was evaporated and the residue partitioned between ethyl acetate and water. The organic phase was washed twice with brine, dried over anhydrous magnesium sulfate and the solvent evaporated. The resulting gum was chromatographed over silica gel eluting with heptane/dichloromethane and the solvent evaporated to give (R)-{1-[4-(2-methoxy-pyridin-3-yl)-phenyl]-ethyl}-carbamic acid tert-butyl ester (593 mg, 1.71 mmol, 83.5%) as a crystalline solid. Trifluoroacetic acid (6.45 ml, 86.8 mmol) was added dropwise to a solution of (R)-{1-[4-(2-methoxy-pyridin-3-yl)-phenyl]-ethyl}carbamic acid tert-butyl ester (645 mg, 1.97 mmol) in dichloromethane (6.45 ml) under a nitrogen atmosphere at 0° C. After stirring for 1 h at 0° C. the solvent was evaporated. Methanol (20 ml) was added and the mixture added to a Strata™ 5 g/20 ml SCX column. The intermediate amine was eluted with 2M ammonia in methanol. The solvent was evaporated to give (R)-1-[4-(2-methoxy-pyridin-3-yl)-phenyl]-ethylamine as a gum (425 mg, 1.86 mmol, 94.6%). The title compound was then prepared in a similar manner to (R)-2,5-dimethyl-furan-3-sulfonic acid [1-(5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethyl]-amide (Example 10) using 4-bromo-3-thiophenesulfonyl chloride and 1-[4-(2-Methoxy-pyridin-3-yl)-phenyl]-ethylamine. Title compound: 1H NMR (400 MHz, CDCl3): δ 8.17 (d, 1H), 7.56 (d, 1H), 7.41, 7.20 (a/b, 4H), 7.38 (m, 1H), 6.99-6.92 (m, 2H), 5.27 (d, 1H), 4.60 (m, 1H), 3.97 (s, 3H), 1.54 (d, 3H) ppm; MS (ESI) m/z: 453 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:22])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH:19]([CH3:21])[CH3:20])[CH:12]=1)[CH2:5]O.P(Br)(Br)[Br:24]>COCCOC>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:22])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH:19]([CH3:21])[CH3:20])[CH:12]=1)[CH2:5][Br:24]
Reactant: BrP(Br)Br
Reactant: COc1ccc(Oc2c(C)cc(CO)cc2C)cc1C(C)C
Solvent: COCCOC
Product: COc1ccc(Oc2c(C)cc(CBr)cc2C)cc1C(C)C
Temperature: 0 °C
Reaction time: 5 h
Yield: 82.6 %

Procedure:
To a stirred solution of 3,5-dimethyl-4-(3′-iso-propyl-4′-methoxyphenoxy)benzyl alcohol (1.0 g, 3.4 mmol) in DME (10 mL) at 0° C. was added phosphorous tribromide (1.8 g, 0.5 mL, 6.8 mmol). The reaction mixture was stirred at 0° C. for 5 h, quenched with methanol (2 mL) and stirred for 30 min. The reaction mixture was poured into ice water and extracted with ether (100 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude 3,5-dimethyl-4-(3′-iso-propyl-4′-methoxyphenoxy)benzyl bromide as an oil (1.02 g, 82%): 1H NMR (300 MHz, CDCl3): δ 7.15 (s, 2 H), 6.81 (d, J=3.0 Hz, 1 H), 6.67 (d, J=9.0 Hz, 1 H), 6.34 (dd, J=3.0, 8.7 Hz, 1 H), 4.51 (s, 2 H), 3.80 (s, 3 H), 3.40-3.25 (m, 1 H), 2.15 (s, 6 H), 1.20 (d, J=7.2 Hz, 6 H); TLC conditions: Uniplate silica gel, 250 microns; mobile phase=ethyl acetate-hexanes (2:4); Rf=0.7.
Reaction SMILES: [Si:1]([O:8][C:9]1([C:12]2[N:17]=[C:16]([C:18]#[N:19])[CH:15]=[CH:14][CH:13]=2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O-]CC.[Na+].Cl.Cl.N[C:27]1[CH:28]=[CH:29][C:30]([N:34]2[CH2:39][CH2:38][CH2:37][C@@H:36]([C:40]([N:42]3[CH2:46][CH2:45][CH2:44][CH2:43]3)=[O:41])[CH2:35]2)=[N:31][C:32]=1[NH2:33].C(N(CC)CC)C>C(O)C.C(O)(=O)C>[Si:1]([O:8][C:9]1([C:12]2[N:17]=[C:16]([C:18]3[NH:33][C:32]4=[N:31][C:30]([N:34]5[CH2:39][CH2:38][CH2:37][C@@H:36]([C:40]([N:42]6[CH2:43][CH2:44][CH2:45][CH2:46]6)=[O:41])[CH2:35]5)=[CH:29][CH:28]=[C:27]4[N:19]=3)[CH:15]=[CH:14][CH:13]=2)[CH2:10][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Reactant: CC(C)(C)[Si](C)(C)OC1(c2cccc(C#N)n2)CC1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OC1(c2cccc(-c3nc4ccc(N5CCC[C@@H](C(=O)N6CCCC6)C5)nc4[nH]3)n2)CC1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a solution of 6-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)picolinonitrile (45.0 mg, 0.164 mmol) in ethanol (0.3 mL) was added dropwise a solution of sodium ethoxide in ethanol (0.1 mL, 21 wt %, 0.2 mmol). The reaction mixture was stirred at room temperature for 50 min and then heated to 35° C. for 1.5 h. To the mixture was added (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone dihydrochloride (77.2 mg, 0.2 mmol), triethylamine (47 μL, 0.3 mmol) and acetic acid (47 μL). The reaction mixture was heated to 110° C. for 50 min. The solution was transferred to a microwave vial and it was heated to 145° C. for 20 min. The solvent was removed under reduced pressure to afford (R)-(1-(2-(6-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)pyridin-2-yl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone. The material was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[N:12][N:13]2[C:18]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)([CH2:23][C:24]([F:27])([F:26])[F:25])[C:19](OC)=[O:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([C:18]([N:13]2[C:14]3[C:10](=[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH:17]=[CH:16][CH:15]=3)[CH:11]=[N:12]2)([CH2:23][C:24]([F:26])([F:27])[F:25])[CH2:19][OH:20])=[CH:29][CH:30]=1
Reactant: COC(=O)C(CC(F)(F)F)(c1ccc(Cl)cc1)n1ncc2c(NC(=O)OC(C)(C)C)cccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccc2c1cnn2C(CO)(CC(F)(F)F)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the product of Step A (300 mg, 0.6 mmol) in THF (5 mL) was added LiAlH4 (38 mg, 0.96 mmol) at 0° C. The mixture was stirred at RT for 1 h and quenched with H2O (5 mL), extracted with ethyl acetate, and washed with brine (10 mL), dried over sodium sulfate, then filtered. After the solvent was removed, the residue was purified by silica gel chromatography (EA/PE=1:3) to afford the title compound. LC/MS m/z=470.1[M+H]+.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:9].[CH2:10]([OH:12])[CH3:11]>[OH-].[Na+]>[C:2]1(/[CH:1]=[CH:11]/[C:10]([C:5]2[CH:6]=[CH:7][C:2]([C:1]([OH:9])=[O:8])=[CH:3][CH:4]=2)=[O:12])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCO
Reactant: O
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccc(C(=O)/C=C/c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of 4-carboxyacetophenone (250 mg, 1.52 mmole) and benzaldehyde (161.6 mg, 1.52 mmole) in absolute ethanol (4 ml), NaOH (25% w/v, 4 ml) was added and allowed to stir at RT for 2 days. Water was added and the mixture acidified to pH 4. The precipitate was filtered, dried and recrystalized with methanol to yield product (98 mg). m/z 251 (M−1)+1HNMR (DMSO) δ 7.4-7.92 (7H, m, ArH & ═CH), 8.09 (2H, d, 2×ArH), 8.19 (2H, d, 2×ArH).
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][C:8]([O:10][C@H:11]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH:29]([F:31])[F:30])=[C:24]([O:32][CH2:33][CH:34]2[CH2:36][CH2:35]2)[CH:23]=1)[CH2:12][C:13]1[C:18]([Cl:19])=[CH:17][N+:16]([O-:20])=[CH:15][C:14]=1[Cl:21])=[O:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:6]([CH2:7][C:8]([O:10][C@H:11]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH:29]([F:31])[F:30])=[C:24]([O:32][CH2:33][CH:34]2[CH2:35][CH2:36]2)[CH:23]=1)[CH2:12][C:13]1[C:18]([Cl:19])=[CH:17][N+:16]([O-:20])=[CH:15][C:14]=1[Cl:21])=[O:9])([OH:37])=[O:5]
Reactant: CC(C)(C)OC(=O)CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 0 °C
Reaction time: 72 h
Yield: 99.9 %

Procedure:
(S)-4-(2-(3-tert-butoxy-3-oxopropanoyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (1.0561 g, 1.878 mmol) was dissolved in DCM (70 ml) and cooled to 0° C. TFA (1.447 ml, 18.78 mmol) was added slowly, and the reaction was stirred at RT for 3 days. Two more additions of TFA (0.723 ml, 9.39 mmol) were performed, and the stirring was continued overnight. The mixture was evaporated to dryness affording (S)-4-(2-(2-carboxyacetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (0.950 g, 1.876 mmol, 100% yield, MS/ESI+ 505.9 [MH]+).
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[N:13]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=2[Cl:25])[N:12]=[C:11]([C:26]#[N:27])[C:10]=1[S:28][CH2:29][CH3:30].C(Br)(Br)[Br:32]>>[Br:32][C:9]1[N:13]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=2[Cl:25])[N:12]=[C:11]([C:26]#[N:27])[C:10]=1[S:28][CH2:29][CH3:30]
Reactant: BrC(Br)Br
Reactant: CCSc1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Agent: CC(C)(C)ON=O
Product: CCSc1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1Br
Temperature: 20 °C
Reaction time: 3 h

Procedure:
90% Tertiary-butyl nitrite (27.9 ml) was slowly added to a stirred solution of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-ethylthio-1H-pyrazole-3-carbonitrile (49.8 g) in bromoform (600 ml) at 0-5° C. The mixture was stirred for three hours whilst warming to 20° C. evaporated and re-evaporated after addition of hexane/ethyl acetate (1:1) to give 5-bromo-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-ethylthio-1H-pyrazole-3-carbonitrile (32.65 g), showing 93.3 area % purity by HPLC and with a retention time of 11.26 minutes on a 25.0 cm by 4.6 mm SUPELCOSIL LC-18 column, eluting with CH3CN/H2O (3: 1) solvent at 1 ml/minute. By proceeding in a similar manner the following compound was prepared:
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[CH2:9]([NH:16][C:17](=[O:24])[C@H:18]([C@H:20]([CH2:22][CH3:23])[CH3:21])[NH2:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[O:25]([C:32]1[CH:37]=[CH:36][C:35]([C:38](=[O:41])[CH2:39]Br)=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[O:25]([C:32]1[CH:33]=[CH:34][C:35]([C:38](=[O:41])[CH2:39][N:1]2[CH2:8][CH2:7][CH2:6][C@H:2]2[C:3]([N:16]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:17](=[O:24])[C@H:18]([C@H:20]([CH2:22][CH3:23])[CH3:21])[NH2:19])=[O:5])=[CH:36][CH:37]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(CBr)c1ccc(Oc2ccccc2)cc1
Reactant: CC[C@H](C)[C@H](N)C(=O)NCc1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)c1ccc(Oc2ccccc2)cc1
Yield: 42.7 %

Procedure:
Using the procedure described in Example 5, treatment of L-proline-L-isoleucine benzylamide (200 mg, 0.63 mmol) with 4'-phenoxy-2-bromoacetophenone (275 mg, 0.95 mmol, 1.5 eq) provided 142 mg of L-isoleucine, N-[1-(2-(4-phenoxyphenyl)-2-oxoethyl)-L-prolyl] benzylamide as a foam.
Reaction SMILES: Br[C:2]1[C:3]([O:32][CH3:33])=[CH:4][C:5]2[CH2:6][CH2:7][N:8]3[C:14]4[C:15](=[O:26])[N:16]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:17][CH2:18][CH2:19][O:20][CH2:21][C:13]=4[C:12]([C:27]4[S:31][CH:30]=[N:29][CH:28]=4)=[C:9]3[C:10]=2[CH:11]=1.[N:34]1[CH:39]=[CH:38][CH:37]=[C:36](B(O)O)[CH:35]=1.C([O-])([O-])=O.[K+].[K+].C(COC)OC>O>[C:22]([N:16]1[C:15](=[O:26])[C:14]2[N:8]3[CH2:7][CH2:6][C:5]4[CH:4]=[C:3]([O:32][CH3:33])[C:2]([C:36]5[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=5)=[CH:11][C:10]=4[C:9]3=[C:12]([C:27]3[S:31][CH:30]=[N:29][CH:28]=3)[C:13]=2[CH2:21][O:20][CH2:19][CH2:18][CH2:17]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: OB(O)c1cccnc1
Reactant: COc1cc2c(cc1Br)-c1c(-c3cncs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCOC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1cc2c(cc1-c1cccnc1)-c1c(-c3cncs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCOC3
Yield: 93.7 %

Procedure:
A solution of 75 mg of 8e, 35 mg of pyridine-3-boronic acid, 60 mg of K2CO3 in 2 ml of degassed 90% aq. dimethoxyethane was heated at 90° C. for 16 h The reaction mixture was cooled, diluted with water and extracted with ethyl acetate. The organic layer was once washed with 1M K2CO3, once with water, dried and concentrated. The crude material was chromatographed over silica gel using a gradient of toluene/acetone. The isolated material was treated with diethyl ether and provided 70 mg of 8f; Mp 200-201° C.; Rf 0.15 (toluene/acetone 7/3). MS-ESI: [M+1] 529.3.