Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](CS([O-])(=O)=O)=[CH:4][CH:3]=1.[NH2:13][C:14]1[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].C([O-])([O-])=O.[K+].[K+]>CC(O)(C)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:13][C:14]2[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=2[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccccc1N
Reactant: O=S(=O)([O-])Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCOC(=O)c1ccccc1Nc1ccc(F)cc1
Temperature: 110 °C
Yield: 91 %

Procedure:
Following general procedure A, a mixture of 4-fluorophenylmethanesulfonate (95 mg, 0.5 mmol), ethyl 2-aminobenzoate (89 μL, 0.6 mmol), K2CO3 (97 mg, 0.7 mmol), 10 (4 mg, 1 mol %), 1 (2.5 mg, 1 mol %), and t-BuOH (6 mL) was heated to 110° C. for 16 h. The crude product was purified via the Biotage SP4 (silica-packed 25+M; 0-20% EtOAc/hexanes) to provide the title compound as a yellow oil (118 mg, 91%). 1H NMR (300 MHz, CDCl3) δ: 9.44 (s, 1H), 7.99 (d, J=8.0 Hz, 1H), 7.30 (t, J=7.5 Hz, 1H), 7.21 (m, 2H), 7.07 (m, 3H), 6.73 (t, J=7.5 Hz, 1H), 4.37 (q, J=7.5 Hz, 2H), 1.42 (t, J=7.5 Hz, 3H) ppm. 13C NMR (75 MHz, CDCl3) δ: 168.8, 161.3, 158.1, 148.8, 136.9, 136.9, 134.4, 131.9, 125.4, 125.3, 117.1, 116.5, 116.2, 113.6, 112.0, 60.9, 14.6 ppm. IR (neat, cm−1): 3316, 2982, 1683, 1583, 1513, 1455, 1260, 1233, 1082, 749. Anal. Calcd. for C15H14FNO2: C, 69.49; H, 5.44. Found: C, 70.14; H, 5.64.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.C[Al](C)C.C[O:14][C:15]([C:17]1[N:18]=[C:19]([CH3:23])[S:20][C:21]=1[Br:22])=O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCOCC1.O>[F:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:15]([C:17]2[N:18]=[C:19]([CH3:23])[S:20][C:21]=2[Br:22])=[O:14])=[N:3][CH:4]=1
Reactant: COC(=O)c1nc(C)sc1Br
Reactant: Nc1ccc(F)cn1
Agent: C[Al](C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc(C(=O)Nc2ccc(F)cn2)c(Br)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.7 %

Procedure:
A solution of 2-amino-5-fluoropyridine (6.0 g, 53 mmol) in 40 ml dry dioxane was treated at 0° C. with trimethylaluminium (2M in hexane, 26.8 ml, 53 mmol). The mixture was stirred at room temperature for 1 h. A solution of 5-bromo-2-methyl-thiazole-4-carboxylic acid methyl ester (4.2 g, 18 mmol) in 40 mL dry dioxane was added and the reaction mixture was refluxed for 4 h. 10 ml water and 10 g sodium sulfate were sequentially added and filtered. The filtrate was evaporated and the residue purified by flash chromatography (hetane, ethyl acetate) to yield 5-bromo-2-methyl-thiazole-4-carboxylic acid (5-fluoro-pyridin-2-yl)-amide (3.0 g, 53%) as a white solid, MS (ISP): m/e=318.0 (M+H+).
Reaction SMILES: [Br-:1].ClC1C=CC=CC=1C(C1C=CC=CC=1Cl)(O)C(O[C@@H:13]1[CH:18]2[CH2:19][CH2:20][N+:15]([CH2:21][C:22](=[O:29])[NH:23][C:24]3[CH:28]=[CH:27][O:26][N:25]=3)([CH2:16][CH2:17]2)[CH2:14]1)=O.[OH:38][C:39]([C:51]1[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=1)([C:43]1[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=1)[C:40]([OH:42])=[O:41]>>[Br-:1].[OH:38][C:39]([C:43]1[CH:44]=[CH:45][C:46]([O:49][CH3:50])=[CH:47][CH:48]=1)([C:51]1[CH:52]=[CH:53][C:54]([O:57][CH3:58])=[CH:55][CH:56]=1)[C:40]([O:42][C@@H:17]1[CH:18]2[CH2:19][CH2:20][N+:15]([CH2:21][C:22](=[O:29])[NH:23][C:24]3[CH:28]=[CH:27][O:26][N:25]=3)([CH2:14][CH2:13]2)[CH2:16]1)=[O:41]
Reactant: COc1ccc(C(O)(C(=O)O)c2ccc(OC)cc2)cc1
Reactant: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(O)(c1ccccc1Cl)c1ccccc1Cl)C2)Nc1ccon1
Agent: [Br-]
Product: COc1ccc(C(O)(C(=O)O[C@H]2C[N+]3(CC(=O)Nc4ccon4)CCC2CC3)c2ccc(OC)cc2)cc1

Procedure:
This compound is prepared analogously to (R)-3-[2,2-bis-(2-chloro-phenyl)-2-hydroxy-acetoxy]-1-(isoxazol-3-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane bromide [Example 1] by substituting bis-(2-chloro-phenyl)-hydroxy-acetic acid with hydroxy-bis-(4-methoxy-phenyl)-acetic acid (Intermediate C).
Reaction SMILES: C(OC([NH:11][C:12]12[CH2:19][CH2:18][C:15]([C:20]([O:22][CH2:23][CH3:24])=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=O)C1C=CC=CC=1.[H][H]>C(O)C.[C].[Pd]>[NH2:11][C:12]12[CH2:17][CH2:16][C:15]([C:20]([O:22][CH2:23][CH3:24])=[O:21])([CH2:14][CH2:13]1)[CH2:18][CH2:19]2
Reactant: [H][H]
Reactant: CCOC(=O)C12CCC(NC(=O)OCc3ccccc3)(CC1)CC2
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C12CCC(N)(CC1)CC2
Yield: 100.4 %

Procedure:
Ethyl 4-benzyloxycarbonylaminobicyclo[2.2.2]octane-1-carboxylate (40.0 g) was dissolved in ethanol (400 mL). To this solution, 10% palladium-carbon (4.00 g) was added and the mixture was stirred at room temperature for 6 hours in a stream of hydrogen. The catalyst in the reaction mixture was filtered through a Celite pad and the filtered catalyst, together with the Celite pad, was washed with ethanol. The filtrate and the washings were combined and concentrated under reduced pressure. The resulting residue was dried under reduced pressure to give ethyl 4-aminobicyclo[2.2.2]octane-1-carboxylate (23.9 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([Cl:16])[CH:9]=2)[CH:5]=[N:6][CH:7]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][S:25](Cl)(=[O:27])=[O:26])=[CH:20][CH:19]=1>N1C=CC=CC=1>[Cl:16][C:10]1[CH:9]=[C:8]([C:4]2[CH:3]=[C:2]([NH:1][S:25]([CH2:24][C:21]3[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=3)(=[O:26])=[O:27])[CH:7]=[N:6][CH:5]=2)[CH:15]=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: N#Cc1ccc(-c2cncc(N)c2)cc1Cl
Reactant: O=S(=O)(Cl)Cc1ccc(F)cc1
Solvent: c1ccncc1
Product: N#Cc1ccc(-c2cncc(NS(=O)(=O)Cc3ccc(F)cc3)c2)cc1Cl
Yield: 23.5 %

Procedure:
According to General Sulfonylation Procedure 2 in Example 1, to a solution of 4-(5-amino-pyridin-3-yl)-2-chloro-benzonitrile (20 mg, 87 μmol, 1 eq) in anhydrous pyridine (500 μl) was added (4-fluoro-phenyl)-methanesulfonyl chloride (20 mg, 96 μmol, 1.1 eq). The crude product was purified by Isco Cornbiflash® Companion™ flash chromatography system on normal phase (4 g SiO2, flow rate 18 mL/min), eluting with mixtures of dichloromethane/methanol, to give N-[5-(3-chloro-4-cyano-phenyl)-pyridin-3-yl]-1-(4-fluoro-phenyl)-methanesulfonamide (8.2 mg, >95% purity, yield: 23.4%). The isolated product was lyophilized and identified by LC-MS (system 1) and NMR (system 2): ESI-MS m/z: 402 [M+H]+, retention time=2.24 min, 1H NMR (400 MHz, DMSO-d6) δ ppm 4.67 (s, 2H) 7.09-7.16 (m, 2H) 7.29-7.37 (m, 2H) 7.66 (t, J=2.27 Hz, 1H) 7.78 (dd, J=8.15, 1.71 Hz, 1H) 8.02 (d, J=1.64 Hz, 1H) 8.09 (d, J=8.08 Hz, 1H) 8.34 (d, J=2.40 Hz, 1H) 8.61 (d, J=2.02 Hz, 1H) 10.24 (br. s., 1H).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]([OH:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)([OH:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH2:21]([O:2][C:1]([C:4]1[CH:13]=[C:12]([O:14][CH2:12][C:11]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)=[O:3])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(O)c1cc(O)c2ccccc2n1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1cc(OCc2ccccc2)c2ccccc2n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 186.4 %

Procedure:
2-carboxy-4-hydroxyquinoline (5 g, 1.0 eq) was dissolved in 50 mL DMF. Cesium carbonate (20 g, 2.3 eq) was added to the solution and the resulting reaction mixture was heated at 50° C. for 20 minutes. Benzyl bromide (10 g, 2.1 eq) was added. The resulting reaction mixture was stirred at 50° C. for 1 hour. Then the reaction mixture was poured into 500 mLice-water, the precipitate was collected by filtration, and dried in vacuo to afford 2-benzyloxycarbonyl-4-benzyloxyquinoline (9.1 g). 2-benzyloxycarbonyl-4-benzyloxyquinoline (9.0 g) was dissolved in 50 mL THF, and 2 N LiOH solution (20 mL) was added, and the resulting reaction mixture was stirred at ambient temperature for 2 hours. The solvent was then removed in vacuo, and the residue acidified by the addition of 2N NaHSO4 to pH 3–4. The white precipitate was collected to afford 2-carboxy-4-benzyloxyquinoline (7.2 g), which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:11]([CH2:20][C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=3)[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.N1C=CC=CC=1.[C:37]1([S:43](Cl)(=[O:45])=[O:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([CH:14]3[CH2:19][CH2:18][N:17]([S:43]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)(=[O:45])=[O:44])[CH2:16][CH2:15]3)[N:11]([CH2:20][C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=3)[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(=O)c1ccc(Cn2nc(-c3cc(Cl)cc(Cl)c3)cc2C2CCNCC2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(Cn2nc(-c3cc(Cl)cc(Cl)c3)cc2C2CCN(S(=O)(=O)c3ccccc3)CC2)cc1

Procedure:
To a solution of the intermediate from Example 142 step F (156 mg, 0.35 mmol) in DCM (5 mL) was added pyridine (5 mL) and benzene sulfonyl chloride (68 μL, 0.53 mmol). After 4 hours the reaction was diluted with DCM and washed with 1N HCl (3×), dried over anhydrous Na2SO4 filtered and concentrated in vacuo. The residue was purified by flash chromatography using 1:5 ethyl acetate-hexanes to give the title compound a white foam. 1H NMR (CDCl3, 500 MHz): δ 7.99(d, J=8.3 Hz, 2H), 7.8(d, J=8.7 Hz, 2H), 7.7(d, J=1.9 Hz, 2H), 7.67(t, J=7.3 Hz, 1H), 7.58(t, J=8.0 Hz, 2H), 7.32(t, J=1.8 Hz, 1H), 7.1(d, J=8.2 Hz, 2H), 6.42(s, 1H), 5.55(s, 2H), 3.93(s, 3H), 3.90(d, J=12.2 Hz, 2H), 2.46(m, 1H), 2.31(m, 2H), 1.77(m, 3H).
Reaction SMILES: [N:1]1(C(OCC2C=CC=CC=2)=O)[CH2:9][CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([NH2:5])=[O:4]>CO.[Pd]>[NH:1]1[CH2:9][CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([NH2:5])=[O:4]
Reactant: NC(=O)[C@H]1CCCCN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NC(=O)[C@H]1CCCCN1
Yield: 88.4 %

Procedure:
3.93 g (15 mmoles) of Z-D-Pip-NH2 are dissolved in 75 ml of methanol, 0.5 g of a 10% palladium-on-carbon catalyst are added, and hydrogen is bubbled through the mixture for one hour. The catalyst is filtered off, the filtrate is evaporated, and the residue is triturated with ether. 1.70 g (90%) of H-D-Pip-NH2 are obtained: m.p.: 161°-163° C., Rf4 =0.10, [α]D25 =+31.0° (c=1%, in methanol).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6]2.[H-].[Na+].[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Br>CN(C)C=O>[F:18][C:2]([F:17])([F:1])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:25][C:24]1[CH:27]=[CH:28][CH:29]=[C:22]([F:21])[CH:23]=1)[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6]2
Reactant: Fc1cccc(CBr)c1
Reactant: CCOC(=O)c1cc2cc(C(F)(F)F)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(C(F)(F)F)ccc2n1Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
A solution of 2.88 g (11.2 mmol) of ethyl 5-trifluoromethyl-1H-indole-2-carboxylate (obtained by Fisher indole synthesis from 4-(trifluoromethyl)phenylhydrazine) in 50 ml of dimethylformamide is added dropwise to a suspension of 0.58 g (14.56 mmol) of sodium hydride in 5 ml of dimethylformamide cooled in an ice bath. The mixture is stirred for 2 hours at room temperature and a solution of 2.54 g (13.44 mmol) of 3-fluorobenzyl bromide in 20 ml of dimethylformamide is then added. Stirring is continued for 24 hours. 2.44 mmol of 3-fluorobenzyl bromide are added and the mixture is stirred for a further 4 hours. The solvent is evaporated off under reduced pressure and the residue is taken up in water and ethyl acetate. After separation of the phases by settling, the organic phase is separated out and then washed with twice 50 ml of water and then with 50 ml of saturated sodium chloride solution. The solution is dried over magnesium sulfate and filtered, and then the filtrate is concentrated under reduced pressure. The residue is purified by chromatography on silica gel. 2.74 g of product are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:19]([OH:20])=[CH:18][C:5]2[C@H:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:7][N:8]([CH3:11])[CH2:9][CH2:10][C:4]=2[CH:3]=1.[CH2:21]([N:23]=[C:24]=[O:25])[CH3:22]>C(#N)C>[Cl:1][C:2]1[C:19]([O:20][C:24]([NH:23][CH2:21][CH3:22])=[O:25])=[CH:18][C:5]2[C@H:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:7][N:8]([CH3:11])[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: CN1CCc2cc(Cl)c(O)cc2[C@H](c2ccccc2)C1
Reactant: CCN=C=O
Solvent: CC#N
Product: CCNC(=O)Oc1cc2c(cc1Cl)CCN(C)C[C@H]2c1ccccc1

Procedure:
Dissolve 1.22 g (0.0042 moles) of the product of step E in 60 ml of refluxing acetonitrile and add dropwise 0.6 ml of ethyl isocyanate with stirring. Reflux for 30 minutes after addition is complete. Evaporate to dryness and crystallize the residue from acetonitrile to obtain analytically pure (S)-7-chloro-8-(ethylaminocarbonyloxy)-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine, m.p. 133°-134.5° C. [α]D26 =+20.2° (c=0.5, ethanol).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].CS(O[CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH3:19])(=O)=O.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH3:19][O:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:7][C:2]1[C:1]([NH2:8])=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCCCOS(C)(=O)=O
Reactant: Nc1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COCCCCNc1ccccc1N
Yield: 56 %

Procedure:
To a solution of phenylenediamine (10.8 g) and 4-methoxybutyl methanesulfonate (9.11 g) in acetonitrile (100 ml) was added potassium carbonate (20.7 g), and the mixture was stirred heated under reflux for 15 hr. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (35:65) was concentrated under reduced pressure to give the object product (5.44 g).
Reaction SMILES: [CH:1]1([C:4]([N:6]2[C:15]3[C:10](=[C:11]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:12]([C:16]4[CH:17]=[N:18][NH:19][CH:20]=4)=[CH:13][CH:14]=3)[CH2:9][CH2:8][C@@H:7]2[CH3:28])=[O:5])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O.Br[CH:41]1[CH2:46][CH2:45][S:44](=[O:48])(=[O:47])[CH2:43][CH2:42]1>C(OCC)(=O)C>[CH:1]1([C:4]([N:6]2[C:15]3[C:10](=[C:11]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:12]([C:16]4[CH:20]=[N:19][N:18]([CH:42]5[CH2:41][CH2:46][CH2:45][S:44](=[O:48])(=[O:47])[CH2:43]5)[CH:17]=4)=[CH:13][CH:14]=3)[CH2:9][CH2:8][C@@H:7]2[CH3:28])=[O:5])[CH2:2][CH2:3]1
Reactant: C[C@H]1CCc2c(ccc(-c3cn[nH]c3)c2Oc2ccccc2)N1C(=O)C1CC1
Reactant: O=S1(=O)CCC(Br)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H]1CCc2c(ccc(-c3cnn(C4CCCS(=O)(=O)C4)c3)c2Oc2ccccc2)N1C(=O)C1CC1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A 100-mL, round-bottom flask was charged with (S)-cyclopropyl(2-methyl-5-phenoxy-6-(1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone (0.200 g, 0.56 mmol), cesium carbonate (0.114 g, 0.35 mmol), N,N-dimethylformamide (5 mL), and 4-bromo-1λ6-thiane-1,1-dione (0.114 g, 0.53 mmol). The resulting mixture stirred at 100° C. for 4 h and was then cooled to room temperature. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (3×10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (gradient elution with 25-50% ethyl acetate/petroleum). The product was further purified by preparative-HPLC with the following conditions (Waters I): Column, SunFire Prep C18, 5 um, 19×100 mm; mobile phase, Water and acetonitrile (55% to 75% acetonitrile in 7 min, flow rate: 20 mL/min); Detector, UV 220&254 nm. This afforded 3-{4-[(2S)-1-cyclopropanecarbonyl-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinolin-6-yl]-1H-pyrazol-1-yl}-1λ6-thiane-1,1-dione (0.122 g, 43%) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm 0.76-0.82 (m, 1H), 0.92-1.02 (m, 2H), 1.13-1.22 (m, 4H), 1.42-1.50 (m, 1H), 1.95-2.08 (m, 3H), 2.08-2.13 (m, 1H), 2.14-2.37 (m, 3H), 2.68-2.77 (m, 1H), 3.11-3.19 (m, 2H), 3.37 (s, 1H), 3.53-3.60 (m, 1H), 4.66-4.72 (m, 1H), 4.74-4.81 (m, 1H), 6.79 (d, J=8.00 Hz, 2H), 6.98 (t, J=7.60 Hz, 1H), 7.23 (t, J=7.60 Hz, 2H), 7.62 (d, J=8.40 Hz, 1H), 7.83 (s, 1H), 8.05 (s, 1H). MS (ESI, pos. ion) m/z 506 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:29])=[C:4]([N:10]2[CH2:15][CH2:14][C@H:13]([NH:16][C:17](=[O:20])[O:18][CH3:19])[C@@H:12]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:11]2)[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.NC1C=CC=CC=1.[CH:37]1([N:40]([CH2:56][C:57]2[CH:62]=[CH:61][C:60]([O:63][CH3:64])=[CH:59][CH:58]=2)[C:41]2[C:46]3=[N:47][CH:48]=[C:49]([C:50]#[N:51])[N:45]3[N:44]=[C:43](S(C)(=O)=O)[N:42]=2)[CH2:39][CH2:38]1>>[Si:22]([O:21][C@@H:12]1[C@@H:13]([NH:16][C:17](=[O:20])[O:18][CH3:19])[CH2:14][CH2:15][N:10]([C:4]2[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=[C:2]([NH:1][C:43]3[N:42]=[C:41]([N:40]([CH:37]4[CH2:39][CH2:38]4)[CH2:56][C:57]4[CH:62]=[CH:61][C:60]([O:63][CH3:64])=[CH:59][CH:58]=4)[C:46]4=[N:47][CH:48]=[C:49]([C:50]#[N:51])[N:45]4[N:44]=3)[C:3]=2[Cl:29])[CH2:11]1)([C:25]([CH3:26])([CH3:28])[CH3:27])([CH3:23])[CH3:24]
Reactant: COC(=O)N[C@H]1CCN(c2cc(C#N)cc(N)c2Cl)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: COc1ccc(CN(c2nc(S(C)(=O)=O)nn3c(C#N)cnc23)C2CC2)cc1
Solvent: Nc1ccccc1
Product: COC(=O)N[C@H]1CCN(c2cc(C#N)cc(Nc3nc(N(Cc4ccc(OC)cc4)C4CC4)c4ncc(C#N)n4n3)c2Cl)C[C@@H]1O[Si](C)(C)C(C)(C)C

Procedure:
methyl ((3S,4S)-3-((tert-butyldimethylsilyl)oxy)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)piperidin-4-yl)carbamate was prepared starting from methyl ((3S,4S)-1-(3-amino-2-chloro-5-cyanophenyl)-3-((tert-butyldimethylsilyl)oxy)piperidin-4-yl)carbamate (127 mg, 0.289 mmol) according to general procedure for the coupling of aniline to 4-(cyclopropyl(4-methoxybenzyl)amino)-2-(methylsulfonyl)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile, method described for Example 7. Methyl ((3S,4S)-3-((tert-butyldimethylsilyl)oxy)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)piperidin-4-yl)carbamate (180 mg) was obtained as a white solid.
Reaction SMILES: [CH:1]([N:4]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:5](=[O:21])[CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:3])[CH3:2].[C:28]1([NH:34][N:35]=[C:36]([C:40](Cl)=[O:41])[C:37](Cl)=[O:38])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[O:41]=[C:40]1[N:7]([CH2:6][C:5]([N:4]([CH:1]([CH3:3])[CH3:2])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:21])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:37](=[O:38])[C:36]1=[N:35][NH:34][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)N(C(=O)CNc1ccccc1Nc1ccccc1)c1ccccc1
Reactant: O=C(Cl)C(=NNc1ccccc1)C(=O)Cl
Solvent: C1CCOC1
Product: CC(C)N(C(=O)Cn1c(=O)c(=NNc2ccccc2)c(=O)n(-c2ccccc2)c2ccccc21)c1ccccc1
Temperature: 25 °C

Procedure:
N-isopropyl-N-phenyl-2-(2-phenylaminophenylamino)-acetamide (10 g) and 2-(phenyl-hydrazono)-propanedioyl dichloride (6.83 g), were each dissolved in THF (100 ml) and added simultaneously, with stirring, to a flask containing THF (100 ml) at 0° C., under nitrogen. The reaction mixture was allowed to warm to R.T. and stirred four hours. The THF was evaporated in vacuo and the residue was dissolved in ethyl acetate (200 ml). The ethyl acetate solution was washed with 10% aqueous sodium carbonate (2×200 ml) and water (2×200 ml), dried (Na2SO4), and concentrated in vacuo. The residual foam was treated with diethyl ether (50 ml) to precipitate the title compound as a bright yellow solid (7.5 g). The mother liquor was concentrated to a tan foam (2.5 g). 1H-NMR (300 MHz, CDCl3): d 11.4 and 10.85 (s, 1H), 7.6-6.8 (m, 19H), 5.05 (m, 1H), 4.4 (m, 2H), 1.05 (m, 6H); MS (FAB)=532 (MH+); TLC, Rf=0.19 (hexane:ethyl acetate, 2:1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.Cl.[CH2:13]([O:17][C:18](=[O:22])[C@H:19]([CH3:21])[NH2:20])[CH:14]([CH3:16])[CH3:15]>>[CH2:13]([O:17][C:18](=[O:22])[C@H:19]([CH3:21])[NH:20][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: CC(C)COC(=O)[C@H](C)N
Agent: Cl
Product: CC(C)COC(=O)[C@H](C)NC(=O)Cc1ccc(Cl)cc1

Procedure:
Following General Procedure BB and using 4-chlorophenylacetic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example BB above), the title compound was prepared as a solid having a melting point of 111°–113° C. The reaction was monitored by tlc on silica gel and purification was by extraction with Et2O followed by washes with aqueous K2CO3 and aqueous HCl.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([CH3:14])([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[I:15]I>CO.FC(F)(F)C([O-])=O.[Ag+]>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([CH3:14])([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[I:15]
Reactant: II
Reactant: COC(=O)C(C)(C)c1ccc(N)nc1
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: CO
Product: COC(=O)C(C)(C)c1cnc(N)c(I)c1
Reaction time: 3 h
Yield: 62.5 %

Procedure:
A solution of methyl 2-(6-aminopyridin-3-yl)-2-methylpropanoate (10.0 g, 51.5 mmol) in MeOH (50 mL) was added over approximately 0.5 h via pressure equalizing addition funnel to a vigorously stirred suspension of iodine (17.0 g, 67.0 mmol) and silver trifluoroacetate (14.8 g, 67.0 mmol) in MeOH (200 mL) at room temperature. After 3 h, the reaction was quenched sequentially with 1M Na2S2O3 followed by saturated aqueous NaHCO3. The resulting mixture was filtered through celite® washing copiously with ethyl acetate, the filtrate concentrated in vacuo and the residue partitioned between ethyl acetate and water. The organic phase was separated and the aqueous phase was re-extracted with ethyl acetate (×3). The combined organic extract was washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (gradient elution; 35-40% ethyl acetate/hexanes as eluent) to give the title compound as an off-white solid (10.3 g, 62%).
Reaction SMILES: [C:1]([OH:11])(=O)[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[NH3:12]>>[C:1]([NH2:12])(=[O:11])[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3]
Reactant: N
Reactant: O=C(O)C(O)c1ccccc1
Product: NC(=O)C(O)c1ccccc1

Procedure:
Following Example 10 and replacing the salicylic acid with mandelic acid (1 cmole; 1.521 g) the result is a solution of the corresponding acid chloride which, when treated with ammonia gives mandelamide.