Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C2C(COC([NH:18][C@@H:19]([CH2:38][S:39][CH2:40][C@H:41]([O:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH3:76])[CH2:42][O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[C:20](=[O:37])[NH:21][C@@H:22]([CH2:35][CH3:36])[C:23](=[O:34])[NH:24][C@@H:25]([C:31](=[O:33])[NH2:32])[CH2:26][CH2:27][C:28]([OH:30])=[O:29])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>C(#N)C>[NH2:18][C@@H:19]([CH2:38][S:39][CH2:40][C@H:41]([O:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH3:76])[CH2:42][O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[C:20](=[O:37])[NH:21][C@@H:22]([CH2:35][CH3:36])[C:23](=[O:34])[NH:24][C@@H:25]([C:31](=[O:33])[NH2:32])[CH2:26][CH2:27][C:28]([OH:30])=[O:29]
Reactant: CCCCCCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](CC)C(=O)N[C@H](CCC(=O)O)C(N)=O)OCCCCCCCCCCCCCCCC
Solvent: CC#N
Solvent: C1CCNCC1
Product: CCCCCCCCCCCCCCCCOC[C@H](CSC[C@H](N)C(=O)N[C@@H](CC)C(=O)N[C@H](CCC(=O)O)C(N)=O)OCCCCCCCCCCCCCCCC
Reaction time: 0.5 h

Procedure:
A solution (4R,7S,10R,14R)-10-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-carbamoyl-7-ethyl-14-(hexadecyloxy)-6,9-dioxo-16-oxa-12-thia-5,8-diazadotriacontan-1-oic acid in acetonitrile (0.1M) was stirred at room temperature. Piperidine (final conc. 20%) was then added and the reaction stirred for 30 min After concentration, the product was purified by flash chromatography on an ISCO COMBIFLASH® system using a 0-10% MeOH/DCM gradient to give (4R,7S,10R,14R)-10-amino-4-carbamoyl-7-ethyl-14-(hexadecyloxy)-6,9-dioxo-16-oxa-12-thia-5,8-diazadotriacontan-1-oic acid. 1H NMR (DMSO d-6): δ 12.12 (br, s, 1H), 8.56(d, 1H), 8.14 (t, 2H), 8.12 (d, 1H), 7.25 (s, 1H), 7.05 (s, 1H), 4.21-4.34 (m, 2H), 3.95-3.97 (m, 1H), 3.44-3.52 (m, 3H), 3.32-3.40 (m, 3H), 2.96 (dd, 1H), 2.66-2.78 (m, 4H), 2.19 (t, 2H), 1.89-1.98 (m, 2H), 1.67-1.76 (m, 4H), 1.56-1.64 (m, 2H), 1.42-1.50 (m, 4H), 1.21-1.28 (m, 48H), 0.83-0.89 (m, 9H). LRMS [M+H]=857.7.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][N:18]=3)=[O:16])[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.[F:28][C:29]([F:45])([F:44])[CH:30]1[CH:35]([NH2:36])[CH2:34][CH2:33][N:32]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:31]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([NH:36][C@H:35]4[CH2:34][CH2:33][N:32]([C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])[CH2:31][C@H:30]4[C:29]([F:28])([F:44])[F:45])=[O:22])=[CH:19][N:18]=3)=[O:16])[CH2:13][CH2:14]2)=[O:8])=[CH:26][CH:27]=1
Reactant: COc1ccc(C(=O)C2CCN(C(=O)c3ccc(C(=O)O)cn3)CC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)C(C(F)(F)F)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)C2CCN(C(=O)c3ccc(C(=O)N[C@H]4CCN(C(=O)OC(C)(C)C)C[C@H]4C(F)(F)F)cn3)CC2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 65.4 %

Procedure:
To a mixture of 6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)nicotinic acid (0.094 g, 0.257 mmol, 1.0 eq), and 3-trifluoromethyl-4-amino-1-Boc-piperidine (0.257 mmol, 1.0 eq) was added dimethylformamide (2.5 mL) and triethylamine (0.054 mL, 0.386 mmol, 1.5 eq). HATU (0.107 g, 0.283 mmol, 1.1 eq) was added and the reaction was stirred at room temperature for 14 hours and partitioned between EtOAc (120 mL) and NaHCO3-water (1:1, 120 mL). The organics were further washed with brine (100 mL), water (100 mL) and brine (100 mL), dried (Na2SO4) and concentrated under reduced pressure. MPLC (0→10% MeOH—CH2Cl2) yielded the coupled product (0.104 g, 68%) as a colourless oil; 1H nmr (CDCl3) δ 8.90 (1H, br s, pyH-6), 8.08 (1H, br d, J 7.0 Hz, pyH-4), 7.92 (2H, d, J 9.0 Hz, 2H of C6H4OMe), 7.50 (2H, m, pyH-3, NH), 6.94 (2H, d, J 9.0 Hz, 2H of C6H4OMe), 4.61 (2H, m, 1H of pipH-2, H-4, H-6, 1H of BzpipH-2, H-6), 3.86 (3H, s, OCH3), 3.86-3.74 (2H, m, 1H of pipH-2, H-4, H-6, 1H of BzpipH-2, H-6), 3.52 (1H, m, BzpipH-4), 3.52-3.38 (2H, m, 2H of pipH-2, H-4, H-6), 3.26-3.04 (1H, m, 1H of pipH-2, H-3, H-4, H-6), 3.22 (1H, m, 1H of BzpipH-2, H-6), 3.12 (1H, t, J 11.5 Hz, 1H of BzpipH-2, H-6), 2.76 (1H, m, 1H of pipH-2, H-3, H-4, H-6), 2.00 (1H, m, 1H of BzpipH-3, H-5), 1.90-1.65 (5H, m, pipH-5, 3H of BzpipH-3, H-5), 1.45 (9H, s, C(CH3)3); 19F nmr (CDCl3) δ −62.7; m/z 619 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[N:13][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:15][CH:16]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1OS(C(F)(F)F)(=O)=O.[N:30]1[C:39]2[C:34](=[CH:35][C:36](B(O)O)=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][N:11]=[C:12]3[C:17]=2[CH:16]=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[N:13]3)=[CH:4][C:3]=1[C:36]1[CH:35]=[C:34]2[C:39](=[CH:38][CH:37]=1)[N:30]=[CH:31][CH:32]=[CH:33]2
Reactant: OB(O)c1ccc2ncccc2c1
Reactant: O=S(=O)(Oc1cc(-c2ccnc3nc(C(F)(F)F)ccc23)ccc1F)C(F)(F)F
Product: Fc1ccc(-c2ccnc3nc(C(F)(F)F)ccc23)cc1-c1ccc2ncccc2c1
Yield: 61 %

Procedure:
Trifluoromethanesulfonic acid 2-fluoro-5-(7-trifluoromethyl[1,8]naphthyridin-4-yl)phenyl ester (30.0 mg, 0.068 mmol) was coupled to 6-quinolinylboronic acid (15.3 mg, 0.089 mmol) as described in Example 35 part c), affording 5-(4-fluoro-3-quinolin-6-ylphenyl)-2-trifluoromethyl[1,8]naphthyridine (17.4 mg, 61%). δH (400 MHz, CDCl3) 7.43-7.57 (3H, m), 7.64 (1H, d, J 4.3), 7.69-7.72 (1H, m), 7.85 (1H, d, J 8.6), 7.97 (1H, dt, J 8.6 and 1.8), 8.06 (1H, s), 8.22 (2H, d, J 8.2), 8.59 (1H, d, J 8.6), 8.98 (1H, dd, J 1.8 and 4.1), 9.30 (1H, d, J 4.3). m/z (ES+) 420 [MH]+.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([CH2:10][C:11]2([C:24]([O:26]CC)=O)[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:8][C:7]([Br:29])=[CH:6][N:5]=1.O>C1COCC1>[Br:29][C:7]1[CH:8]=[C:9]2[C:4](=[N:5][CH:6]=1)[NH:3][C:24](=[O:26])[C:11]1([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:13][CH2:12]1)[CH2:10]2
Reactant: CCOC(=O)C1(Cc2cc(Br)cnc2N)CCN(C(=O)OC(C)(C)C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)Cc1cc(Br)cnc1NC2=O
Reaction time: 1 h

Procedure:
Sodium hydride (201 mg, 5.3 mmol) was added to a solution of 1-tert-butyl 4-ethyl 4-((2-amino-5-bromopyridin-3-yl)methyl)piperidine-1,4-dicarboxylate (1.71 g, 3.87 mmol) suspended in THF (17 mL) at room temperature. The reaction mixture was stirred for 1 hour and then diluted by addition of water (50 mL). The resulting precipitate was filtered and washed with pentane. The title compound was obtained as a beige solid (1.2 g, 78%).
Reaction SMILES: [CH:1]12[O:10][CH:2]1[CH2:3][C:4]1[C:9]2=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH3:11]>>[NH2:11][C@@H:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@H:2]1[OH:10]
Reactant: c1ccc2c(c1)CC1OC21
Reactant: N
Product: N[C@@H]1c2ccccc2C[C@H]1O

Procedure:
treating said indene oxide with ammonia or a primary amine to produce a trans-1-amino-2-indanol;
Reaction SMILES: [C:1]1([C:11]([OH:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Br:14]Br>C(O)(=O)C>[Br:14][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[CH:3][CH:2]=[C:1]2[C:11]([OH:13])=[O:12]
Reactant: BrBr
Reactant: O=C(O)c1cccc2ccccc12
Solvent: CC(=O)O
Product: O=C(O)c1cccc2c(Br)cccc12
Reaction time: 1.5 h
Yield: 76.6 %

Procedure:
To a stirred suspension of 1-naphthoic acid (90 g, 0.52 mol) in glacial acetic acid at 100° C. was added bromine (84 g, 0.52 mol). The reaction was stirred at this temperature for 1.5 hours and then allowed to cool overnight. The resulting slurry was diluted with glacial acetic acid, the solid collected by filtration, resuspended in water, filtered and dried in vacuo to give 5-bromo-1-napthoic acid (100 g). The acid was converted to the title compound using a similar procedure to Description 3 (68%).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[BH4-].[Na+]>C(O)C>[F:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH:4]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[OH:5]
Reactant: O=C(c1ccccc1)c1ccccc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC(c1ccccc1)c1ccccc1F
Reaction time: 20 h
Yield: 99 %

Procedure:
2-Fluorobenzophenone (15.0 g) is dissolved in ethanol and sodium borohydride (3.8 g) is added in portions and the mixture is stirred for 20 hours. The reacted solution is concentrated under reduced pressure and extracted with chloroform and water to give crude (2-fluorophenyl)phenylmethanol (15.0 g) (quantitative) as colorless liquid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH2:12])[CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[F:14][C:15]([F:28])([F:27])[C:16]1[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=1[CH:18]=[CH:19][C:20](Cl)=[O:21].C(OCC)C>C(O)(=O)C>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:20](=[O:21])[CH:19]=[CH:18][C:17]3[CH:23]=[CH:24][CH:25]=[CH:26][C:16]=3[C:15]([F:27])([F:28])[F:14])[CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1
Reactant: O=C(Cl)C=Cc1ccccc1C(F)(F)F
Reactant: Cc1cc(N)c2cc(N)ccc2n1
Solvent: CC(=O)O
Solvent: CCOCC
Product: Cc1cc(N)c2cc(NC(=O)C=Cc3ccccc3C(F)(F)F)ccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.4 %

Procedure:
4,6-Diamino-2-methyl-quinoline (0.5 g, 2.9 mmol) was placed in an oven-dried 100-mL three-necked flask under nitrogen followed by 3 mL of glacial acetic acid. A solution of 2-(trifluoro-methyl)cinnamoyl chloride (0.68 g, 2.89 mmol) in 1 mL of glacial acetic acid was added dropwise over a 2 min period to this mixture. A heavy precipitate resulted. The mixture was stirred at room temperature for 1 hr, diethyl ether (25 mL) added, and the hydrochloride salt filtered, washed with ether, and dried at room temperature in vacuo. The hydrochloride salt was dissolved in a warm mixture of 50% aqueous methanol and the solution filtered. The solution was made basic with sodium bicarbonate solution and the resulting solid filtered, washed with water, and dried at 50° C. under high vacuum. Recrystallization from hot methanol gave 0.68 g (63%) of the desired product; m.p. 272-273°.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-])=O.C(O)(=O)C.[H][H]>C(OCC)(=O)C.CO.[Pd]>[O:2]=[C:3]1[CH:4]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH2:5][C:6]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:12]1
Reactant: COC(=O)C(Cc1ccccc1[N+](=O)[O-])C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
tert-butyl 4-(1-methoxy-3-(2-nitrophenyl)-1-oxopropan-2-yl)piperidine-1-carboxylate (660 mg, 1.7 mmol) was dissolved in a mixture of ethyl acetate (15 mL) and methanol (15 mL). Acetic acid (250 μL, 4.4 mmol) was added to the mixture. A catalytic amount of 50% wet 10% palladium on carbon was added to the mixture. Reaction vessel was charged with 15 psi of hydrogen gas. Reaction shook on a Parr apparatus at room temperature for 2 hours. Reaction mixture was filtered to removed the catalyst. Filtrated was concentrated in vacuo. Silica gel chromatography gave the title compound as orange foam in 47% yield. MS m/e (M−H)−=329.1.
Reaction SMILES: [I-].[CH3:2][O:3][C:4]([C@@H:6]([O:11][C@H:12]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[N+:21]([CH3:25])[CH:22]=[CH:23][CH:24]=2)=[CH:15][CH:14]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])=[O:5].C([BH3-])#N.[Na+]>CO>[CH3:9][CH:8]([CH3:10])[CH2:7][C@H:6]([O:11][C@@H:12]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH2:20][N:21]([CH3:25])[CH2:22][CH2:23][CH:24]=2)=[CH:15][CH:14]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:4]([O:3][CH3:2])=[O:5]
Reactant: COC(=O)[C@H](CC(C)C)O[C@H](c1ccccc1)c1ccc(-c2ccc[n+](C)c2)cc1
Agent: [BH3-]C#N
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@H](CC(C)C)O[C@H](c1ccccc1)c1ccc(C2=CCCN(C)C2)cc1
Temperature: 65 °C

Procedure:
To a solution of 3-{4-[(R)-{[(1S)-1-(methoxycarbonyl)-3-methylbutyl]oxy}(phenyl)methyl]phenyl}-1-methylpyridinium iodide from example 36 step 3 (1.45 g, 2.72 mmol) in methanol (25 mL) was added in portions sodium cyanoborohydride (4.25 g, 67.6 mmol). The mixture was heated at 65° C. for 1 h and then concentrated. The residue was partitioned between diethyl ether (75 mL) and water (25 mL). The separated aqueous layer was extracted again with diethyl ether (75 mL). The combined ether layers were dried (Na2SO4), filtered, concentrated and chromatographed on silica gel using 10% methanol in dichloromethane as eluent to obtain the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:19](=[O:21])[CH3:20])[CH:6]=[C:7]([O:17][CH3:18])[C:8]=1[O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].C([N-]C(C)C)(C)C.[Li+].[S:30]1[C:34]([C:35]2[C:36]([O:45][CH3:46])=[CH:37][C:38]([O:43][CH3:44])=[C:39]([CH:42]=2)[CH:40]=O)=[CH:33][C:32]2[CH:47]=[CH:48][CH:49]=[CH:50][C:31]1=2>O1CCCC1>[S:30]1[C:34]([C:35]2[C:36]([O:45][CH3:46])=[CH:37][C:38]([O:43][CH3:44])=[C:39]([CH:40]=[CH:20][C:19]([C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][Si:10]([C:13]([CH3:16])([CH3:14])[CH3:15])([CH3:11])[CH3:12])=[C:7]([O:17][CH3:18])[CH:6]=3)=[O:21])[CH:42]=2)=[CH:33][C:32]2[CH:47]=[CH:48][CH:49]=[CH:50][C:31]1=2
Reactant: COc1cc(C(C)=O)cc(OC)c1O[Si](C)(C)C(C)(C)C
Reactant: COc1cc(OC)c(-c2cc3ccccc3s2)cc1C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(OC)c(-c2cc3ccccc3s2)cc1C=CC(=O)c1cc(OC)c(O[Si](C)(C)C(C)(C)C)c(OC)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 20 %

Procedure:
Ex-59B: To a solution of 3′,5′-dimethoxy-4′-(tert-butyldimethylsiloxy)acetophenone, from Ex-59A (0.5 g, 1.6 mmol) in tetrahydrofuran (10 mL) chilled with ice/water was added lithium diisopropylamide (2 M, 0.8 mL, 1.6 mmol). The mixture was stirred for 20 minutes while chilled. Then 5-(benzo[b]thien-2-yl)-2,4-dimethoxybenzaldehyde, from Ex-6A,(0.48 g, 1.6 mmol) in tetrahydrofuran (6 mL) was added, and the mixture was stirred at room temperature for 2 hours. Upon quenching with water, the mixture was extracted with dichloromethane. The organic phase was dried and evaporated. Crystallization from ethanol gave 0.19 g (20%) of the desired 3-[5-(benzo[b]thien-2-yl)2,4-dimethoxyphenyl]-1-(4-tert-butyldimethylsiloxy-3,5-dimethoxyphenyl)-2-propen-1-one as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[C:21](=[O:22])[CH:20]=[CH:19][C:18]4[C:23]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[C:24]([C:26]([NH2:28])=O)[S:25][C:17]3=4)=[CH:12][CH:11]=2)[CH:4]=[CH:5][N:6]=1.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl.C1COCC1>[CH3:1][C:2]1[N:3]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([N:16]3[C:21](=[O:22])[CH:20]=[CH:19][C:18]4[C:23]([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)=[C:24]([C:26]#[N:28])[S:25][C:17]3=4)=[CH:14][CH:15]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1nccn1CCOc1ccc(-n2c(=O)ccc3c(-c4ccccc4)c(C(N)=O)sc32)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1nccn1CCOc1ccc(-n2c(=O)ccc3c(-c4ccccc4)c(C#N)sc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
To a suspension of the compound of Example 107 (93 mg, 0.20 mmol) and pyridine (32 μL, 0.4 mmol) in DCM (1 mL) was added trifluoroacetic anhydride (34 μL, 0.24 mmol) and the reaction stirred at r.t. for 30 mins. A further 60 μL of trifluoroacetic anhydride was added and the reaction stirred for 18 h before being diluted with DCM (10 mL) and THF (5 mL). The mixture was washed with 2M NaOH(aq), brine and the organic layer separated and dried over MgSO4. Solvent was removed in vacuo and the residue purified by column chromatography (silica, 2–5% MeOH in DCM) to give the title compound as a solid (60 mg, 67%). δH (CDCl3) 7.62 (1H, d, J 9.7 Hz), 7.51–7.44 (5H, m), 7.30–7.27 (2H, m), 7.01–6.98 (2H, m), 6.89 (2H, d, J 0.9 Hz), 6.61 (1H, d, J 9.7 Hz), 4.30–4.20 (4H, m), 2.43 (3H, s). LCMS (ES+) RT 2.46 minutes, 453 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][O:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C.C(=O)([O-])[O-].[K+].[K+].Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33].C1(C)C=CC=CC=1>O>[CH3:1][N:2]([CH2:4][CH2:5][CH2:6][O:7][CH:8]([C:18]1[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=1)[CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:32]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: CCOC(=O)Cl
Reactant: CN(C)CCCOC(CCCc1ccccc1)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)N(C)CCCOC(CCCc1ccccc1)c1ccc(F)cc1

Procedure:
A mixture of 1.0 g of 1-[3-(N,N-dimethylamino)propoxy]-1-(p-fluorophenyl)-4-phenylbutane, 2.75 g of potassium carbonate, 11 ml of ethyl chloroformate and 20 ml of toluene was heated under refluxing for 2 hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1-[3-(N-methyl-N -ethoxycarbonylamino)propoxy]-1-(p-fluorophenyl)-4-phenylbutane.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[N:14]=[C:13]([O:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:12]([NH:22][C:23]2[C:24]3[C:31]([CH3:32])=[C:30]([C:33]([O:35]C)=[O:34])[S:29][C:25]=3[N:26]=[CH:27][N:28]=2)=[CH:11][CH:10]=1.OS([O-])(=O)=O.[K+]>>[CH3:3][O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[N:14]=[C:13]([O:15][CH:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)[C:12]([NH:22][C:23]2[C:24]3[C:31]([CH3:32])=[C:30]([C:33]([OH:35])=[O:34])[S:29][C:25]=3[N:26]=[CH:27][N:28]=2)=[CH:11][CH:10]=1
Reactant: COCCCOc1ccc(Nc2ncnc3sc(C(=O)OC)c(C)c23)c(OC2CCOCC2)n1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Product: COCCCOc1ccc(Nc2ncnc3sc(C(=O)O)c(C)c23)c(OC2CCOCC2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.3 %

Procedure:
Aqueous NaOH (2M, 0.175 mL) was added into a suspension of methyl 4-(6-(3-methoxypropoxy)-2-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-ylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylate (0.034 g, 0.07 mmol) and the reaction mixture stirred at ambient temperature for 18 hours. The solution was adjusted to pH 2 using 10% aqueous KHSO4 and the resultant suspension was filtered. The solid was washed with water, diethyl ether and dried in vacuo over P2O5 to afford off-white solid (0.024 g, 73%).
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].C([O-])(=O)C.[NH4+].[O:13]([C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)(=O)C>[O:13]([C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=[C:5]1[S:1][C:2](=[O:7])[NH:3][C:4]1=[O:6])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=C1NC(=O)C(=Cc2cccc(Oc3ccccc3)c2)S1
Temperature: 115 °C
Reaction time: 16 h

Procedure:
A solution of thiazolidine-2,4-dione (90%, 78 mg, 0.6 mmol) and ammonium acetate (92 mg, 1.2 mmol) in acetic acid (1 mL) was added to 3-phenoxybenzaldehyde (52 μL, 0.6 mmol) and the resulting mixture was shaken at 115° C. for 16 hours. After cooling, the mixture was concentrated in vacuo to afford the title compound.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Si]([O:26][CH2:27][CH2:28][O:29][C:30]1[C:35]([C:36]2[C:41]3[N:42]([CH2:54][C@H:55]4[CH2:60][CH2:59][C@H:58]([CH3:61])[CH2:57][CH2:56]4)[C:43]([N:45]4[CH2:50][CH2:49][O:48][C@@H:47]5[CH2:51][CH2:52][CH2:53][C@@H:46]45)=[N:44][C:40]=3[CH:39]=[C:38]([C:62]3[NH:66][C:65](=[O:67])[O:64][N:63]=3)[N:37]=2)=[CH:34][C:33]([Cl:68])=[CH:32][N:31]=1)(C(C)(C)C)(C)C>C1COCC1>[Cl:68][C:33]1[CH:34]=[C:35]([C:36]2[N:37]=[C:38]([C:62]3[NH:66][C:65](=[O:67])[O:64][N:63]=3)[CH:39]=[C:40]3[N:44]=[C:43]([N:45]4[CH2:50][CH2:49][O:48][C@@H:47]5[CH2:51][CH2:52][CH2:53][C@@H:46]45)[N:42]([CH2:54][C@H:55]4[CH2:56][CH2:57][C@H:58]([CH3:61])[CH2:59][CH2:60]4)[C:41]=23)[C:30]([O:29][CH2:28][CH2:27][OH:26])=[N:31][CH:32]=1
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ncc(Cl)cc1-c1nc(-c2noc(=O)[nH]2)cc2nc(N3CCO[C@@H]4CCC[C@H]43)n(C[C@H]3CC[C@H](C)CC3)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@H]1CC[C@H](Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3cc(-c4noc(=O)[nH]4)nc(-c4cc(Cl)cnc4OCCO)c32)CC1
Reaction time: 16 h

Procedure:
TBAF (0.1 mL, 1 M in THF, 0.1 mmol) was added to solution of 3-{4-[2-(2-{[tert-butyl(dimethyl)silyl]oxy]ethoxy)-5-chloropyridin-3-yl}-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one (racemic, 20 mg, 0.027 mmol) in THF (1.0 mL) at room temperature and stirred for 16 hours. The reaction was concentrated, and the residue was dissolved in CH2Cl2/IPA (4:1, 15 mL) and washed twice using water (10 mL). The layers were separated, and the organic layer was concentrated under reduced pressure. Purification of the residue on a silica gel column with 0 to 10% MeOH/CH2Cl2 afforded 3-{4-[5-chloro-2-(2-hydroxyethoxy)pyridin-3-yl]-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-d]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one (racemic). 1H NMR (400 MHz, CDCl3) δ 8.28 (br s, 2H), 7.26 (s, 1H), 4.70 (d, J=10.2 Hz, 1H), 3.90 (t, J=12.2 Hz, 2H), 3.70-3.80 (m, 3H), 3.45-3.74 (m, 2H), 3.17-3.32 (m, 2H), 3.10 (t, J=12.4 Hz, 2H), 2.39 (m, 1H), 1.99 (m, 1H), 1.88 (m, 1H), 1.66-1.76 (m, 2H), 1.45-1.62 (m, 6H), 1.02-1.32 (m, 2H), 0.88 (m, 1H), 0.77 (d, J=7.4 Hz, 3H), 0.42-0.60 (m, 2H). MS ES calc'd. for C30H36ClN7O5 [M−1]− 608. found 608.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:13]([O:15]C)=[O:14])[S:10][C:11]=2[CH3:12])=[C:5]([CH3:17])[CH:4]=[N:3]1.[OH-].[Na+]>O1CCCC1>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:13]([OH:15])=[O:14])[S:10][C:11]=2[CH3:12])=[C:5]([CH3:17])[CH:4]=[N:3]1
Reactant: COC(=O)c1cc(-c2c(C)cnn2C)c(C)s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cnn(C)c1-c1cc(C(=O)O)sc1C
Temperature: 70 °C
Reaction time: 8 h
Yield: 105.2 %

Procedure:
To a 100 mL round-bottomed flask was added methyl 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylate (1.31 g, 5.23 mmol) in Tetrahydrofuran (THF) (25 mL). 6N NaOH (30 mL, 180 mmol) was added slowly and the reaction stirred at 70° C. overnight. The reaction was cooled to room temperature, partitioned between CHCl3 and H2O and the pH of the aqueous layer adjusted to pH 3 by the addition of 6N HCl. The layers were separated, the organic layer was dried with Na2SO4 and the solvent was removed affording the title compound (1.3 g, 5.5 mmol, quant.) which was used without further purification: LC-MS (ES) m/z=237 (M+H)+.