Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([OH:5])=O.[NH2:13][C@H:14]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:16][CH2:17][CH3:18].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([NH:13][C@H:14]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:16][CH2:17][CH3:18])=[O:5]
Reactant: CCCC[C@H](N)C(=O)OCC
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCC[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)OCC
Temperature: 0 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
Boc-Gly-OH (4.4 g, 0.025 mol.) and Nleu-OEt (3.2 g, 0.02 mol.) were dissolved in 100 ml DMF and the solution was chilled to 0° C. on a water-ice bath. BOP (11 g, 0.025 mol.) was added to the solution. Triethylamine was used to adjust the pH of the solution to about 9. The solution was stirred overnight. The DMF was removed under reduced pressure and the resulting mixture was poured into 300 ml ethyl acetate. The ethyl acetate solution was washed by H2O, saturated NaHCO3, brine, saturated Na2SO4 and brine again. The organic layer was dried by Na2SO4 and the ethyl acetate was removed under reduced pressure to get the crude product. Column chromatography (elution solvents: E/H, 2:1) was carried out to obtain the pure product (5.9 g, 94%). TLC Rf=0.52 (developing solvents: E/H, 2:1). 1H-NMR (360 MHz, DMSO-d6) δ 6.74 (m, Gly-NH), 6.68 (m, Gly-NH), 4.18 (s, Nleu-α), 4.12 (q, ethyl ester-CH2), 4.04 (q, ethyl ester-CH2), 3.94 (s, Nleu-α), 3.79 (d, Gly-α), 3.65 (d, Gly-α), 3.07 (m, Nleu-β), 1.79 (m, 1H, Nleu-γ), 1.34 (s, 9H, Boc-CH3), 1.16 (m, ethyl ester-CH3), 0.87 (d, Nleu-δ), 0.78 (d, Nleu-δ).
Reaction SMILES: [C:1]1([S:7]([NH:10][NH:11][C:12](=[O:25])[C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:15][CH:14]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(O)C=CC=CC=1>O>[C:1]1([S:7]([NH:10][NH:11][C:12](=[O:25])[C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[CH:17][CH:18]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)C#Cc1ccc(C(=O)NNS(=O)(=O)c2ccccc2)cc1
Solvent: O
Solvent: Oc1ccccc1
Product: CC(C)(C)CCc1ccc(C(=O)NNS(=O)(=O)c2ccccc2)cc1

Procedure:
Example 38 was synthesized in accordance with the methods of Example 33, except that 4-(3,3-dimethyl-1-butynyl)benzoic acid, 2-(phenylsulfonyl)hydrazide (Example 37) was used instead of 4-phenacetylenyl-benzoic acid, 2-(phenylsulfonyl)hydrazide. MS: 361 (M+1 for C19H24N2O3S1); mp 168-169° C.; TLC (SiO2) Rf=0.7 (50% EtOAc/hexanes); HPLC (phenol hexal column, 1:1CH3CN/H2O+0.1% TFA) 99%, RT=16.8 min. 1H NMR (CDCl3) δ 0.95 (s, 9 H), 1.42-1.50 (m, 2H), 2.56-2.62 (m, 2H), 7.21-7.26 (m, 2H), 7.40-7.60 (m, 6H), 7.94 (d, 2H, J=7.8 Hz), 8.13-8.14 (m, 1H).
Reaction SMILES: C(OC(=O)C)C.Cl.C(OCC)(=O)C.C(O[C:19](=O)[N:20](C)[CH2:21][CH2:22][N:23]([CH2:31][CH2:32][CH2:33][O:34][C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][CH:44]=1)[N:41]([CH3:45])[C:40](=[O:46])[CH:39]=[CH:38]2)[CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1)(C)(C)C>CO>[CH3:45][N:41]1[C:42]2[C:37](=[CH:36][C:35]([O:34][CH2:33][CH2:32][CH2:31][N:23]([CH2:22][CH2:21][NH:20][CH3:19])[CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)=[CH:44][CH:43]=2)[CH:38]=[CH:39][C:40]1=[O:46]
Reactant: CN(CCN(CCCOc1ccc2c(ccc(=O)n2C)c1)Cc1ccncc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CNCCN(CCCOc1ccc2c(ccc(=O)n2C)c1)Cc1ccncc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 109.4 %

Procedure:
A 4N-hydrogen chloride ethyl acetate solution (48 ml) was added to an ethyl acetate solution (300 ml) of methyl-(2-{[3-(1-methyl-2-oxo-1,2-dihydro-quinolin-6-yloxy)-propyl]-pyridin-4-ylmethyl-amino}-ethyl)-carbamic acid tert-butyl ester (11.5 g), and the mixture was stirred at room temperature overnight. The reaction mixture was condensed under reduced pressure. PL-HCO3 (40 g) was added to the methanol solution of the residue and followed by celite filtration. The filtrate was condensed under reduced pressure to give the title compound (9.96 g) as a brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:12])C(=O)[NH:8]2)=[C:4]([F:13])[CH:3]=1.[OH:14]O>[OH-].[Na+]>[NH2:8][C:9]1[CH:10]=[C:2]([Br:1])[CH:3]=[C:4]([F:13])[C:5]=1[C:6]([OH:12])=[O:14]
Reactant: OO
Reactant: O=C1Nc2cc(Br)cc(F)c2C1=O
Agent: [Na+]
Agent: [OH-]
Product: Nc1cc(Br)cc(F)c1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-bromo-4-fluoroindoline-2,3-dione (7.4 g, 31.8 mmol) in 1 M NaOH (100 mL) was added 38% H2O2 (13 mL) dropwise. The resulting solution was stirred at rt for 2 h. The mixture was filtered and the filtrate was acidified using hydrochloric acid (2 N) till pH became around 2. The precipitate was formed and filtered, washed with water, dried under vacuum to give 2.8 g of the desired product. MS (ESI): 232, 234 (MH−).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:22])[CH2:13][CH2:12][C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:14]#[N:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-].[K+].Br[CH2:26][CH:27]1[CH2:29][CH2:28]1.O>CS(C)=O>[CH:27]1([CH2:26][O:22][C:8]2([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:13][CH2:12][C:11]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)([C:14]#[N:15])[CH2:10][CH2:9]2)[CH2:29][CH2:28]1
Reactant: N#CC1(c2ccccc2)CCC(O)(c2ccc(F)cc2)CC1
Reactant: BrCC1CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: N#CC1(c2ccccc2)CCC(OCC2CC2)(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
500 mg of 4-(4-fluorophenyl)-4-hydroxy-1-phenylcyclohexanecarbonitrile were dissolved in 10 ml of dry dimethyl sulfoxide, treated with 190 mg of potassium hydroxide and stirred for 30 min at room temperature. Subsequently, 0.17 ml of bromomethylcyclopropane were slowly added dropwise. The reaction mixture was stirred for 24 h, treated with water and extracted with EA. The combined organic phases were dried over magnesium sulfate and the solvent was removed in vacuo. The crude product, a clear oil, was purified by chromatography on silica gel using HEP/EA (2:1). 510 mg of the title compound were obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([F:9])=[CH:4][N:3]=1.[H-].[Na+].[Cl:12][C:13]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[C:14]=1[C:15](Cl)=[O:16].O>CN(C)C=O>[Cl:12][C:13]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[C:14]=1[C:15]([NH:8][C:6]1[C:5]([F:9])=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=1)=[O:16]
Reactant: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Reactant: Nc1cc(Cl)ncc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1cc(Cl)ncc1F)c1c(Cl)cc(Cl)cc1Cl
Reaction time: 0.25 h
Yield: 54 %

Procedure:
To a solution of 2-chloro-5-fluoropyridin-4-amine (200 mg, 1.36 mmol) in dry N,N-dimethylformamide (10 mL) was added sodium hydride (65.5 mg, 2.73 mmol) in one portion at room temperature under N2. The reaction mixture was then stirred for 15 min and then a solution of 2,4,6-trichlorobenzoyl chloride (320 uL, 2.0 mmol) in N,N-dimethylforamide (400 uL) was added dropwise. The mixture was stirred at room temperature for 10 mins, and then poured into water (30 mL). The mixture was extracted with ethyl acetate (2×50 mL), and combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-5% methanol/dichloromethane) to give 2,4,6-trichloro-N-(2-chloro-5-fluoropyridin-4-yl)benzamide (260 mg, yield: 54%). 1H NMR (DMSO-d6, 400 MHz): δ 11.52 (s, 1H), 8.49 (s, 1H), 8.33 (d, J=5.5 Hz, 1H), 7.84 (s, 2H). LCMS (ESI) m/z: 354.9 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.Cl.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:16][CH2:17][N:18]([C:22](=[O:29])[C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[CH2:19][CH2:20]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=C(Cl)c1ccncc1
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)c2ccncc2)CC1
Reaction time: 2 h
Yield: 76 %

Procedure:
1-(5-Chloro-8-piperazin-1-ylquinolin-7-yl)ethanone (0.030 g, 0.10 mmol, from Example 47, Step 1) was combined with isonicotinoyl chloride hydrochloride (0.028 g, 0.16 mmol) and triethylamine (0.058 mL, 0.41 mmol) in methylene chloride (1.0 mL) at room temperature and stirred for 2 hrs. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4, concentrated and purified on silica gel (eluting with 0 to 5% methanol in dichloromethane) to give the desired product (30 mg, 73%). LCMS calculated for C21H20ClN4O2 (M+H)+: m/z=395.1; Found: 395.1.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:24])[NH:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([C:19]([F:22])([F:21])[F:20])[CH:11]=2)[C:5]1=[O:23].CS(O[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][S:39][CH2:40][CH2:41][CH2:42][C:43]([F:49])([F:48])[C:44]([F:47])([F:46])[F:45])(=O)=O.O>CN(C=O)C>[CH3:3][C:4]1([CH3:24])[N:8]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][S:39][CH2:40][CH2:41][CH2:42][C:43]([F:49])([F:48])[C:44]([F:45])([F:46])[F:47])[C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([C:19]([F:22])([F:21])[F:20])[CH:11]=2)[C:5]1=[O:23]
Reactant: CS(=O)(=O)OCCCCCCCCCSCCCC(F)(F)C(F)(F)F
Reactant: CC1(C)NC(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCCCCCSCCCC(F)(F)C(F)(F)F
Temperature: 23 °C
Yield: 72 %

Procedure:
NaH (at 60%) (44 mg, 1.1 mmole), is added under argon to a solution of 5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]-imidazolidine-2,4-dione (317 mg, 1 mmole) in anhydrous DMF (8 ml). A release of gas accompanies the change in colour of the reaction medium which becomes orange. Stirring is maintained for 1 hour at 23° C. before adding 9-[(4,4,5,5,5-pentafluoropentyl)-thio]nonyl methanesulphonate (prepared according to an experimental protocol described in WO 2005077968) (332 mg, 0.8 mmole). After reaction for 15 hours, the reaction medium is poured into water (25 ml) and extracted with AcOEt (2×25 ml). The organic phases are combined and washed successively with water (25 ml) and salt water (25 ml). After drying over Na2SO4, the organic solution is filtered and concentrated under vacuum. The evaporation residue is purified on a silica column (eluent: CH2Cl2/AcOEt: 1/1 to 0/1). The expected compound is obtained in the form of a pale yellow oil with a yield of 72% (364 mg).
Reaction SMILES: [CH3:1][C:2]([C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]3[N:17](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:18]=[CH:19][C:12]=23)[S:9][CH:10]=1)([CH3:5])[C:3]#[N:4].C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:17]1[C:13]2=[N:14][CH:15]=[CH:16][C:11]([C:8]3[S:9][CH:10]=[C:6]([C:2]([CH3:5])([CH3:1])[C:3]#[N:4])[N:7]=3)=[C:12]2[CH:19]=[N:18]1
Reactant: CC(C)(C#N)c1csc(-c2ccnc3c2cnn3C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C#N)c1csc(-c2ccnc3[nH]ncc23)n1
Reaction time: 1 h
Yield: 77.5 %

Procedure:
A solution of 2-methyl-2-[2-(1-tritylpyrazolo[5,4-b]pyridin-4-yl)thiazol-4-yl]propanenitrile (239 mg, 0.4671 mmol) in DCM (6 mL) was treated with triethylsilane (727.8 mg, 999.7 μL, 6.259 mmol) followed by dropwise addition of TFA (296.0 mg, 200.0 μL, 2.596 mmol). The mixture was allowed to stir for 1 hour and then concentrated in vacuo and purified by column chromatography (EtOAc) to give the desired product as a yellow solid (97.5 mg, 78% Yield). 1H NMR (DMSO, 400 MHz) δ 1.84 (6H, s), 7.73 (1H, d), 8.04 (1H, s), 8.64 (1H, s), 8.67 (1H, d), 13.98 (1H, br s); MS (ES+) 270.03
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH2:11]1[O:21][C:14]2([CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]2)[O:13][CH2:12]1.[S:22]1[C:26]2[CH:27]=[C:28]([C:31](Cl)=[O:32])[CH:29]=[CH:30][C:25]=2[N:24]=[CH:23]1.O>C1COCC1>[S:22]1[C:26]2[CH:27]=[C:28]([C:31]([CH:18]3[C:17](=[O:20])[CH2:16][CH2:15][C:14]4([O:13][CH2:12][CH2:11][O:21]4)[CH2:19]3)=[O:32])[CH:29]=[CH:30][C:25]=2[N:24]=[CH:23]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: O=C(Cl)c1ccc2ncsc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1CCC2(CC1C(=O)c1ccc3ncsc3c1)OCCO2
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 35.6 %

Procedure:
Under a nitrogen atmosphere, lithium hexamethyldisilazide (2.4 mL, 2.4 mmol) was mixed with THF (5 mL). The reaction was cooled to −78° C. 1,4-cyclohexane-dione monoethylene acetal (374 mg, 2.4 mmol), dissolved in THF (2 mL) was slowly added via dropping funnel. The reaction was stirred for 20 min at −78° C. It was then cannulated to a flask, cooled at −78° C., containing benzothiazole-6-carbonyl chloride (498 mg, 2.52 mmol) dissolved in THF (5 mL). After the addition, the reaction was stirred at −78° C. for 1 hr, and then allowed to warm to room temperature. After 12 h, water (30 mL) was added and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with 10% citric acid (20 mL), water (20 mL), bicarb (20 mL), and brine (20 mL). It was then dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by silica gel column (1:1 EtOAc/Hexanes) to yield 7-(Benzothiazole-6-carbonyl)-1,4-dioxa-spiro[4.5]decan-8-one (271 mg, 35%, light yellow solid).
Reaction SMILES: [OH:1][CH:2]1[CH2:11][CH2:10][NH:9][C:8]2[N:7]=[CH:6][C:5]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)=[O:19])=[CH:14][CH:13]=3)=[CH:4][C:3]1=2.[Cl:27][C:28]1[CH:29]=[C:30](O)[CH:31]=[CH:32][CH:33]=1>CO.C(Cl)Cl>[Cl:27][C:28]1[CH:33]=[C:32]([CH:31]=[CH:30][CH:29]=1)[O:1][CH:2]1[CH2:11][CH2:10][NH:9][C:8]2[N:7]=[CH:6][C:5]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([N:20]4[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]4)=[O:19])=[CH:16][CH:17]=3)=[CH:4][C:3]1=2
Reactant: Oc1cccc(Cl)c1
Reactant: CN1CCN(C(=O)c2ccc(-c3cnc4c(c3)C(O)CCN4)cc2)CC1
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(C(=O)c2ccc(-c3cnc4c(c3)C(Oc3cccc(Cl)c3)CCN4)cc2)CC1
Yield: 50 %

Procedure:
[4-(5-Hydroxy-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)phenyl]-(4-methylpiperazin-1-yl)methanone (20 mg) was reacted with 3-chlorophenol (21.8 mg) as in General Procedure 12. Silica gel chromatography using a gradient of 0-15% methanol/CH2Cl2 as the eluting solvent gave the title compound as a yellow foam (50% yield). LCMS: m/z=463.12(M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.00-2.12 (m, 1H), 2.27-2.33 (m, 1H), 2.33 (s, 3H), 2.34-2.6 (m, 4H), 3.4-3.7 (m, 4H), 3.7-3.9 (m, 2H), 5.18 (bs, 1H), 5.38 (t, J=3.6 Hz, 1H), 6.91 (dd, J=1.6 and 8.3 Hz, 1H), 6.99-7.04 (m, 2H), 7.23-7.27 (m, 1H), 7.43-7.50 (m, 4H), 7.61 (d, J=2.0 Hz), 8.30 (d, J=2.2 Hz).
Reaction SMILES: [CH3:1][Mg]Br.[F:4][C:5]([F:44])([F:43])[C:6]1[CH:7]=[C:8]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[CH2:9][N:10]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[C:26]1[CH:31]=[C:30]([CH:32]=[O:33])[CH:29]=[CH:28][C:27]=1[O:34][CH3:35])[C:11](=[O:14])[O:12][CH3:13].[Cl-].[NH4+]>O1CCCC1>[F:4][C:5]([F:43])([F:44])[C:6]1[CH:7]=[C:8]([CH:36]=[C:37]([C:39]([F:40])([F:42])[F:41])[CH:38]=1)[CH2:9][N:10]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[C:26]1[CH:31]=[C:30]([CH:32]([OH:33])[CH3:1])[CH:29]=[CH:28][C:27]=1[O:34][CH3:35])[C:11](=[O:14])[O:12][CH3:13]
Reactant: C[Mg]Br
Reactant: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C=O)ccc1OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)O)ccc1OC
Temperature: 25 °C

Procedure:
Methylmagnesium bromide (0.59 mL, 0.83 mmol) was added dropwise to a solution of methyl [3,5-bis(trifluoromethyl)benzyl]{[5′-formyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate (Example 73, 289 mg, 0.49 mmol) in anhydrous tetrahydrofuran at 0° C. The solution was allowed to warm to room temperature. Once the reaction was complete, saturated ammonium chloride solution was added to quench the reaction. The mixture was extracted with methylene chloride, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The title compound was obtained by flash chromatography using 30% acetone/hexane. 1H NMR (CDCl3, 600 MHz) δ 7.73 (s, 1H), 7.58 (m, 1H), 7.32-7.51 (m, 5H), 7.11 (m, 1H), 6.94 (m, 1H), 4.87 (m, 1H), 4.25-4.43 (m, 4H), 3.69 (m, 6H), 1.48 (d, J=4.2 Hz, 3H). LC-MS (M+Na) 632.0 (4.18 min).
Reaction SMILES: N.[C:2]1([CH:8]([CH3:10])C)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:11]>>[C:8]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:11])[CH3:10]
Reactant: CC(C)c1ccccc1
Reactant: O
Agent: N
Product: CC(=O)c1ccccc1

Procedure:
Binary Azeotrope: A water borne solution of SMA ammonia adducts (25% solid) was heated. At 93° C., a binary azeotrope mixture of cumene and acetophenone was formed that carried cumene and acetophenone out of the resin solution. After keeping the solution at 93° C. for six hours, the level of acetophenone was reduced to 2% (a 98% reduction) and the level of cumene was reduced to 25% (a 75% reduction) of their original levels. An azeotrope can also be formed under reduced pressure. Similar results in the reduction of cumene and acetophenone levels were obtained under reduced pressure (0.15 atmosphere) at 93° C. and four hours.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[OH:11].Cl[C:13]([C:15]1[CH:33]=[CH:32][C:18]([CH2:19][N:20]([CH3:31])[C:21](=[O:30])[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:17][CH:16]=1)=O>>[CH2:23]([O:22][C:21]([N:20]([CH2:19][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[O:11][C:3]3[C:4]([C:5]([OH:7])=[O:6])=[CH:8][CH:9]=[CH:10][C:2]=3[N:1]=2)=[CH:33][CH:32]=1)[CH3:31])=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CN(Cc1ccc(C(=O)Cl)cc1)C(=O)OCc1ccccc1
Reactant: Nc1cccc(C(=O)O)c1O
Product: CN(Cc1ccc(-c2nc3cccc(C(=O)O)c3o2)cc1)C(=O)OCc1ccccc1

Procedure:
2-(4-(((Benzyloxycarbonyl)(methyl)amino)methyl)phenyl)benzo[d]oxazole-7-carboxylic acid is prepared from 3-aminosalicylic acid and benzyl 4-(chlorocarbonyl)benzyl(methyl)carbamate using identical conditions described in Example 3A. MS (ESI) m/e 417 [M+H]+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:24]=[CH:23][CH:22]=[CH:21][C:11]=1[O:12][C:13]1[N:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=1[Cl:20].[Cl:25][C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=1[S:36](Cl)(=[O:38])=[O:37]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:24]=[CH:23][CH:22]=[CH:21][C:11]=1[O:12][C:13]1[N:18]=[CH:17][C:16]([NH:19][S:36]([C:27]2[CH:28]=[CH:29][C:30]([C:32]([F:33])([F:34])[F:35])=[CH:31][C:26]=2[Cl:25])(=[O:38])=[O:37])=[CH:15][C:14]=1[Cl:20]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Cl
Reactant: Nc1cnc(Oc2ccccc2-c2nc3ccccc3s2)c(Cl)c1
Product: O=S(=O)(Nc1cnc(Oc2ccccc2-c2nc3ccccc3s2)c(Cl)c1)c1ccc(C(F)(F)F)cc1Cl

Procedure:
The title compound was prepared by reacting 6-(2-(benzo[d]thiazol-2-yl)phenoxy)-5-chloropyridin-3-amine (obtained as per procedure described in preparation 4) and 2-chloro-4-(trifluoromethyl)benzene-1-sulfonyl chloride.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[CH:22]=O)[CH:7]=1)[CH3:2].[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[CH2:22][NH:32][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:7]=1)[CH3:2]
Reactant: NCc1ccccc1
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2C=O)c1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CNCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 3, Step 2, using the following starting materials: [3-(4-bromo-2-formyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester and benzylamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[O:11][CH2:10][CH:9]=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[H][H]>C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[C:12]2[O:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1OCC=C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1cccc2c1OCCC2

Procedure:
The compound obtained in Step B (1 g:6.84 mmol) dissolved in glacial acetic acid (10 ml) is poured into the reactor of a Paar apparatus. 10% palladium on carbon (10% by weight; 100 mg), acting as catalyst, is added. The whole is then subjected to a hydrogen pressure of 45 psi for 12 hours at room temperature. After filtration, the solvent is removed under reduced pressure and then extraction is carried out with dichloromethane. The recovered organic phase, dried over magnesium sulphate, is purified after concentration over a silica column eluted with pure dichloromethane. The title product is obtained pure in the form of a yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].O1CCCC1.Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>CN(C)C=O>[CH2:20]([O:19][C:17]([C:9]1[N:10]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:11]2[C:16]([C:8]=1[NH:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:18])[CH3:21]
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)c1[nH]c2ccccc2c1Nc1ccncc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)Cn1c(C(=O)OCC)c(Nc2ccncc2)c2ccccc21
Temperature: 0 °C
Yield: 50 %

Procedure:
Under nitrogen, stir and cool to 0° C. a mixture of ethyl 3-(4-pyridinylamino)indole-2-carboxylate (see U.S. Pat. No. 5,328,920; 0.20 g, 0.711 mmol) in dimethylformamide (5 mL). Add a 1M solution of potassium tert-butoxide in tetrahydrofuran (0.75 mL, 0.75 mmol) in one portion, stir for 10 min, and then add ethyl bromoacetate (0.12 g, 0.72 mmol) in one portion. Stir at 0° C. for 50 min and quench the reaction into water (30 mL). Extract the aqueous mixture with ethyl acetate (2×20 mL), combine the extracts, wash with water (25 mL), brine (25 mL) and dry over MgSO4. Concentrate under vacuum, chromatograph the residue on a Redisep silica gel cartridge (10 g) eluting with 5% methanol/dichloromethane to 20% methanol/dichloromethane. Combine non-homogeneous fractions concentrate and chromatograph again as above. Combine all homogenous fractions and concentrate to obtain 0.13 g (50%) of the title compound as a white solid: MS 368(M+H).