Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([F:20])=[CH:16][C:17]=3[F:19])[N:12]=[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[C:10]=2[CH3:27])=[CH:6][C:5]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:4][N:3]=1.[CH3:34][O:35][C:36]1[CH:41]=[C:40](B(O)O)[CH:39]=[CH:38][N:37]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[F:19][C:17]1[CH:16]=[C:15]([F:20])[CH:14]=[C:13]2[C:18]=1[C:9]([NH:8][C:7]1[C:2]([C:40]3[CH:39]=[CH:38][N:37]=[C:36]([O:35][CH3:34])[CH:41]=3)=[N:3][CH:4]=[C:5]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)[CH:6]=1)=[C:10]([CH3:27])[C:11]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)=[N:12]2
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1Cl
Reactant: COc1cc(B(O)O)ccn1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(-c2ncc(N3CCOCC3)cc2Nc2c(C)c(-c3ccccn3)nc3cc(F)cc(F)c23)ccn1
Temperature: 90 °C
Reaction time: 19 h

Procedure:
N-(2-chloro-5-morpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)-quinolin-4-amine (42.8 mg, 0.091 mmol), 2-methoxypyridin-4-ylboronic acid (28.7 mg, 0.19 mmol), tricyclohexylphosphine (5.1 mg, 0.018 mmol), and tris(dibenzylideneacetone)dipalladium (0) (5.7 mg, 6.2 μmol) were added to a flask then degassed and backfilled with argon. To the flask, 1,4-dioxane (1.0 mL) and aq. 1.3M potassium phosphate tribasic (0.22 mL, 0.29 mmol) were added by syringe. The resulting reaction was heated to 90° C. and monitored with TLC and LC-MS. After 19 h, the reaction was cooled to rt then poured into water. After extracting twice with EtOAc and twice with DCM, the combined organic extractions were dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on basic alumina (0-100% EtOAc in hexanes) to afford an impure yellow residue. The light yellow film was further purified with HPLC (10-90% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution). The desired fractions were cond then diluted with EtOAc. After washing twice with satd aq. sodium bicarbonate solution and once with brine, the solvent was removed under reduced pressure to yield a light yellow solid as 5,7-difluoro-N-(2′-methoxy-5-morpholino-2,4′-bipyridin-3-yl)-3-methyl-2-(pyridin-2-yl)quinolin-4-amine. 1H NMR (400 MHz, CDCl3) δ ppm 8.69 (1H, dt, J=4.8, 1.4 Hz), 8.35 (1H, m), 8.10 (1H, m), 7.98 (2H, m), 7.70 (1H, m), 7.47 (1H, m), 7.37 (1H, m), 7.21 (1H, s), 7.00 (2H, ddd, J=13.5, 8.6, 2.5 Hz), 6.55 (1H, d, J=2.3 Hz), 4.05 (3H, m), 3.89 (4H, m), 3.28 (4H, m), 2.31 (3H, m). Mass Spectrum (pos.) m/e: 541.2 (M+1).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[C:12]([CH2:14]OS(C)(=O)=O)[N:11]=[C:10]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:28])=[CH:22][CH:21]=2)[N:9]=1.[NH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)Cl>[NH:36]([CH2:14][C:12]1[CH:13]=[C:8]([N:3]2[CH2:4][CH2:5][O:6][CH2:7][C@@H:2]2[CH3:1])[N:9]=[C:10]([C:20]2[CH:21]=[CH:22][C:23]([NH:26][C:27]([NH:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[O:28])=[CH:24][CH:25]=2)[N:11]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: C[C@H]1COCCN1c1cc(COS(C)(=O)=O)nc(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Reactant: Nc1ccccc1
Solvent: ClCCl
Product: C[C@H]1COCCN1c1cc(CNc2ccccc2)nc(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 39.5 %

Procedure:
1-[4-[4-[(3S)-3-Methylmorpholin-4-yl]-6-(methylsulfonyloxymethyl)pyrimidin-2-yl]phenyl]-3-phenyl-urea (105 mg, 0.21 mmol) dissolved in a solution of DCM (5 mL) was added to aniline (0.097 mL, 1.06 mmol) and stirred at RT for 18 h. The mixture was vacuumed to dryness and purified by prep-HPLC (basic) to give the desired material (41 mg) as a white solid.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4([C:24]#[N:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.P([O-])(OCC)(SCC)=[S:27]>>[CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4([C:24](=[S:27])[NH2:25])[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CCOP([O-])(=S)SCC
Reactant: N#CC1(c2ccc(OC3CCN(C4CCC4)CC3)cc2)CCOCC1
Product: NC(=S)C1(c2ccc(OC3CCN(C4CCC4)CC3)cc2)CCOCC1
Yield: 50 %

Procedure:
The title compound (223 mg, 50%) was prepared from 4-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}tetrahydro-2H-pyran-4-carbonitrile and diethyl dithiophosphate similarly to the procedure used for intermediate 50. LRMS APCI+ m/z 375 [MH]+.
Reaction SMILES: [CH3:1][C:2](=[O:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH:13]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([CH3:24])[CH3:23])[C:17]=1[N:25]=[C:26]=[O:27])([CH3:15])[CH3:14].C([N-]C(C)C)(C)C.[Li+]>>[CH3:15][CH:13]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([CH3:23])[CH3:24])[C:17]=1[NH:25][C:26](=[O:27])[CH2:1][C:2](=[O:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH3:14]
Reactant: CCCCCCCCCC(C)=O
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CCCCCCCCCC(=O)CC(=O)Nc1c(C(C)C)cccc1C(C)C

Procedure:
The title compound was prepared from 2-undecanone (5.0 g, 0.029 mol), 2,6-diisopropylphenyl isocyanate (5.96 g, 0.029 mol), and lithium diisopropylamide (0.029 mol) using the procedure described in Example 1. The desired product was obtained in 79.4% yield (8.6 g, 0.023 mol).
Reaction SMILES: S(Cl)([Cl:3])=O.N1C2C=CC=CC=2N=N1.[F:14][C:15]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:16]=1[CH:17]=[CH:18][CH2:19]O>ClCCl>[Cl:3][CH2:19]/[CH:18]=[CH:17]/[C:16]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:15]=1[F:14]
Reactant: OCC=Cc1cc(F)ccc1F
Reactant: O=S(Cl)Cl
Agent: c1ccc2[nH]nnc2c1
Solvent: ClCCl
Product: Fc1ccc(F)c(/C=C/CCl)c1
Reaction time: 0.17 h
Yield: 100 %

Procedure:
A solution of 0.66 cm3 (9.07 mmol) of thionyl chloride and 1.08 g (9.07 mmol) of benzotriazole in 70 cm3 of dichloromethane are added at a temperature in the region of 20° C., under an argon atmosphere, to 1.25 g (7.34 mmol) of 2,5-difluorocinnamyl alcohol in solution in 130 cm3 of dichloromethane. After stirring for 10 minutes, the reaction mixture is filtered on No. 3 sintered glass and the solid residue rinsed with twice 20 cm3 of dichloromethane. The filtrate is washed with 3 times 75 cm3 of water. The organic phase is dried over anhydrous magnesium sulfate and filtered to give a solution of 2-[(1E)-3-chloro-1-propenyl]-1,4-difluorobenzene (7.34 mmol) which is immediately used as it is in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH:7]([C:13]([O:15]C)=[O:14])[CH2:8]2.P([O-])([O-])([O-])=O.OS(O)(=O)=O.CC(=O)OCC(COC(=O)C)OC(=O)C.[OH-].[Na+].C(=O)(O)[O-].[Na+]>C(O)(C)(C)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C@@H:7]([C:13]([OH:15])=[O:14])[CH2:8]2
Reactant: COC(=O)C1CCc2c(cccc2OC)C1
Agent: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: CC(=O)OCC(COC(C)=O)OC(C)=O
Solvent: CC(C)(C)O
Product: COc1cccc2c1CC[C@@H](C(=O)O)C2
Reaction time: 8 h
Yield: 16.2 %

Procedure:
0.8 g (0.0036 mol) of methyl 5-methoxy-1,2,3,4-tetrahydro-2-naphthoate is dissolved in 28 ml of tert-butanol, and 80 ml of phosphate buffer at pH 7 are added to the solution prepared in this way. The pH of the solution, which rises to 7.3-7.5, is lowered to 7.1 by the addition of dilute H2SO4. 0.450 g of Sigma PPL enzyme (known as porcine pancreatic lipase type II, crude, Sigma L-3126--46 U/mg using triacetin) is added to the mixture. The pH tends to drop as the reaction progresses, but is kept constant by the addition of a 0.25N solution of NaOH, the pH being controlled by an automatic titration apparatus. After 8 hours, sodium bicarbonate is added to the solution until the pH is 7.7 in order to stop the reaction by inactivation of the enzyme. Extraction is carried out with isopropyl ether and the two phases are separated. The organic phase contains the unreacted ester principally of (S) configuration. The aqueous phase is acidified with concentrated sulfuric acid and extracted with ethyl ether, the organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure. The product obtained is crystallized from isopropyl ether to give 0.12 g of the title compound. M.p. 150°-152° C.; [α]D20 =+55.9° (c=1.4%, CHCl3); ee 85.6% (HPLC performed under conditions (e)).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH2:28]([CH2:30][NH2:31])[OH:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[OH:29][CH2:28][CH2:30][NH:31][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:13]
Reactant: NCCO
Reactant: Cn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)NCCO)ccc21
Yield: 82 %

Procedure:
1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethyl)-amide (91 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100 mg), ethanolamine (17 mg), HBTU (116 mg), and DIEA (67 uL). LC/MS: m/z 436.9. 1H NMR (DMSO-d6, 400 MHz): δ 12.46 (bs, 1H), 8.38 (s, 1H), 8.24 (s, 1H), 8.09 (s, 1H), 7.77 (s, 2H), 7.67 (d, 1H), 7.48 (d, 1H), 4.72 (t, 1H), 3.65 (bs, 3H), 3.52 (q, 2H), 3.34 (q, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:11][C:10](=O)[CH2:9]2)=[CH:4][CH:3]=1.[CH3:13][C@@H:14]1[CH2:18][CH2:17][CH2:16][NH:15]1>C(O)C.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:11][C@H:10]([N:15]3[CH2:16][CH2:17][CH2:18][C@H:14]3[CH3:13])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: C[C@@H]1CCCN1
Reactant: O=C1CC(c2ccc(Br)cc2)C1
Solvent: CCO
Solvent: Cc1ccccc1
Product: C[C@@H]1CCCN1[C@H]1C[C@@H](c2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52 %

Procedure:
To a solution of 3-(4-bromo-phenyl)-cyclobutanone (1 g, 4.44 mmol) in ethanol (20 mL) was added a solution of (R)-2-methylpyrrolidine (prepared according to the procedure that described in: R. Altenbach et al., WO 2004043458, and Y. Pu et al., Organic Process Research & Development, 9(1), 45-50, 2005) (0.75 g, 8.9 mmol) in toluene. Borane-pyridine complex (0.67 mL, 6.6 mmol) was added subsequently and stirred at ambient temperature for 16 hours. The mixture was concentrated under reduced pressure to dryness and partitioned between ethyl acetate and H2O. The organic layers were washed with brine, dried (MgSO4) and concentrated under reduced pressure. Chromatography of the residue eluting with a gradient of 1-2% (9:1 MeOH:concentrated NH4OH) in dichloromethane provided the title compound (680 mg, 52%) as the faster eluting component and the product from Example 1B (76 mg, 6%) as the slower eluting component. 1H NMR (300 MHz, CD3OD) δ 1.15 (d, J=6 Hz, 3 H), 1.46 (m, 1 H), 1.77 (m, 2 H), 1.99 (m, 1 H), 2.07 (m, 2 H), 2.34 (m, 1 H), 2.58 (m, 3 H), 3.04 (m, 2 H), 3.17 (m, 1 H), 7.17 (d, J=9 Hz, 2 H), 7.41 (d, J=9 Hz, 2 H); (DCl/NH3) m/z 294 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]2=[N:6][S:7][N:8]=[C:4]2[CH:3]=1.[Br:11]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)Cl>[Br:11][CH2:1][C:2]1[CH:10]=[CH:9][C:5]2=[N:6][S:7][N:8]=[C:4]2[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2nsnc2c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Product: BrCc1ccc2nsnc2c1
Temperature: 25 °C
Yield: 62.9 %

Procedure:
5-Methylbenzo-2,1,3-thiadiazole (5 g, 33.3 mmol) in CHCl3 (75 mL) was treated with N-bromosuccinimide (5.32 g, 33.3 mmol) and a catalytic amount of AIBN and heated at reflux for 16 hours. After cooling to ambient temperature, the resulting precipitate was fitered off and the filtrate was concentrated under reduced pressure. The residue was recrystallized from ethanol to provide 4.8 g of the title compound. 1H NMR (300 MHz, CDCl3) δ 4.62 (s, 2H), 7.65 (dd, 1H), 8.0 (m, 2H).
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H](C2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)C)[CH2:6][CH2:5]1.BrC1C=CC(=O)N(C(F)F)C=1.C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCOCC1>[OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[NH:7][CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: O=C([O-])[O-]
Agent: O=c1ccc(Br)cn1C(F)F
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(O)CC1(c2ccccc2)CCNC(=O)O1
Temperature: 110 °C
Yield: 100.7 %

Procedure:
A microwave vial equipped with a flea stirbar was charged with (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan -2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (20 mg, 0.047 mmol), 5-bromo-1-(difluoromethyl)pyridin-2(1H)-one (25 mg, 0.113 mmol), Cs2CO3 (27 mg, 0.083 mmol), H2O (0.1 mL) and dry dioxane (1 mL). The mixture was sparged with N2 for 10 min and heated at 110° C. in the microwave for 0.5 h. The mixture was diluted with glacial HOAc (0.1 mL) and MeOH (0.5 mL) and filtered. The filtrate was directly purified by prep HPLC to afford (S)-3-(S)-1-(4-(1-(difluoromethyl)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one (11.8 mg, 57%) as an oil. LC-MS Method 1 tR=1.55 min, m/z=497, 248; 1H NMR (CDCl3) 1.13 (s, 3H), 1.19 (s, 3H), 1.56 (d, 3H), 2.15-2.35 (s, 4H), 2.42 (m, 2H), 2.88 (m, 1H), 5.71 (q, 1H), 6.64 (d, 1H), 7.04 (d, 2H), 7.18 (d, 2H), 7.30-7.40 (5H), 7.52 (1H), 7.60 (m, 1H), 7.75 (t, 1H).
Reaction SMILES: C([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]2[O:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]([CH3:30])[CH3:29])=[C:23]([CH3:31])[CH:22]=3)=[N:19][N:20]=2)=[CH:11][C:10]=1[CH2:32][CH3:33])C1C=CC=CC=1>C1COCC1.CCO.[Pd]>[CH2:32]([C:10]1[CH:11]=[C:12]([C:16]2[O:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]([CH3:29])[CH3:30])=[C:23]([CH3:31])[CH:22]=3)=[N:19][N:20]=2)[CH:13]=[C:14]([CH3:15])[C:9]=1[OH:8])[CH3:33]
Reactant: CCc1cc(-c2nnc(-c3ccc(OC(C)C)c(C)c3)o2)cc(C)c1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCc1cc(-c2nnc(-c3ccc(OC(C)C)c(C)c3)o2)cc(C)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.5 %

Procedure:
To a solution of 2-(4-benzyloxy-3-ethyl-5-methyl-phenyl)-5-(4-isopropoxy-3-methyl-phenyl)-[1,3,4]oxadiazole (1.25 g, 2.82 mmol) in THF (10 mL), Pd/C (100 mg, 10% Pd) in EtOH (10 mL) is added. The mixture is stirred at rt under 1 atmosphere of H2 for 16 h before the catalyst is removed by filtration. The filtrate is concentrated and separated by CC on silica gel eluting with heptane:EA 4:1 to 1:1 to give 2-ethyl-4-[5-(4-isopropoxy-3-methyl-phenyl)-[1,3,4]oxadiazol-2-yl]-6-methyl-phenol (0.79 g) as a greenish solid; LC-MS: tR=1.12 min, [M+1]+=353.17, 1H NMR (D6-DMSO): δ 9.02 (s br, 1H), 7.90-7.86 (m, 2H), 7.70-7.66 (m, 2H), 7.13 (d, J=9.4 Hz, 1H), 4.72 (hept, J=5.0^9 Hz, 1H), 2.65 (q, J=7.6 Hz, 2H), 2.26 (s, 3H), 2.20 (s, 3H), 1.31 (d, J=5.9 Hz, 6H), 1.17 (t, J=7.6 Hz, 3H).
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.[CH2:12]([C:14]1(O)[C:22]2[C:17](=[CH:18][C:19]([F:23])=[CH:20][CH:21]=2)[CH2:16][CH2:15]1)[CH3:13].[CH3:25][S:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:36]=1[NH:35][CH:34]=[CH:33]2>ClCCl>[CH2:12]([C:14]1([C:33]2[C:32]3[C:36](=[C:28]([CH2:27][S:26][CH3:25])[CH:29]=[CH:30][CH:31]=3)[NH:35][CH:34]=2)[C:22]2[C:17](=[CH:18][C:19]([F:23])=[CH:20][CH:21]=2)[CH2:16][CH2:15]1)[CH3:13]
Reactant: CCC1(O)CCc2cc(F)ccc21
Reactant: CSCc1cccc2cc[nH]c12
Agent: [Cl-]
Agent: [In+3]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC1(c2c[nH]c3c(CSC)cccc23)CCc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
515 mg (2.33 mmol) of indium(III) chloride and 0.17 ml (2.22 mmol) of trifluoroacetic acid were added to 400 mg (2.22 mmol) of the compound from Example 135A and 393 mg (2.22 mmol) of the compound from Example 8A in 12 ml of dichloromethane at 0° C., and the mixture was stirred at RT for 1 h. It was diluted with dichloromethane, washed with water, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 33 mg (4% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [CH3:1][C:2]1[C:6](=[O:7])[O:5][CH2:4][C:3]=1[N:8]1[CH:12]=[CH:11][C:10]2([CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[C:9]1=[O:25].C(O)(C(F)(F)F)=O>>[CH3:1][C:2]1[C:6](=[O:7])[O:5][CH2:4][C:3]=1[N:8]1[CH:12]=[CH:11][C:10]2([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:9]1=[O:25]
Reactant: CC1=C(N2C=CC3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)COC1=O
Solvent: O=C(O)C(F)(F)F
Product: CC1=C(N2C=CC3(CCNCC3)C2=O)COC1=O

Procedure:
The title compound was prepared from tert-Butyl 2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2,8-diazaspiro[4.5]dec-3-ene-8-carboxylate using TFA in an analogous fashion to that described for making 1-19, Step B. LC/MS: [(M+1)]+=249.
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[K+].[K+].BrC[C:9]1[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([C:19]([O:21][CH2:22]C)=O)[CH:10]=1.Cl>CO.O>[CH3:22][O:21][CH2:19][C:11]1[N:12]=[C:13]([C:15]([F:18])([F:16])[F:17])[N:14]=[C:9]([C:1]([OH:2])=[O:4])[CH:10]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cc(CBr)nc(C(F)(F)F)n1
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: COCc1cc(C(=O)O)nc(C(F)(F)F)n1
Reaction time: 2 h

Procedure:
Potassium carbonate (1.2 g, 8.7 mmol) was added to a solution of ethyl 6-(bromomethyl)-2-(trifluoromethyl)pyrimidine-4-carboxylate (0.65 g, 1.2 mmol, prepared in the manner outlined in Example 47, Step A) in methanol (10 mL). After stirring for 2 hours, the reaction was then treated with 1N HCl to achieve pH 4, was diluted with water and extracted with six portions of 10% isopropanol in chloroform. The combined extracts were dried over sodium sulfate and concentrated to afford product as an oil which was used without further purification (0.25 g, 88%). 1H NMR (300 MHz, CDCl3) δ 8.48 (s, 1H), 4.74 (s, 2H), 3.58 (s, 3H); LCMS (M+H)+: 237.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][N:10]=[C:11]3[C:16]([CH2:17]Br)=[CH:15][CH:14]=[CH:13][C:12]=23)=[CH:4][CH:3]=1.[C-:19]#[N:20].[K+].O1CCOCC1.O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][N:10]=[C:11]3[C:16]([CH2:17][C:19]#[N:20])=[CH:15][CH:14]=[CH:13][C:12]=23)=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: Clc1ccc(-c2onc3c(CBr)cccc23)cc1
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: N#CCc1cccc2c(-c3ccc(Cl)cc3)onc12
Yield: 60 %

Procedure:
A solution of 11.5 g (0.036 mole) of crude 3-(4-chlorophenyl)-7-(bromomethyl)-2,1-benzisoxazole, 9.8 g (0.15 mole) of potassium cyanide, 150 ml of dioxane and 75 ml of water was heated at reflux under a nitrogen atmosphere for 2.5 hr. The solution was cooled and poured into 400 ml of methylene chloride. The layers were separated and the organic layer was washed with four 200 ml portions of water, dried over sodium sulfate, and concentrated to give a solid as residue. The solid was recrystallized (charcoal) twice from ethyl acetate to yield 5.8 g (61%) of crystals, m.p. 165°-169° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH3:9])[CH:8]=1)[NH2:5].[NH:10]([C:17]1[C:30]2[C:29](=[O:31])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22](=[O:32])[C:21]=2[C:20](S(C2C=CC(C)=CC=2)(=O)=O)=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[NH:10]([C:17]1[C:30]2[C:29](=[O:31])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22](=[O:32])[C:21]=2[C:20]([NH:5][C:4]2[CH:6]=[C:7]([CH3:9])[CH:8]=[C:2]([CH3:1])[CH:3]=2)=[CH:19][CH:18]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1cc(C)cc(N)c1
Reactant: Cc1ccc(S(=O)(=O)c2ccc(Nc3ccccc3)c3c2C(=O)c2ccccc2C3=O)cc1
Product: Cc1cc(C)cc(Nc2ccc(Nc3ccccc3)c3c2C(=O)c2ccccc2C3=O)c1
Yield: 56 %

Procedure:
1-anilino-4-(3,5-dimethylanilino)anthraquinone was prepared by reaction of 3,5-dimethylaniline with 1-(anilino)-4-tosylanthraquinone. The isolated and purified reaction product has the structure illustrated below. ##STR16## The yield was 56% and m.p. 219.5°-220.5° C. Mass spectrum, m/e 418 (M+); H-NMR (CD2Cl2)δ12.20 (br s, 2H), 8.41-8.30 (m, 2H) 7.80-7.69 (m, 2H), 7.52-7.34 (m, 7H), 6.90 (br s, 3H), 2.32 (s, 6H); UV/VIS max (Xylenes) 404 nm (ε6 600), 600 (13 400), 641 (14 400).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C@:12]([C:17]2[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:18]=2[F:24])([CH:14]([F:16])[F:15])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].[C:26]([C:28]1[CH:29]=[C:30]([CH3:37])[C:31]([C:34](O)=[O:35])=[N:32][CH:33]=1)#[N:27].CN1CCOCC1.ClC(OCC(C)C)=O>C1COCC1>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C@:12]([C:17]2[CH:22]=[C:21]([NH:23][C:34]([C:31]3[C:30]([CH3:37])=[CH:29][C:28]([C:26]#[N:27])=[CH:33][N:32]=3)=[O:35])[CH:20]=[CH:19][C:18]=2[F:24])([CH:14]([F:16])[F:15])[N:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(C#N)cnc1C(=O)O
Reactant: CC(C)(C)OC(=O)NC1=N[C@@](c2cc(N)ccc2F)(C(F)F)COC1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: Cc1cc(C#N)cnc1C(=O)Nc1ccc(F)c([C@]2(C(F)F)COCC(NC(=O)OC(C)(C)C)=N2)c1

Procedure:
To a mixture of [(R)-5-(5-amino-2-fluoro-phenyl)-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (636 g, 1.77 mol) and 5-cyano-3-methylpyridine-2-carboxylic acid (301 g, 1.86 mol) was added THF (4.2 L) under N2 atmosphere at ambient temperature. To the stirring mixture was added N-methylmorpholine (428 mL, 3.89 mol) and the mixture was stirred to form a homogeneous solution. The reaction solution was cooled to 0-5° C. before addition of isobutyl chloroformate (256 mL, 1.95 mol) via an addition funnel while keeping the reaction temperature under 10° C. After the addition, the mixture was stirred at 0-10° C. for 1 h before filtration. The filtrate was evaporated in vacuo and the resulting residue was dissolved in the mixture of CH2Cl2 (3 L) and methanol (1 L). The mixture was concentrated in vacuo at 400 mbar/35° C. till no more volatile coming out to give a slurry. The slurry was filtered and the filter cake was washed with methanol till the wash getting colorless. The wet cake was dried in a vacuum oven at 45° C. for 24 h to give title compound as a white solid: ESIMS: 504; [(M+H)+]; 1H NMR (400 MHz, DMSO-d6): δ 10.72 (s, 1H), 10.00 (s, 1H), 8.98 (s, 1H), 8.39 (s, 1H), 7.92 (m, 1H), 7.81 (m, 1H), 7.24 (m, 1H), 6.30 (t, 1H), 4.56 (d, 1H), 4.44 (d, 1H), 4.12 (m, 1H), 3.90 (m, 1H), 2.55 (s, 3H), 1.41 (s, 9H).