Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[N:3]1.[Li]CCCC.[C:12]([O:16][C:17]([N:19]1[CH2:22][CH:21]([C:23]([C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[N:31]=[C:30]([O:35][CH3:36])[C:29]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=2)=[C:28]3[Cl:48])=[O:24])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>C1COCC1>[C:12]([O:16][C:17]([N:19]1[CH2:20][CH:21]([C:23]([C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[N:31]=[C:30]([O:35][CH3:36])[C:29]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:42][CH:43]=2)=[C:28]3[Cl:48])([OH:24])[C:6]2[N:2]([CH3:1])[N:3]=[N:4][CH:5]=2)[CH2:22]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: Cn1ccnn1
Reactant: COc1nc2ccc(C(=O)C3CN(C(=O)OC(C)(C)C)C3)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3cnnn3C)C3CN(C(=O)OC(C)(C)C)C3)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: -43 °C
Reaction time: 0.5 h

Procedure:
To a flask containing 1-methyl-1H-1,2,3-triazole (430 mg, 0.8 mmol) was added THF (15 mL) and the solution was cooled to −43° C. using a CH3CN—CO2 bath. Then, n-BuLi, (2.5 M in hexanes, 0.7 mL, 1.75 mmol) was added dropwise. The reaction mixture was stirred at −40° C. for 30 minutes, then tert-butyl-3-(4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline-6-carbonyl)-azetidine-1-carboxylate (430 mg, 0.8 mmol, Intermediate 61: step b) in 2 mL THF was introduced. The reaction mixture was allowed to warm to room temperature over 30 minutes, and was quenched after 45 minutes with aqueous NH4Cl solution. The aqueous portion was extracted with EtOAc (3×30 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated. Chromatography on Silica gel (10% acetone-hexane increasing to 30% acetone) afforded the title compound as a white amorphous solid. 1H NMR (500 MHz, CDCl3) δ 8.24 (d, J=2.1 Hz, 1H), 7.78 (d, J=8.8 Hz, 1H), 7.56-7.47 (m, 3H), 7.40 (d, J=8.1 Hz, 2H), 7.35 (dd, J=8.7, 2.1 Hz, 1H), 4.35 (s, 2H), 4.20 (t, J=8.8 Hz, 1H), 4.07 (s, 3H), 4.00 (dd, J=9.3, 5.6 Hz, 1H), 3.92 (dd, J=8.9, 5.7 Hz, 1H), 3.67 (s, 3H), 3.62 (t, J=8.8 Hz, 1H), 3.52-3.38 (m, 1H), 1.38 (s, 9H); MS (ESI): mass calcd: Chemical Formula: C30H31ClF3N5O4; Exact Mass: 617.2. m/z found 617.8 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C:17]1[CH:18]=[C:19]([CH:26]=[CH:27][C:28]=1[OH:29])[CH2:20][C@@H:21]([C:23]([OH:25])=[O:24])[NH2:22]>>[NH2:16][C:17]1[CH:18]=[C:19]([CH2:20][C@H:21]([NH:22][C:2]2[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=3)[N:3]=2)[C:23]([OH:25])=[O:24])[CH:26]=[CH:27][C:28]=1[O:29][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: Nc1cc(C[C@H](N)C(=O)O)ccc1O
Product: Nc1cc(C[C@H](Nc2nc3ccc(Cl)cc3cc2C(=O)O)C(=O)O)ccc1Oc1nc2ccc(Cl)cc2cc1C(=O)O

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 3-amino-4-hydroxy-L-phenylalanine and crude product is separated by flash chromatography on SiO2 to provide the title compound in good yield.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.[CH3:26][N:27]1[C:35]2[CH2:34][CH2:33][CH2:32][NH:31][C:30]=2[CH:29]=[N:28]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>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].O1CCOCC1>[C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([N:31]3[CH2:32][CH2:33][CH2:34][C:35]4[N:27]([CH3:26])[N:28]=[CH:29][C:30]3=4)[N:3]=2)[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: Cn1ncc2c1CCCN2
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1ncc2c1CCCN2c1cnc2c(n1)c(C(=O)NC(C)(C)C)cn2COCC[Si](C)(C)C
Temperature: 150 °C
Yield: 99.5 %

Procedure:
A microwave vial was charged with a mixture of 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (68.5 mg, 160 μmol), 1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine (22 mg, 160 μmol), xantphos (27.8 mg, 48.1 μmol), Pd2(dba)3 (14.7 mg, 16.0 μmol), Cs2CO3 (105 mg, 321 μmol) and dioxane (2 mL). The reaction mixture was purged with argon and then heated to 150° C. for 20 min under microwave irradiation. The mixture was diluted with CH2Cl2 and then filtered through a pad of celite. The filtrate was concentrated in vacuo and the residue purified by chromatography (40 g column, 50 μm silica-gel from Analogix, 0 to 5% 9:1 methanol:ammonium hydroxide in CH2Cl2, min) to give N-tert-butyl-2-(1-methyl-6,7-dihydro-1H-pyrazolo[4,3-b]pyridin-4(5H)-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (77 mg, 99%) as a yellow foam. 1H NMR (CHLOROFORM-d) δ: 8.29 (s, 1H), 8.14 (s, 1H), 8.10 (s, 1H), 7.88 (s, 1H), 5.63 (s, 2H), 3.93-4.01 (m, 2H), 3.87 (s, 3H), 3.52-3.63 (m, 2H), 2.80-2.91 (m, 2H), 2.16-2.29 (m, 2H), 1.55-1.61 (m, 11H), 0.87-1.02 (m, 2H), 0.00 (s, 9H). MS (EI/CI) m/z: 484.0 [M+H]+.
Reaction SMILES: [S:1]1[C:5]([NH:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)=[N:4][N:3]2[CH:15]=[CH:16][N:17]=[C:2]12.[I:18]N1C(=O)CCC1=O>CN(C)C=O>[I:18][C:15]1[N:3]2[C:2]([S:1][C:5]([NH:6][C:7]3[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=3)=[N:4]2)=[N:17][CH:16]=1
Reactant: COc1ccc(Nc2nn3ccnc3s2)cc1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: COc1ccc(Nc2nn3c(I)cnc3s2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 16 %

Procedure:
Imidazo[2,1-b][1,3,4]thiadiazol-2-yl-(4-methoxyphenyl)amine (0.455 g, 1.85 mmol) was dissolved in N,N-dimethylformamide (8 mL) and N-iodosuccinimide (2.03 mmol, 0.48 g) was added in one portion. The reaction mixture was stirred at room temperature for 22 hours in the absence of light. Solvent was evaporated and the residue was purified by column chromatography (Biotage™/Flash, silica, ethylacetate:dichloromethane 2:8 to 0:10) to give 0.11 g of (5-iodo-imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-(4-methoxyphenyl)amine as an off-white solid (16% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:10])=[C:6]([CH:9]=1)[C:7]#[N:8].B.C1COCC1.Cl.[OH-].[K+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:10])=[C:6]([CH2:7][NH2:8])[CH:9]=1
Reactant: N#Cc1cc(Br)ccc1I
Agent: B
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: NCc1cc(Br)ccc1I
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66.3 %

Procedure:
To a solution of 5-bromo-2-iodobenzonitrile (9.21 g, 0.03 mol) in tetrahydrofuran (140 mL) at 0° C. was added BH3-THF (66 mL, 66 mmol, 1 M solution in tetrahydrofuran) dropwise over 1 hour. The reaction solution was stirred at room temperature for 10 minutes, and then heated to reflux for overnight. 10% aqueous HCl was added (to adjust to pH 2-3) and stirred for 20 minutes, then the mixture was basified with 10 M aqueous KOH up to pH>10. The mixture was extracted with ethyl acetate three times. Organics were combined, dried with sodium sulfate, filtered and concentrated in vacuo to yield 6.2 g of crude (5-bromo-2-iodophenyl)methanamine as a yellow oil. LCMS (ESI): M+H=311.7; 1H NMR (400 MHz, DMSO-d6): δ 7.71 (d, J=8.4 Hz, 1H), 7.67 (d, J=2.4 Hz, 1H), 7.18 (dd, J=2.4, 8.4 Hz, 1H).
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.Cl.[CH2:13]([O:20][C:21](=[O:27])[C@H:22]([CH:24]([CH3:26])[CH3:25])[NH2:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])(=O)C.[Na+].C([BH3-])#N.[Na+]>C(O)(C)C>[CH2:13]([O:20][C:21](=[O:27])[C@H:22]([CH:24]([CH3:25])[CH3:26])[NH:23][CH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)[C@H](N)C(=O)OCc1ccccc1
Reactant: O=CCCc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [BH3-]C#N
Solvent: CC(C)O
Product: CC(C)[C@H](NCCCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of dihydrocinnamaldehyde (7 mmol), valine benzyl ester dihydrochloride (7 mmol), anhydrous sodium acetate (0.7 g, 21 mmol), and sodium cyanoborohydride (11 mmol) in 200 mL of isopropyl alcohol was stirred at ambient temperature. After 16 h, an additional 0.2 g portion of sodium cyanoborohydride was added and stirring was continued for 4.5 h. After removal of the solvent in vacuo, the residue was taken up in ethyl acetate, washed sequentially with saturated aqueous NaHCO3 and saturated brine, dried over MgSO4, and concentrated. Silica gel chromatography gave the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14](=[C:15]=O)[CH:13]=[CH:12][C:11]([NH:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:10]1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C(O)(=O)C.O>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([NH:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:12]=[CH:13][C:14]=1[CH2:15][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: CC(C)(C)OC(=O)NCCNC1=CC(c2ccc(Cl)cc2Cl)C(=C=O)C=C1
Reactant: C1COCCN1
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCNc1ccc(CN2CCOCC2)c(-c2ccc(Cl)cc2Cl)c1
Temperature: 70 °C
Yield: 52 %

Procedure:
(1M in THF) is added to a solution of aldehyde 8 (50 mg, 0.121 mmol), morpholine (2eq) and glacial acetic acid (5 ml) dissolved in THF (5 ml) at room temperature with stirring. The mixture is heated to 70° C. for 18 h, after which, a slow addition of water (1 ml) is used to decompose excess reagent. The mixture is partitioned between ethyl acetate (30 ml) and saturated citric acid solution (10 ml). The organic layer is discarded, and the aqueous layer is carefully basified with 1M aq. sodium hydroxide to pH 9. Then the basic aqueous layer is extracted with ethyl acetate (2×25 ml). The combined organic layers are dried (sodium sulfate), concentrated, and purified by chromatography (silica gel, 10% methanol/methylene chloride) to afford pure product 9 (52% yield).
Reaction SMILES: [CH3:1][N:2]([CH3:37])[C:3]1[CH:8]=[C:7]([N:9]([CH3:11])[CH3:10])[CH:6]=[CH:5][C:4]=1[C:12]1([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH2:34][CH3:35])[C:26]=2[CH3:36])[C:21]2[C:16](=[CH:17][C:18]([N+:22]([O-])=O)=[CH:19][CH:20]=2)[C:14](=[O:15])[O:13]1>Cl>[CH3:1][N:2]([CH3:37])[C:3]1[CH:8]=[C:7]([N:9]([CH3:10])[CH3:11])[CH:6]=[CH:5][C:4]=1[C:12]1([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH2:34][CH3:35])[C:26]=2[CH3:36])[C:21]2[C:16](=[CH:17][C:18]([NH2:22])=[CH:19][CH:20]=2)[C:14](=[O:15])[O:13]1
Reactant: CCn1c(C)c(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3cc([N+](=O)[O-])ccc32)c2ccccc21
Agent: Cl
Product: CCn1c(C)c(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3cc(N)ccc32)c2ccccc21
Temperature: 60 °C
Reaction time: 1 h
Yield: 11.5 %

Procedure:
A solution of 25.0 g (0.054 mole) of 3-[2,4-bis(dimethylamino)phenyl]-3-(1-ethyl-2-methyl-3-indolyl)-6-nitrophthalide, prepared as described in part B above, in 285 ml of concentrated hydrochloric acid was heated to 60° C. at which temperature 31.25 g (0.142 mole) of stannous chloride dihydrate was added at such a rate as to maintain the temperature at 60° C. After the addition was complete, the solution was heated to 70° C. and held there for a period of one hour and then allowed to cool to 25° C. The green-colored solid which separated was collected by filtration and was slurried in five percent aqueous sodium hydroxide solution. The resulting suspension was extracted with 500 ml of toluene at room temperature and the toluene extract was filtered, decolorized, and dried over sodium sulfate. On standing, a cream solid separated from the toluene solution. The solid was filtered off and dried to obtain 2.9 g of 3-[2,4-bis(dimethylamino)phenyl]-3-(1-ethyl-2-methyl-3-indolyl)-6-aminophthalide (Formula III: R°=R1 =R3 =Y1 =H; R2 =NH2 ; R=R5 =CH3 ; R4 =N(CH3)2 ; R6 =CH2CH3) having a melting point of 206°-209° C. Infrared analysis showed a maximum at 1727 cm-1 (C=O; s). The nuclear magnetic resonance spectrum was concordant with the assigned structure. A toluene solution of the above compound developed an intense grape-black color when spotted on a paper coated with phenolic resin.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[C:5]#[N:6].CN.[CH:13]([N:16](C(C)C)CC)(C)C>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH:16][CH3:13])[C:5]#[N:6]
Reactant: CCN(C(C)C)C(C)C
Reactant: N#Cc1ccc(F)c(Cl)c1
Agent: CN
Solvent: CO
Product: CNc1ccc(C#N)cc1Cl

Procedure:
A solution of 3-chloro-4-fluorobenzonitrile (1.0 g), methylamine (16 mL of a 2 M solution in methanol) and diisopropylethylamine was reacted in the microwave at 120° C. for min. The mixture was then partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer was washed with brine (30 mL), dried (MgSO4) and reduced in vacuo to give 3-chloro-4-methylamino-benzonitrile. A suspension of 3-chloro-4-methylamino-benzonitrile (900 mg) in 2 M aqueous sodium hydroxide solution (30 mL) was heated at reflux for 3 h. After cooling to room temperature, the solution was acidified with 2 M aqueous hydrochloric acid and the resulting solid collected by filtration and air-dried to give 3-chloro-4-methylamino-benzoic acid. To a solution of 3-chloro-4-methylamino-benzoic acid (860 mg) in DMF (20 mL) was added carbonyl diimidazole (630 mg) and the reaction stirred at room temperature for 1 h. Then, methylamine hydrochloride (262 mg) and triethylamine (1.62 mL) were added and the reaction stirred at room temperature for 16 h. The reaction was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer was washed with brine (3×40 mL), dried (MgSO4), reduced in vacuo and purified on silica to give 3-chloro-N-methyl-4-methylamino-benzamide.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].CI.[CH3:24]COC(C)=O.CCCCCC>C1COCC1>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]([CH3:24])[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)NCCCO[Si](C)(C)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CI
Solvent: C1CCOC1
Product: CN(CCCO[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C
Temperature: 10 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
50 g (1 eq.) tert-butyl 3-(tert-butyldimethylsilyloxy)propylcarbamate dissolved in 200 ml THF were added dropwise to a mixture of 20.7 g (5 eq.) sodium hydride and 300 ml THF at 0° C. After heating the reaction mixture to 10° C., 32.3 ml (3 eq.) methyl iodide were added dropwise. On completion of the addition, the mixture was stirred for 3 h at room temperature. The reaction course was monitored by thin-layer chromatography (30% EtOAc/hexane). Once the conversion was complete, the reaction mixture was quenched with saturated NH4Cl solution and then extracted with ethyl acetate. The combined organic phases were dried over Na2SO4. Following removal of the solvent under reduced pressure, 48 g (92%) of product were obtained in the form of an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7]2[CH:8]=[C:9](B(O)O)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:15])[O:3]1.Br[C:18]1[N:23]=[C:22]([CH2:24][C:25]#[N:26])[CH:21]=[CH:20][CH:19]=1>>[CH3:1][C:2]1([CH3:16])[C:7]2[CH:8]=[C:9]([C:18]3[N:23]=[C:22]([CH2:24][C:25]#[N:26])[CH:21]=[CH:20][CH:19]=3)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:15])[O:3]1
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Reactant: N#CCc1cccc(Br)n1
Product: CC1(C)OC(=O)Nc2ccc(-c3cccc(CC#N)n3)cc21

Procedure:
Prepared according to procedure B from (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid and (6-bromo-2-pyridyl)acetonitrile (J. Org. Chem. 1988, 53, 786-790). An off-white solid, mp 210-212.5° C. 1H NMR (DMSO-d6) δ1.68 (s, 6H), 4.27 (s, 2H), 7.00 (d, 1H, J=8.3 Hz), 7.34 (d, 1H, J=7.1 Hz), 7.89-7.96 (m, 2H), 8.00-8.05 (m, 2H), 10.42 (s, 1H). MS (ESI) [M−H]−=292. Anal. calcd. for C17H15N3O2: C, 69.61; H, 5.15; N, 14.33. Found: C, 68.49; H, 5,19; N, 13.74.
Reaction SMILES: [CH3:1][Mg]Br.[CH2:4]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:12](=O)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1>C1COCC1>[CH2:1]=[C:12]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=2[CH2:4][CH2:5][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]1=2
Reactant: O=C1c2ccccc2CCc2ccccc21
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: C=C1c2ccccc2CCc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
Add methylmagnesium bromide (3M solution in Et2O, 48.0 mL, 144 mmol) dropwise to a cooled (0° C.) solution of dibenzosuberone (20.0 g, 96.03 mmol) in THF (140 mL) under N2 (exothermic). Let solution warm up to room temperature and continue stirring for 2 h. Cool solution to 0° C. and quench with saturated aqueous NH4Cl (exothermic, emits gas). Extract into ethyl acetate, dry organics (MgSO4) and concentrate in-vacuo. Dissolve residue in 4N HCl/dioxane (40 mL) and stir at room temperature overnight. Concentrate and dilute with H2O. Extract into ethyl acetate, dry organics (MgSO4) and concentrate to a yellow oil. Purify crude product by loading onto a 30 g plug of silica gel and eluting with hexanes until eluent shows no UV activity. Combine and concentrate hexane washes to afford 16.72 g (84%) of the title compound as a white solid, mp 65.1° C. HPLC shows 98% purity.
Reaction SMILES: [CH:1]([OH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:15][C:16]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:17]=1[O:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([O-:23])=[O:22].[F:36][C:37]([F:53])([F:52])[C:38]1[CH:39]=[C:40]([S:48](Cl)(=[O:50])=[O:49])[CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1>N1C=CC=CC=1>[CH:1]([OH:14])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:47][C:44]([F:45])([F:46])[C:42]1[CH:41]=[C:40]([S:48]([NH:15][C:16]2[CH:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:29]=[CH:28][C:17]=2[O:18][C:19]2[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=2[C:21]([O-:23])=[O:22])(=[O:49])=[O:50])[CH:39]=[C:38]([C:37]([F:53])([F:52])[F:36])[CH:43]=1
Reactant: O=S(=O)(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Nc1cc(C(F)(F)F)ccc1Oc1ccccc1C(=O)[O-]
Agent: OC(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: O=C([O-])c1ccccc1Oc1ccc(C(F)(F)F)cc1NS(=O)(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
Benzhydrol 2-(2-amino-4-trifluoromethylphenoxy)benzoate (4 g, 8.6 mmol) was dissolved in pyridine (25 mL) and stirred under argon at room temperature. 3,5-bis(trifluoromethyl)benzenesulfonyl chloride (4.05 g, 12.9 mmol) was added in portions, and the mixture stirred for 16 h. The solvent was evaporated, and the residue was purified by flash chromatography (silica gel, ethyl acetate/hexane) to give the title compound as a white solid. 1H NMR (250 MHz, CDCl3) δ8.25 (br s, 1H), 8.15 (s, 2H), 7.99 (dd, 1H), 7.85-7.92 (m, 2H), 7.1-7.5 (m, 13H), 7.01 (s, 1H), 6.72 (d, 1H), 6.45 (dd, 1H).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][O:8][C:9]1[CH:17]=[CH:16]C(C(O)=O)=[CH:11][C:10]=1[N+:18]([O-:20])=[O:19]>C1COCC1>[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:1]([C:2]([Cl:4])=[O:3])=[CH:11][C:10]=1[N+:18]([O-:20])=[O:19]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(C(=O)O)cc1[N+](=O)[O-]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Cl)cc1[N+](=O)[O-]

Procedure:
Oxalyl chloride (15.8 ml, 180 mmol) was added dropwise with stirring to a solution of 4-methoxy-3-nitrobenzoic acid (7.00 g, 36.00 mmol) in THF containing 10 μL DMF. After 1 h the solvent was removed under reduced pressure. The product was used directly in the next step.
Reaction SMILES: [C:1]([NH:9][CH:10]([C:21]([OH:23])=O)[CH2:11][S:12][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([NH:28][C@H:29]([C:40]([OH:42])=[O:41])[CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH:32]=1)(C)(C)C>>[C:1]([NH:9][C@H:10]([C:21]([NH:28][C@H:29]([C:40]([OH:42])=[O:41])[CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH:32]=1)=[O:23])[CH2:11][S:12][C:13](=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC(CSC(=O)c1ccccc1)C(=O)O)c1ccccc1
Reactant: CC(C)(C)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Product: O=C(N[C@@H](CSC(=O)c1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)c1ccccc1

Procedure:
N-(N,S-Dibenzoyl-D,L-cysteinyl)-tryptophan was obtained as a diastereomer mixture (melting point 175°-178° C., petroleum ether; Rf=0.19 and 0.16 in system II) by a procedure similar to that described in Example 16, using N,S-dibenzoyl-D,L-cysteine and tert.-butyl tryptophan as starting materials. Recrystallization from diethyl ether gave N-(N,S-dibenzoylcysteinyl)-tryptophan (melting point 210°-213° C., Rf=0.19 in system II) in a form which was pure according to thin-layer chromatography. N-(N,S-dibenzoyl-D-cysteinyl)-tryptophan (melting point 157°-160° C., Rf=0.16 in system II) which was pure according to thin-layer chromatography was obtained from the mother liquor after crystallization from petroleum ether.
Reaction SMILES: C[O:2][C:3](=[O:33])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:29](=[CH:30][CH:31]=1)[O:28][C:11]1([CH2:16][CH2:15][N:14]([CH2:17][C:18]3[C:26]4[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:32].[OH-].[Na+]>>[F:27][C:23]1[CH:22]=[C:21]2[C:26]([C:18]([CH2:17][N:14]3[CH2:15][CH2:16][C:11]4([CH2:10][C:9](=[O:32])[C:8]5[C:29](=[CH:30][CH:31]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:33])=[O:2])[CH:7]=5)[O:28]4)[CH2:12][CH2:13]3)=[CH:19][NH:20]2)=[CH:25][CH:24]=1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3c[nH]c4cc(F)ccc34)CC1)O2
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3c[nH]c4cc(F)ccc34)CC1)O2
Yield: 75.4 %

Procedure:
(E)-3-{1′-(6-Fluoro-1H-indol-3-ylmethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (130 mg, 0.29 mmol) was hydrolyzed with 4 M NaOH following the procedure described in Example 40, Step B, giving (E)-3-{1′-(6-fluoro-1H-indol-3-ylmethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid as a yellow solid (95 mg, 76%). The product was treated with NH2OTHP according to the procedure described in Example 40, Step C, giving (E)-3-{1′-(6-fluoro-1H-indol-3-ylmethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide. Removal of the THP protecting group following the procedure described in Example 40, Step C gave (E)-3-{1′-(6-fluoro-1H-indol-3-ylmethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-hydroxy-acrylamide that was purified by preparative LC-MS and obtained as its trifluoroacetate salt (15 mg, white solid).
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][NH:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[S:11](=[O:13])(=[O:12])[C:5]=2[CH:4]=[C:3]([C:18]([O:20]C)=[O:19])[CH:2]=1.[OH-].[K+].O.C(O)C>O1CCOCC1>[CH:1]1[C:6]2[CH2:7][NH:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[S:11](=[O:13])(=[O:12])[C:5]=2[CH:4]=[C:3]([C:18]([OH:20])=[O:19])[CH:2]=1
Reactant: COC(=O)c1ccc2c(c1)S(=O)(=O)c1ccccc1NC2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc2c(c1)S(=O)(=O)c1ccccc1NC2

Procedure:
Stir a mixture of 3.03 gm. (10 mmole) of the ester of Example 15, 2.24 gm. (20 mmole) of 85% aqueous potassium hydroxide, 11 ml. of water, 55 ml. of ethanol and 5.5 ml. of dioxane under nitrogen for 2 hours. Concentrate the reaction mixture to the point of crystallization and dilute with 40 ml. of water. Filter and acidify with acetic acid. Separate the precipitate by filtration and wash with water and dry to obtain the title product (m.p. 304°-306° C.).