Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([C:13]1[NH:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1)[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH:24](=O)[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1.[BH4-].ClCCl>CO>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][NH:1][C@@H:2]([C:13]2[NH:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:17]=2)[CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][CH:5]=2)=[CH:26][CH:27]=1
Reactant: N[C@H](Cc1c[nH]c2ccccc12)c1nc(-c2ccccc2)c[nH]1
Reactant: COc1ccc(C=O)cc1
Agent: [BH4-]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(CN[C@H](Cc2c[nH]c3ccccc23)c2nc(-c3ccccc3)c[nH]2)cc1
Reaction time: 8 h
Yield: 76.2 %

Procedure:
2-{(R)-1-Amino-2-[indol-3-yl]ethyl}-4-phenyl-1H-imidazole (36.3 mg, 0.12 mmol) and p-anisaldehyde (12 μL, 0.1 mmol) in 1 mL of methanol were shaken for about 2 hours at about 22° C. Borohydride resin (76 mg, 2.5 mmol/g, AMBERLITE® IRA-400) was then added and the slurry was stirred overnight before addition of dichloromethane (1 mL) and aldehyde Wang resin (31 mg, 3.22 mmol/g, Novabiochem). After about 8 hours of stirring, the slurry was then filtered and evaporated in vacuo to give a yellow solid (32.2 mg, 76%). 1H-NMR (CDCl3, 100 MHz) δ: 8.86 (br s, 1H); 7.73-6.68 (m, 15H); 4.62 (s, 1H); 4.33 (dd, J=4.7 and 8.5 Hz, 1H); 3.81 (s, 2H); 3.74 (s, 3H); 3.27 (ABX system, 2H); 2.26 (s, 1H). LC/MS: m/z=423 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[N:6]=[C:5]2[C:19](O)=[O:20].Cl.[OH:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH2:26][CH2:27][NH:28][CH2:29]2>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=1)[N:6]=[C:5]2[C:19]([N:28]1[CH2:27][CH2:26][C:25]2[C:30](=[CH:31][CH:32]=[CH:33][C:24]=2[OH:23])[CH2:29]1)=[O:20]
Reactant: Oc1cccc2c1CCNC2
Reactant: O=C(O)c1nc(-c2ccc(F)cc2)nc2ccc(F)cc12
Agent: Cl
Product: O=C(c1nc(-c2ccc(F)cc2)nc2ccc(F)cc12)N1CCc2c(O)cccc2C1
Yield: 22.8 %

Procedure:
Reaction of 6-fluoro-2-(4-fluorophenyl)quinazoline-4-carboxylic acid with 5-hydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 101 (22.8% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.62 and 2.88 (2t, 2H), 3.54 and 4.05 (2t, 2H), 4.49 and 4.95 (2s, 2H), 6.35-6.79 (m, 2H), 6.85-7.07 (m, 1H), 7.42-7.45 (m, 1H), 7.64-7.80 (m, 2H), 8.04-8.10 (m 1H), 8.15-8.39 (m, 3H), 9.49 and 9.53 (2s, 1H); MS (ESI) m/z 418 ([M+H]+).
Reaction SMILES: C([O:8][C:9](=[O:37])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:36])[CH2:16][CH2:17][C:18](=[O:35])[C@@H:19]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)C1C=CC=CC=1.[H][H]>CCOC(C)=O.CO.[Pd]>[C:21]1([CH2:20][C@H:19]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:18](=[O:35])[CH2:17][CH2:16][C:15]([N:11]2[CH2:12][CH2:13][CH2:14][C@H:10]2[C:9]([OH:37])=[O:8])=[O:36])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)CCC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)CCC(=O)N1CCC[C@H]1C(=O)O
Yield: 89.9 %

Procedure:
To a stirred solution of the benzyl ester 10 (100 mg, 0.1968 mmol) in dry EtOAc-MeOH (3:1 ratio) (10 mL) was added 10% Pd/C (50 mg) and the resulting mixture stirred at room temperature under 1 atmosphere of hydrogen for 24 h. Filtration of the black Pd residue and evaporation of the filtrate gave a crude residue. Column chromatography on silica gel elution with 20% MeOH-EtOAc afforded (5S)-6-phenyl-5-[(tert-butyloxycarbonyl)-amino]-4-oxo-hexanoyl-L-proline 11a as a pale colourless oil (74 mg, 90%); Rf 0.23 (20% MeOH-EtOAc); IR (liquid film) ν 1720 (CO), 3000 (broad, COOH) cm−1; 1H NMR (300 MHz, CDCl3) δH 1.39 (9H, s, (CH3)3), 2.04 (2H, m, —CH2—), 2.44 (1H, br-s, —COOH), 2.62 (4H, m,), 2.94 (3H, m), 3.16 (1H, m), 3.60 (2H, m, —CH2N—), 4.52 (2H, m, 2×—CH—), 5.08 (1H, m, —NH—) and 7.14-7.35 (5H, m, Ar—H); 13C NMR (75 MHz, CDCl3) δC 21.0, 22.6, 24.7, 28.0, 29.2, 30.9, 31.4, 34.6, 46.9, 58.7, 60.4, 126.8, 127.0, 128.5, 128.7, 129.5, 136.4, 155.3, 171.8, 173.7, 207.5 and 208.0; HRMS m/z calcd for C22H30N2O6 (M+) 418.21734, found 418.21039.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:10]=[N:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.C(OC([N:26]1[CH:30]=[C:29]([NH2:31])[CH:28]=[N:27]1)=O)(C)(C)C.O>COCCO>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([N:8]2[C:6]3[N:7]=[C:2]([NH:31][C:29]4[CH:30]=[N:26][NH:27][CH:28]=4)[N:3]=[CH:4][C:5]=3[N:10]=[N:9]2)=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)n1cc(N)cn1
Reactant: COc1ccc(-n2nnc3cnc(Cl)nc32)cc1
Solvent: O
Solvent: COCCO
Product: COc1ccc(-n2nnc3cnc(Nc4cn[nH]c4)nc32)cc1
Temperature: 25 °C

Procedure:
A solution of 262 mg (1.00 mmol) 5-chloro-3-(4-methoxy-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 183 mg (1.00 mmol) 4-amino-pyrazole-1-carboxylic acid tert-butyl ester in 2.5 ml 2-methoxy-ethanol is stirred for 3 hours at 100° C. The reaction mixture is cooled to room temperature and water is added. The resulting precipitate is filtered off, washed with water and dried. The crude product is recrystallized from isopropanol giving “A3” as brown crystals; HPLC/MS (A): 1.6 min, [M+H] 309;
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:10][CH3:11])=[N:4][C:5]([Cl:9])=[C:6]([Cl:8])[N:7]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:13]>>[Cl:1][C:2]1[C:3]([S:10][CH2:11][Cl:13])=[N:4][C:5]([Cl:9])=[C:6]([Cl:8])[N:7]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CSc1nc(Cl)c(Cl)nc1Cl
Product: ClCSc1nc(Cl)c(Cl)nc1Cl
Temperature: 0 °C

Procedure:
A mixture of 22.6 grams (0.1 mole of 3,5,6-trichloro-2-methylthiopyrazine and 20 grams (0.1 mole) of phosphorus pentachloride were heated at reflux (170° C) in an oil bath until the phosphorus pentachloride ceased to sublime. An additional 18 grams (0.095 mole) of phosphorus pentachloride were incrementally added until the reaction was complete (6 days). The reaction mixture was poured into ice water and extracted with chloroform. The extract was washed with a saturated sodium bicarbonate solution followed by washing with a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The chloroform was removed by evaporation and the yellow-orange oil which remained was recrystallized from hexane. The 3,5,6-trichloro-2-(chloromethylthio)pyrazine product was recovered in a yield of 8.0 grams (~30 percent of theoretical) and melted at 68°-70° C. Upon analysis, the product was found to have carbon, hydrogen and nitrogen contents of 22.80, 0.88 and 10.83 percent, respectively, as compared with the theoretical contents of 22.72, 0.76 and 10.61 percent, respectively, calculated for the above-named compound.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[CH:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[SH:18])([CH3:11])[CH3:10].C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[CH:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:11])[CH3:10]
Reactant: Cc1ccccc1I
Reactant: CC(C)c1ccccc1S
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Product: Cc1ccccc1Sc1ccccc1C(C)C
Yield: 87.9 %

Procedure:
The general procedure in example 39 was followed. 2-Iodotoluene (218 mg, 1.0 mmol), 2-Isopropylbenzenethiol (90% purity, 168 μL, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-propanol (1.0 mL) were used to obtain the 2-tolyl 2-Isopropylphenyl sulfide (213 mg, 88% yield) as colorless liquid. Column chromatographic solvent (hexane). Rf=0.4 (hexane). 1H NMR (CDCl3, 300 MHz) δ 7.32 (d, 1 H, J=7.5 Hz), 7.18-7.26 (m, 2 H), 7.13 (dd, 1 H, J=1.5 Hz, 7.2 Hz), 7.09-7.11 (m, 1 H), 7.01-7.08 (m, 2 H), 7.00 (dd, 1 H, J=1.5 Hz, 7.2 Hz), 3.49 (hept, 1 H, J=6.6 Hz), 2.37 (s, 3 H), 1.25 (s, 3 H), 1.22 (s, 3 H). 13C NMR (CDCl3, 75 MHz) δ 149.6, 138.6, 135.5, 133.1, 132.2, 131.1, 130.6, 127.9, 127.0, 126.8, 126.7, 126.1, 30.9, 23.9, 20.9. IR (neat, cm−1) 3060, 3012, 2962, 2867. MS (EI) m/z (relative intensity) 242 (100), 225 (80). Anal. Cald. for C16H18S, Cald. C, 79.29; H, 7.49. Found C, 79.33; H, 7.62.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].CC(O)=O.[O:16]([C:18]#[N:19])[Na].[OH-].[Na+]>O>[Br:11][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:2]=1[N:1]=[C:18]([OH:16])[N:19]=[C:4]2[OH:5]
Reactant: N#CO[Na]
Reactant: Nc1c(Br)cccc1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Oc1nc(O)c2cccc(Br)c2n1
Temperature: 35 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
To a 2000 mL flask charged with 2-amino-3-bromobenzoic acid (67.0 g, 310 mmol) was added water (750 mL) and AcOH (18.8 mL). The suspension was heated to 35° C. A solution of NaOCN (30.82 g, 403 mmol, 85% purity) in water (250 mL) was added dropwise at 35° C. The reaction mixture was stirred at 35° C. for 2 hrs. NaOH (415 g, 10.38 mol) was added in portions, the reaction temperature was kept below 40° C. during the addition. The mixture turned clear for a short time, then an off-white suspension was formed. The reaction mixture was cooled to room temperature, and filtered. The obtained solid was dissolved in hot water, pH was adjusted to 5 by addition of 6 N HCl. The resulting mixture was cooled to room temperature, and the precipitate was collected by filtration, rinsed with a small amount of DCM, cold MeOH, ether, then dried in vacuo to yield the title compound as a off-white solid (43.32 g, 58%). 1HNMR (DMSO-d6, 400 MHz): δ 11.60-11.40 (br s, 1H), 10.40-10.20 (br s, 1H), 7.92 (d, J=7.6 Hz, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.12 (dd, J=7.6, 8.0 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=O)=[CH:6][C:5]([CH3:10])=[C:4]([CH3:11])[N:3]=1.C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15].N1CCCCC1>N1C=CC=CC=1>[Cl:1][C:2]1[C:7]([CH:8]=[CH:13][C:14]([OH:16])=[O:15])=[CH:6][C:5]([CH3:10])=[C:4]([CH3:11])[N:3]=1
Reactant: O=C(O)CC(=O)O
Reactant: Cc1cc(C=O)c(Cl)nc1C
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: Cc1cc(C=CC(=O)O)c(Cl)nc1C
Yield: 87 %

Procedure:
A mixture of 2-chloro-5,6-dimethyl-3-pyridinecarboxaldehyde (16.85 g), malonic acid (11.45 g), piperidine (10 ml) and pyridine (100 ml) was heated under reflux for 1 hour and evaporated to an oil. This oil was dissolved in sodium hydroxide solution and was extracted with chloroform, the residual aqueous phase was acidified with hydrochloric acid and extracted with chloroform. The second chloroform extracts were washed with wafter and evaporated to give 3-(2-chloro-5,6-dimethyl-3-pyridyl)acrylic acid (18.3 g, 87%), m.p. 150°-8°. This acid was esterified using ethanol and sulphuric acid to give the ethyl ester, m.p. 85°-8°.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][OH:18])=[CH:11][CH:10]=2)O1.I[C:21]1[CH:33]=[CH:32][CH:31]=[CH:30][C:22]=1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>O>[OH:18][CH2:17][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:21]2[C:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)c1ccccc1I
Reactant: CC1(C)OB(c2ccc(CCCO)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CCCO)cc1
Temperature: 80 °C

Procedure:
A mixture of 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanol (37.9 mmol), tert-butyl 2-iodobenzoate (11.5 g, 37.9 mmol), sodium carbonate (10 g, 94.8 mmol), 1,1′-bis(diphenylphosphino)ferroncene-palladium dichloride dichloromethane complex (1:1), DMF (170 mL) and water (22 mL) was heated at 80° C. under nitrogen overnight. The reaction mixture was cooled to RT, poured into water, and the product was extracted with EtOAc-Hexanes (1:1). The combined organic extracts were washed with water and brine, dried (Na2SO4) and concentrated, and the residue was purified on silica gel (Hexane/EtOAc, from 2/1 to 1/1) to afford tert-butyl 4′-(3-hydroxypropyl)biphenyl-2-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](/[CH:17]=[CH:18]/[C:19]([OH:21])=O)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.C(Cl)(=O)C(C)(C)C.C([Li])CCC.[Li].[C:42]1([C@@H:48]2[CH2:52][O:51][C:50](=[O:53])[NH:49]2)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C1COCC1>[O:21]=[C:19]([N:49]1[C@H:48]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:52][O:51][C:50]1=[O:53])/[CH:18]=[CH:17]/[C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH:9]=1
Reactant: O=C1N[C@H](c2ccccc2)CO1
Reactant: CC(C)(C)OC(=O)n1cc(/C=C/C(=O)O)c2ccccc21
Agent: CC(C)(C)C(=O)Cl
Agent: [Li]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1cc(/C=C/C(=O)N2C(=O)OC[C@H]2c2ccccc2)c2ccccc21
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of (E)-3-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)acrylic acid (7.14 g, 24.85 mmol) in THF (400 mL) at −78° C. were added Et3N (10.39 ml, 74.6 mmol) and pivaloyl chloride (6.12 ml, 49.7 mmol). The mixture was stirred for 15 min at −78° C. then warmed to 0° C. for 1.5 h. The mixture was cooled to −78° C., to which was added n-Butyllithium (1.6 M in Hexanes)(14 mL, 22.4 mmol), then added the lithium salt of (R)-4-phenyl-2-oxazolidinone [prepared by adding n-Butyllithium (1.6 M in Hexanes)(31 ml, 49.7 mmol), to a solution of (R)-4-phenyloxazolidin-2-one (8.11 g, 49.7 mmol)] in THF (200 mL) at −78° C.) via cannula. The reaction was stirred at −78° C. for 2 h then at rt for 16 h. The reaction was quenched with saturated NH4Cl aqueous solution. The organics were removed under vacuum and the aqueous was extracted with EtOAc. The organic layer was collected, washed with brine, dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel chromatography using a gradient of 10-20% EtOAc/Hexanes. The product fractions were collected and the solvent removed under vacuum to give ((R,E)-tert-butyl 3-(3-oxo-3-(2-oxo-4-phenyloxazolidin-3-yl)prop-1-en-1-yl)-1H-indole-1-carboxylate, 7.12 g (66%). ESI-MS (+) m/z 433.4 (M+1).
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([NH:9][C:10](=[O:14])[N:11]([CH3:13])[CH3:12])[CH:6]=[CH:5][CH:4]=1)#[N:2].[C:15](OC)(=[O:23])[C:16]1[C:17](=[CH:19][CH:20]=[CH:21][CH:22]=1)[SH:18].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:13][N:11]([CH3:12])[C:10]([NH:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([C:1]2[S:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[C:15](=[O:23])[N:2]=2)[N:8]=1)=[O:14]
Reactant: COC(=O)c1ccccc1S
Reactant: CN(C)C(=O)Nc1cccc(C#N)n1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN(C)C(=O)Nc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 50 %

Procedure:
N′-(6-Cyano-2-pyridyl)-N,N-dimethylurea (0.72 g, 3.8 mmol) and methyl thiosalicylate (0.89 g, 5.2 mmol) were dissolved in toluene (4 ml), and triethylamine (2.0 ml, 14.3 mmol) was added thereto. The mixture was refluxed for 8 hrs. After cooling, the precipitates were collected and recrystallized from diisopropyl ether-methanol to give the titled compound (0.62 g, 50%) as white crystals.
Reaction SMILES: C([O:5][C:6](=[O:52])[CH2:7][CH:8]1[CH2:13][CH:12]([CH2:14][CH2:15][N:16]2[CH:20](C(C)C)[CH:19](C(=O)NC3C=CC=CC=3)[CH:18](C3C=CC=CC=3)[CH:17]2C2C=CC(F)=CC=2)OB(C2C=CC=CC=2)O1)(C)(C)C.O.[O-2].[Ca+2]>C(#N)C>[N:16]1([CH2:15][CH2:14][CH2:12][CH2:13][CH2:8][CH2:7][C:6]([OH:52])=[O:5])[CH:20]=[CH:19][CH:18]=[CH:17]1
Reactant: CC(C)C1C(C(=O)Nc2ccccc2)C(c2ccccc2)C(c2ccc(F)cc2)N1CCC1CC(CC(=O)OC(C)(C)C)OB(c2ccccc2)O1
Agent: [Ca+2]
Agent: [O-2]
Solvent: CC#N
Solvent: O
Product: O=C(O)CCCCCCn1cccc1
Temperature: 55 °C
Reaction time: 12 h

Procedure:
A mixture of (6-{2-[2-(4-Fluoro-phenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrolidin-1-yl]-ethyl}-2-phenyl-[1,3,2]dioxaborinan-4-yl)-acetic acid tert-butyl ester (100 g, 0.14 mol), water (3.0 L), acetonitrile (3.0 L) and calcium oxide (75 g, 1.35 mol) was stirred at 50-60° C. for 12 hours. After filtering the reaction mixture, the resulting clear filtrate was concentrated to about 3.0 L and washed with methyl tert-butyl ether (1.0 L). The aqueous layer was evaporated and the solid obtained was dissolved in acetonitrile (1.0 L). The solution was filtered and concentrated to yield [R-(R*R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-, 1H-Pyrrole-1-heptanoic acid hemicalcium salt.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[OH:9].Br[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH:12]1([CH2:11][O:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([OH:9])[CH:4]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: BrCC1CCCCC1
Reactant: Cc1ccc(O)cc1O
Product: Cc1ccc(OCC2CCCCC2)cc1O

Procedure:
Alkylation of 4-methylbenzene-1,3-diol using (bromomethyl)cyclohexane following the method used in Example 154 gave 5-(cyclohexylmethoxy)-2-methylphenol as a light yellow oil. Yield (0.15 g, 8.5%): 1H NMR (400 MHz, CDCl3) δ 6.96 (d, J=8.4 Hz, 1H), 6.36-6.41 (m, 2H), 3.68 (d, J=6.4 Hz, 2H), 2.16 (s, 3H), 1.64-1.89 (m, 6H), 1.14-1.34 (m, 3H), 0.96-1.08 (m, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])[N:7]([CH3:23])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:24]Br.O>C(O)(=O)C>[Br:24][C:9]1[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6][N:7]([CH3:23])[C:8]=1[NH:10][C:11]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: BrBr
Reactant: COC(=O)c1cc(OC)ccc1Nc1cc(C(C)(C)C)nn1C
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cc(OC)ccc1Nc1c(Br)c(C(C)(C)C)nn1C
Reaction time: 0.08 h

Procedure:
To a solution of 2-(5-tert-butyl-2-methyl-2H-pyrazol-3-ylamino)-5-methoxy-benzoic acid methyl ester (Example 155, 1.34 g, 4.22 mmol) in acetic acid (27 mL), was added dropwise a solution of Br2 (6.74 g, 4.22 mmol) in acetic acid (5 mL). The reaction was stirred for 5 min, and then water (100 mL) was added. The aqueous phase was extracted with EtOAc, and the combined organic layers were washed with water, and then with NaHCO3 (10% aqueous solution) 10 times. The organic layer was then dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 5 to 10% EtOAc in hexane) to give the title compound as a light yellow solid. (1.49 g, 89%). 1H NMR (400 MHz, CDCl3) δ 1.40 (s, 9H), 3.66 (s, 3H), 3.78 (s, 3H), 4.05 (s, 3H), 6.32 (d, 1H), 7.06 (dd, 1H), 7.48 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([OH:23])=O)=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.[NH2:35][C:36]([CH3:49])([CH3:48])[CH2:37][CH2:38][CH2:39][NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44].O>CN(C=O)C.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:35][C:36]([CH3:49])([CH3:48])[CH2:37][CH2:38][CH2:39][NH:40][C:41](=[O:47])[O:42][C:43]([CH3:45])([CH3:44])[CH3:46])=[O:23])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(F)cc21
Reactant: CC(C)(N)CCCNC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)CCCNC(=O)OC(C)(C)C)c3n2)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 46 %

Procedure:
To a stirred solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.32 mmol) in 6 mL of DMF was added EDCI (123 mmol, 0.64 mmol), DMAP (110 mg, 0.90 mmol) and tert-butyl 4-amino-4-methylpentylcarbamate (139 mg, 0.64 mmol) in one portion at room temperature and the mixture stirred at room temperature for 16 hours. The reaction mixture was poured into 40 mL of water, filtered, the filter cake washed with petroleum ether then dried to give crude tert-butyl 4-(2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamido)-4-methylpentylcarbamate (75 mg, 46%) as a yellow solid. MS: (M+H)+=510.2.
Reaction SMILES: [C:1]1([C:7]2[CH:57]=[CH:56][C:10]([CH2:11][N:12]3[C:16]4=[N:17][CH:18]=[CH:19][CH:20]=[C:15]4[N:14]=[C:13]3[CH2:21][O:22][C:23]3[CH:55]=[CH:54][C:26]([CH2:27][CH:28]4[S:32][C:31](=[O:33])[N:30](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[C:29]4=[O:53])=[CH:25][CH:24]=3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C>O>[C:1]1([C:7]2[CH:57]=[CH:56][C:10]([CH2:11][N:12]3[C:16]4=[N:17][CH:18]=[CH:19][CH:20]=[C:15]4[N:14]=[C:13]3[CH2:21][O:22][C:23]3[CH:55]=[CH:54][C:26]([CH2:27][CH:28]4[S:32][C:31](=[O:33])[NH:30][C:29]4=[O:53])=[CH:25][CH:24]=3)=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1SC(Cc2ccc(OCc3nc4cccnc4n3Cc3ccc(-c4ccccc4)cc3)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: O=C1NC(=O)C(Cc2ccc(OCc3nc4cccnc4n3Cc3ccc(-c4ccccc4)cc3)cc2)S1

Procedure:
A procedure similar to that described in Example 12 was repeated, except that 0.9 g of 5-(4-{3-(4-phenylbenzyl)imidazo[5,4-b]pyridin-2-ylmethoxy}benzyl)-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 55) and 36 ml of a 3:1 by volume mixture of acetic acid and water were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a 1:3 by volume mixture of hexane and ethyl acetate as the eluent, to give 450 mg of the title compound, melting at 189°-191° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][C:10]#[N:11].[N+:12]([O-])([OH:14])=[O:13]>O>[CH3:1][C:2]1[CH:7]=[C:6]([N+:12]([O-:14])=[O:13])[C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][C:10]#[N:11]
Reactant: Cc1ccc(C)c(CC#N)c1
Reactant: O=[N+]([O-])O
Solvent: O
Product: Cc1cc([N+](=O)[O-])c(C)cc1CC#N
Reaction time: 0.5 h

Procedure:
To (2,5-dimethylphenyl)acetonitrile (30 g), under ice cooling, fuming nitric acid (103 mL) was added dropwise, and the resultant was stirred for 30 minutes under ice cooling. Water was added thereto, followed by extraction with ethyl acetate. The organic layer was dried over magnesium sulfate, and the desiccant was filtered off. Then, the solvent was distilled off under reduced pressure. A saturated aqueous solution of sodium bicarbonate was added to the obtained residue, followed by extraction with ethyl acetate. The organic layer was dried over magnesium sulfate, and the desiccant was filtered off. Then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH-type silica gel; chloroform/ethyl acetate-gradient elution=100/0→90/10) and then further purified twice by silica gel column chromatography (OH-type silica gel; hexane/ethyl acetate-gradient elution=90/10→60/40) to obtain the title compound (12 g) as a pale yellow solid.
Reaction SMILES: O[CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:4]([C:15](=[O:29])[NH:16][C@H:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:20]=2)[CH3:18])[CH2:3]1.CCN(S(F)(F)[F:36])CC>C(Cl)Cl>[F:36][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:4]([C:15](=[O:29])[NH:16][C@H:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:20]=2)[CH3:18])[CH2:3]1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CC(O)CCN2C(=O)OC(C)(C)C)cc1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CC(F)CCN2C(=O)OC(C)(C)C)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
A solution of (2R)-tert-butyl 4-hydroxy-2-(((S)-1-(4-(methoxycarbonyl)phenyl)ethyl)carbamoyl)piperidine-1-carboxylate (D61) (261 mg, 0.64 mmol) in DCM (10 ml) cooled at −20° C. was treated with DAST (0.17 ml, 1.28 mmol) and the reaction mixture stirred 1 h at −20° C. then at RT for 18 hrs. DAST (0.17 ml, 1.28 mmol) was added and the mixture further stirred 24 hrs. The reaction was quenched with NaHCO3 sat. sol. and extracted with DCM (3×10 ml), dried over MgSO4 and evaporated in vacuo. The residue was loaded onto a SPE-Si cartridge (20 g) eluting with a mixture DCM/EtOAc 90/10. Collected fractions after solvent evaporation afforded the title compound (D62) (89 mg)