Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1CCCCC1.C([Li])CCC.[CH3:12][O:13][CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:24])[F:23])=[N:20][CH:21]=1.[CH:26](=[O:28])[CH3:27]>C1COCC1>[CH3:12][O:13][CH2:14][O:15][C:16]1[C:17]([CH:26]([OH:28])[CH3:27])=[CH:18][C:19]([C:22]([F:25])([F:23])[F:24])=[N:20][CH:21]=1
Reactant: COCOc1ccc(C(F)(F)F)nc1
Reactant: CC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: C1CCNCC1
Product: COCOc1cnc(C(F)(F)F)cc1C(C)O
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of piperidine, 2,2,6,6-tetramethyl- (9.2 ml, 54 mmol) in THF (400 ml) at −78° C. was added butyllithium (˜2.5 m in toluene; 18 ml, 45 mmol) dropwise. The reaction was then stirred at 0° C. for 5 min at −78° C., and a solution of 5-(methoxymethoxy)-2-(trifluoromethyl)pyridine (7.5 g, 36 mmol) in THF (100 ml) was added dropwise. The mixture was stirred for an additional 10 min, then acetaldehyde (20 ml, 362 mmol) was added and stirring continued for 15 min. the reaction was slowly quenched with H2O, warmed to RT, extracted with EtOAc (3×), combine organic layers were dried over MgSO4, filtered, concentrated and the crude product was purified by ISCO (20% EtOAc/Hexanes) to give the title compound as a light yellow solid. MS (m+1): 252.2.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CS(O[CH2:10][CH2:11][N:12]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][N:14]=[C:13]1[CH3:20])(=O)=O.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[N:1]([CH2:10][CH2:11][N:12]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][N:14]=[C:13]1[CH3:20])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ncc([N+](=O)[O-])n1CCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ncc([N+](=O)[O-])n1CCN=[N+]=[N-]

Procedure:
To 10 parts of sodium azide is added a solution of 32 parts of 2-(5-nitro-2-methyl-1-imidazolyl)ethyl methanesulfonate (Ger. Pat. No. 2,030,314) in 250 parts of warm N,N-dimethylformamide. The resultant mixture is stirred at approximately 50° for 6 hours, then diluted with 1000 parts of cold water. Sufficient potassium carbonate is added to insure basicity. The mixture thus obtained is extracted with toluene. The toluene extract is washed with water, dried over anhydrous potassium carbonate, and stripped of solvent by vacuum distillation, affording 1-(2-azidoethyl)-2-methyl-5-nitroimidazole as a yellow oil which is further purified by crystallization from ether. Isolated by filtration, washed with a 1:1 mixture of ether and hexane, and dried in air the purified product melts at 53°-54°. It has the formula ##SPC6##
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH:5]([CH3:7])[CH3:6].C(N(CC)CC)C.[F:19][C:20]1[CH:30]=[CH:29][CH:28]=[CH:27][C:21]=1[CH:22]=[CH:23][C:24](O)=[O:25].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:19][C:20]1[CH:30]=[CH:29][CH:28]=[CH:27][C:21]=1[CH:22]=[CH:23][C:24]([NH:2][C@H:3]([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH:5]([CH3:7])[CH3:6])=[O:25]
Reactant: O=C(O)C=Cc1ccccc1F
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](CC(C)C)NC(=O)C=Cc1ccccc1F
Yield: 88.8 %

Procedure:
The same procedures as in Example 2 were carried out from methyl L-leucinate hydrochloride (3.0 g), triethylamine (2.5 mL), 2-fluorocinnamic acid (3.0 g), WSC.HCl (3.5 g), and methylene chloride (100 mL), to give the captioned compound (4.3 g, 88%) as crystals.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8](/[CH:10]=[CH:11]/[B:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl>[F:1][C:2]1[CH:9]=[C:8](/[CH:10]=[CH:11]/[B:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]2)[CH:7]=[CH:6][C:3]=1[CH2:4][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: C1COCCN1
Reactant: CC1(C)OB(/C=C/c2ccc(C=O)c(F)c2)OC1(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC1(C)OB(/C=C/c2ccc(CN3CCOCC3)c(F)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To a mixture of (E)-2-fluoro-4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)benzaldehyde (0.61 g, 2.2 mmol) and morpholine (0.3 mL) in DCE (20 mL) was added NaBH(OAc)3 (636 mg, 3 mmol), followed by AcOH (0.5 mL). The resulting mixture was stirred for 2 h at rt. The reaction was quenched with sat. NaHCO3 (10 mL), H2O (10 mL), and extracted with EtOAc (2×30 mL). The solvents were removed in vacuo to afford the title compound as a white solid (0.72 g, 94%). 1H NMR (400 MHz, CDCl3) δ 7.20-7.12 (m, 2H), 7.04 (d, J=7.6 Hz, 1H), 6.99 (d, J=10.8 Hz, 1H), 5.98 (d, J=18.4 Hz, 1H), 3.55-3.45 (m, 4H), 3.36 (s, 2H), 2.33-2.23 (m, 4H), 1.14 (s, 12H); MS ESI 348.2 [M+H], calcd for [C19H27BFNO3+H]+ 348.2.
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH2:13])[C:8]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[C:29](O)(=[O:32])[CH2:30][CH3:31]>>[NH2:13][C:9]1[N:10]=[CH:11][N:12]=[C:7]([O:6][C:5]2[CH:27]=[CH:28][C:2]([NH:1][C:29](=[O:32])[CH:30]=[CH2:31])=[CH:3][CH:4]=2)[C:8]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:16][CH:15]=1
Reactant: CCC(=O)O
Reactant: Nc1ccc(Oc2ncnc(N)c2-c2ccc(Oc3ccccc3)cc2)cc1
Product: C=CC(=O)Nc1ccc(Oc2ncnc(N)c2-c2ccc(Oc3ccccc3)cc2)cc1
Yield: 51 %

Procedure:
N-(4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide was prepared from 6-(4-aminophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine and propionic acid using Method E (51% yield). HPLC: 96%, RT=4.165 min. MS: m/z=427 [M+H]+, RT=4.11 min. 1H-NMR (DMSO-d6) δ 9.78 (s, 1H), 7.94 (s, 1H), 7.48 (d, 2H), 7.36-7.32 (m, 4H), 7.09 (t, 1H), 7.02 (t, 4H), 6.91 (d, 2H), 6.39 (broad s, 2H), 2.24 (q, 2H), 1.01 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[CH:11](=[O:15])[CH:12]([CH3:14])[CH3:13]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[C:12]([CH3:14])([CH3:13])[CH:11]=[O:15])=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CC(C)C=O
Product: CC(C)(C=O)C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.8 %

Procedure:
p-Chlorophenyl isocyanate (21.08 g) and the morpholinoenamide of isobutyraldehyde (38.7 g) were stirred together in a 100 mL round bottom flask. After an initial exotherm, the solution was allowed to stir at ambient temperature overnight. The excess enamine was then removed in vacuo at 60° C., and the residue was taken up in ether and hexane added. The material was filtered to remove an unwanted urea side product, then the filtrate was washed with dilute HCl, and additional ether was added to redissolve some precipitated product. The organic layer was then dried and concentrated in vacuo to give a solid. Recrystallization furnished 21 g of N-(4-chlorophenyl)-2,2-dimethyl-3-oxopropanamide, m.p. 99°-100° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[C:8]([CH2:19][NH2:20])=[CH:7]2.Cl[C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[N:28](C(OC(C)(C)C)=O)[CH:29]=[N:30][C:23]=12.C(N(C(C)C)CC)(C)C.C(O)CCC>CC1C(NC(CN2CCOCC2)=O)=C(C)C=C(OCC2C=CC=CC=2)C=1>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[C:8]([CH2:19][NH:20][C:22]1[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[N:30][C:23]=13)=[CH:7]2
Reactant: NCc1cc2cccc(Cl)c2nc1-c1ccccc1Cl
Reactant: CC(C)(C)OC(=O)n1cnc2c(Cl)ccnc21
Agent: Cc1cc(OCc2ccccc2)cc(C)c1NC(=O)CN1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Clc1ccccc1-c1nc2c(Cl)cccc2cc1CNc1ccnc2[nH]cnc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 15 %

Procedure:
A sealed flask was charged with (8-chloro-2-(2-chlorophenyl)quinolin-3-yl)-methanamine, made in procedure E in A-1216 US PSP, tert-butyl 7-chloro-3H-imidazo[4,5-b]pyridine-3-carboxylate (109 mg, 429 μmol), diisopropylethylamine (0.075 mL, 429 μmol) and 1-butanol (2.0 mL, 21856 μmol). The mixture was subjected to microwave at 180° C. for 120 min. After cooled to room temperature, the mixture was concentrated, and the residue was diluted with MeOH. The solution was purified by HPLC, 25%-45% of B in 35 min. The collected fractions were dissolved in CH2Cl2 and neutralized by washing with aq. NaHCO3, the CH2Cl2 layer was dried, concentrated and gave N-((8-chloro-2-(2-chlorophenyl)-quinolin-3-yl)methyl)-3H-imidazo[4,5-b]pyridin-7-amine (20.2 mg, 15%), 1H NMR (DMSO-d6) δ ppm 12.72 (1 H, s), 8.43 (1 H, s), 8.15 (1 H, s), 8.09 (1 H, d, J=8.0 Hz), 8.05 (1 H, d, J=8.0 Hz), 7.73-7.80 (2 H, m), 7.63-7.70 (4 H, m), 7.45 (1 H, s), 6.13 (1 H, d, J=8.0 Hz), 4.60 (2 H, br). Mass Spectrum (ESI) m/e=420.0 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:11]=2[C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]3[C:22]([CH:23]=2)=[N:21][N:20]([CH3:24])[CH:19]=3)=[O:13])[CH:5]=[CH:4][N:3]=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+].[CH3:78][N:79]([CH3:83])[C:80]([NH2:82])=[O:81]>O1CCOCC1.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].CN(C=O)C>[CH3:78][N:79]([CH3:83])[C:80](=[O:81])[NH:82][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:11]=2[C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]3[C:22]([CH:23]=2)=[N:21][N:20]([CH3:24])[CH:19]=3)=[O:13])[CH:5]=[CH:4][N:3]=1
Reactant: CN(C)C(N)=O
Reactant: Cn1cc2ccc(NC(=O)c3c(F)cccc3NCc3ccnc(Br)c3)cc2n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CN(C)C(=O)Nc1cc(CNc2cccc(F)c2C(=O)Nc2ccc3cn(C)nc3c2)ccn1
Temperature: 110 °C
Yield: 40.3 %

Procedure:
2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-6-fluoro-N-(2-methyl-2H-indazol-6-yl)-benzamide (227 mg, 0.5 mmol) was suspended in dioxane (4 mL) and treated consecutively with DMF (1.6 mL), Pd2 dba3 (13 mg, 0.013 mmol), Xantphos (18 mg, 0.031 mmol), cesium carbonate (193 mg, 0.59 mmol) and 1,1-dimethylurea (232 mg, 2.63 mmol). The reaction mixture was placed under an argon atmosphere and heated for 3 hours at 110° C. (bath temperature). On cooling the reaction was partitioned between EtOAc and water. The organic phase was dried and concentrated in vacuo. The residue was purified by chromatography on Isolute® Flash silica get (Separtis) (Gradient elution: 100% CH2Cl2 to CH2Cl2/EtOH 9:1) to give 2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-6-fluoro-N-(2-methyl-2H-indazol-6-yl)-benzamide (93 mg, 40%) as a resin. Further purification was accomplished by preparative reverse phase HPLC [Column: Kromasil C8 5μ, 125×20 mm. Eluant: 38% CH3CN in H2O (containing 0.2% NH3) to 95% CH3CN in H2O (containing 0.2% NH3)]; 1H-NMR (300 MHz, d6-DMSO) 10.43 (1H, s), 8.77 (1H, s), 8.26 (1H, s), 8.23 (1H, s), 8.13 (1H, d), 7.80 (1H, s), 7.64 (1H, d), 7.13-7.25 (2H, m), 6.93 (1H, d), 6.73 (1H, t), 6.48 (1H, t), 6.29 (1H, d), 4.40 (2H, d), 4.14 (3H, s), 2.92 (6H, s); m/z (ES+) 462 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[CH:14])=[C:8]3[N:7]=[C:6]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH:5]=2)[CH2:3][CH2:2]1.Br[C:26]1[CH:27]=[C:28]([S:32]([NH2:35])(=[O:34])=[O:33])[CH:29]=[N:30][CH:31]=1>>[CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[C:14][C:26]4[CH:27]=[C:28]([S:32]([NH2:35])(=[O:34])=[O:33])[CH:29]=[N:30][CH:31]=4)=[C:8]3[N:7]=[C:6]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: NS(=O)(=O)c1cncc(Br)c1
Product: NS(=O)(=O)c1cncc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-cyclopropyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.7) (82 mg, 0.25 mmol) and 5-bromo-pyridine-3-sulfonic acid amide (59 mg, 0.25 mmol) (Example B.1) according to general procedure II. Obtained as a yellow solid (57 mg, 47%). MS (ISP) 484.0 [(M+H)+]; mp 276-277° C.
Reaction SMILES: [N+:1]1([O-])[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.F[B-](F)(F)F.[CH3:14][O+:15](C)C.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+]>C(Cl)Cl.O>[OH:15][CH2:14][C:2]1[CH:3]=[C:4]([CH3:7])[CH:5]=[CH:6][N:1]=1
Reactant: Cc1cc[n+]([O-])cc1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Product: Cc1ccnc(CO)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
A solution of 4-picoline-N-oxide (3.0 g, 27.52 mmol) in 90 ml of methylene chloride at room temperature is reacted with trimethyloxonium tetrafluoroborate (4.07 g, 27.52 mmol, 1.0 equiv.) for 1.5 h. The reaction mixture is concentrated directly at reduced pressure, the white solid dissolved in 60 ml of refluxing methanol and treated with ammonium persulfate (1.25 g, 5.50 mmol, 0.20 equiv.) in 5.5 ml of water with another addition of ammonium persulfate (0.625 g, 0.10 equiv.) in 2.5 ml of water 30 min later. After refluxing for an additional 40 min, the contents are concentrated at reduced pressure, treated with 75 ml of saturated brine plus 75 ml of water and finally 50 ml of 3N HCl. After stirring at room temperature for 1 h, the mixture is basified with 20 ml of 29% ammonium hydroxide, extracted 4 times with chloroform, dried the combined organic extracts with anhydrous Na2SO4 and concentrated in vacuo. Chromatography with 250 g of silica gel, packed and eluted with acetone-chloroform-methanol (1:2:2%), yielded 2.65 g (78%) of 2-hydroxymethyl-4-methylpyridine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=[CH2:5])[CH3:2].[Cl:13][C:14]([Cl:19])([Cl:18])[C:15](Cl)=[O:16]>N1C=CC=CC=1.C(Cl)Cl>[Cl:13][C:14]([Cl:19])([Cl:18])[C:15](=[O:16])[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[C:6]1[CH:7]=[CH:8][C:9]([F:12])=[CH:10][CH:11]=1
Reactant: C=C(OCC)c1ccc(F)cc1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=CC(=O)C(Cl)(Cl)Cl)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 7.49 g 1-(1-Ethoxy-vinyl)-4-Fluorobenzene in 3.6 mL of Pyridine was added at 0° C. to 8.19 g of Trichloroacetyl chloride. The suspension was diluted with 15 ml of dry methylene chloride and stirred at room temperature overnight. The resulting dark brown suspension was concentrated in vaccuo, filtered over a silica gel column with a 9:1 mixture of Heptane and Ethyl acetate as eluant. One obtains after concentration 28 g of a reddish brown oil which was repurified by chromatography on silica gel using a 19:1 mixture of Heptane and Ethyl acetate as eluant. The obtained brown oil (10.15 g) was directly used in the next step.
Reaction SMILES: [CH3:1]C1C=CC(S(O)(=O)=O)=CC=1.[NH2:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[NH:20][C:21]1[N:29]=[C:28]2[C:24]([NH:25][C:26](=[O:41])[N:27]2[C@H:30]2[C:39]3[C:34](=[C:35]([F:40])[CH:36]=[CH:37][CH:38]=3)[O:33][CH2:32][CH2:31]2)=[CH:23][N:22]=1>COC(OC)OC>[F:19][C:17]1[CH:16]=[CH:15][C:14]2[N:20]([C:21]3[N:29]=[C:28]4[C:24]([NH:25][C:26](=[O:41])[N:27]4[C@H:30]4[C:39]5[C:34](=[C:35]([F:40])[CH:36]=[CH:37][CH:38]=5)[O:33][CH2:32][CH2:31]4)=[CH:23][N:22]=3)[CH:1]=[N:12][C:13]=2[CH:18]=1
Reactant: Nc1cc(F)ccc1Nc1ncc2[nH]c(=O)n([C@@H]3CCOc4c(F)cccc43)c2n1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(OC)OC
Product: O=c1[nH]c2cnc(-n3cnc4cc(F)ccc43)nc2n1[C@@H]1CCOc2c(F)cccc21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A catalytic amount of p-TsOH was added to a solution of the above amine in trimethylorthoformate (2 mL). The mixture was stirred at RT for 15 hr then the solvents were reduced and the resultant material partitioned between DCM and brine and separated. The crude product was purified via column chromatography (eluted with 5% MeOH/DCM) to yield the titled compound (9 mg). 1H-NMR (300 MHz, CDCl3) δ 10.0 (s, 1H), 8.9 (s, 1H), 8.3 (s, 1H), 7.8 (dd, 1H), 7.4 (d, 1H), 7.1 (m, 2H), 6.8 (m, 2H), 5.9 (dd, 1H), 4.7 (m 1H), 4.4 (td, 1H), 2.9 (m, 1H), 2.4 (m, 1H).
Reaction SMILES: C([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:6][CH2:7][CH2:8][CH:9]1[C:15]2[CH:16]=[CH:17][C:18]([O:20][C:21](=[O:25])[N:22]([CH3:24])[CH3:23])=[CH:19][C:14]=2[CH:13]=[CH:12][CH2:11][N:10]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[CH3:24][N:22]([CH3:23])[C:21]([O:20][C:18]1[CH:17]=[CH:16][C:15]2[CH:9]([CH2:8][CH2:7][OH:6])[N:10]([C:26]([O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:27])[CH2:11][CH:12]=[CH:13][C:14]=2[CH:19]=1)=[O:25]
Reactant: CN(C)C(=O)Oc1ccc2c(c1)C=CCN(C(=O)OC(C)(C)C)C2CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)Oc1ccc2c(c1)C=CCN(C(=O)OC(C)(C)C)C2CCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To a solution of t-butyl 1-[2-(t-butyl-diphenyl-silanyloxy)-ethyl]-7-dimethylcarbamoyloxy-1,3-dihydro-benzo[c]azepine-2-carboxylate (1.82 g, 2.96 mmol) synthesized in step (k) of Example 192 in tetrahydrofuran (10 ml) was added 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (6.0 ml, 6.0 mmol) at room temperature, and the resulting mixture was stirred for 1 hour at room temperature under a nitrogen atmosphere. After stirring, water (30 ml) was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (40 ml×2). The organic layer was washed successively with water (40 ml×1) and saturated aqueous sodium chloride solution (40 ml×1), dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to afford the crude product. The crude product was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (1:1-0:1) as the eluent to afford the title compound (1.07 g, yield: 96%) as a colorless oil.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].C(=O)([O-])[O-].[K+].[K+].[C:18]([O:22][C:23](=[O:26])[CH2:24]Br)([CH3:21])([CH3:20])[CH3:19].O>CN(C=O)C>[C:18]([O:22][C:23](=[O:26])[CH2:24][N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3])([CH3:21])([CH3:20])[CH3:19]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1C(=O)C(=O)c2ccccc21

Procedure:
44.1 g (0.3 mol) of isatin, 62.5 g (0.45 mol) of potassium carbonate and 66.2 g (0.34 mol) of bromoacetic acid tert-butyl ester (from Aldrich) are stirred in 100 ml of N,N′-dimethylformamide at room temperature for 24 hours. The mixture is then poured into 800 ml of water, and the precipitate formed is filtered off, washed with water and dried at 60° C. After recrystallising once from toluene-hexane (1:1), 608 g (78% of theory) of product having a melting point of 119-121° C. are obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[O:12]=[C:13]1[C:18]2=[CH:19][NH:20][C:21]([CH:22]=O)=[C:17]2[CH2:16][CH2:15][O:14]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:22][C:21]1[NH:20][CH:19]=[C:18]2[C:13](=[O:12])[O:14][CH2:15][CH2:16][C:17]=12
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Product: O=C1Nc2ccc(F)cc2C1=Cc1[nH]cc2c1CCOC2=O

Procedure:
5-Fluoro-1,3-dihydro-indol-2-one was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde to give the title compound.
Reaction SMILES: I[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][CH:3]=1.C(OC([N:15]1[CH:19]=[C:18](B(O)O)[CH:17]=[N:16]1)=O)(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C1(C)C=CC=CC=1>[CH3:7][N:6]1[C:2]([C:18]2[CH:19]=[N:15][NH:16][CH:17]=2)=[CH:3][CH:4]=[N:5]1
Reactant: Cn1nccc1I
Reactant: CC(C)(C)OC(=O)n1cc(B(O)O)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: Cn1nccc1-c1cn[nH]c1
Temperature: 100 °C
Reaction time: 14 h
Yield: 32.9 %

Procedure:
Under a nitrogen atmosphere, a mixture of 5-iodo-1-methyl-1H-pyrazole (750 mg), [1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl]boronic acid (1.27 g), tetrakis(triphenylphosphine)palladium(0) (209 mg), 2 M sodium carbonate aqueous solution (3.6 mL), ethanol (3.6 mL) and toluene (7.2 mL) was stirred at 100° C. for 14 hours. Thereafter, water was added to the reaction solution, and the obtained mixture was then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and was then concentrated under a reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane:ethyl acetate=4:1 to 0:10), so as to obtain the title compound (176 mg) in the form of a light yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)#[N:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH:43]1([C@H:49]([NH:56][CH3:57])[CH2:50][N:51]2[CH2:54][CH:53]([OH:55])[CH2:52]2)[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:56]([C@@H:49]([CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)[CH2:50][N:51]2[CH2:52][CH:53]([OH:55])[CH2:54]2)[CH3:57])=[O:9])=[CH:10][CH:11]=1)#[N:2]
Reactant: N#Cc1ccc(C(=O)O)cc1
Reactant: CN[C@H](CN1CC(O)C1)C1CCCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C(=O)c1ccc(C#N)cc1)[C@H](CN1CC(O)C1)C1CCCCC1
Reaction time: 0.17 h
Yield: 49 %

Procedure:
4-cyanobenzoic acid (65.0 mg, 0.44 mmol) in DCM (2 mL) was treated with DIPEA (0.231 mL, 1.32 mmol) and TBTU (142 mg, 0.44 mmol) and the suspension was stirred for 10 min. A 125 mg/mL solution of (S)-1-(2-cyclohexyl-2-(methylamino)ethyl)azetidin-3-ol (Compound G2.3) (125 mg, 0.44 mmol) in DCM (1 mL) was added and the reaction was stirred at ambient temperature overnight. The reaction was washed with 8% aq. sol. of NaHCO3 and concentrated. The residue was dissolved in DMSO (0.4 mL) and filtered through a syringe filter. The residue was purified by HPLC to give the title compound (73.6 mg, 49%). Mixture of rotamers. 1H NMR (600 MHz, DMSO-d6) δ 0.53-0.70, 0.89-1.81, 2.43-2.59, 2.64-2.78, 3.03, 3.28-3.31, 3.43-3.54, 4.11-4.30, 5.23, 5.26, 7.48, 7.61, 7.87-7.94. HRMS (M+H)+: calculated 342.2181. found 342.2193
Reaction SMILES: C[O:2][C:3](=[O:43])[C@@H:4]([NH:32][C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])[CH2:5][NH:6][C:7]([CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[S:23])[CH:16]=2)[CH2:11][CH2:10]1)=[O:8].[OH-].[Na+].FC(F)(F)C(O)=O>CO>[CH2:25]([NH:24][C:22]([NH:21][C:17]1[CH:16]=[C:15]([N:12]2[CH2:11][CH2:10][CH:9]([C:7]([NH:6][CH2:5][C@H:4]([NH:32][C:33]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:34])[C:3]([OH:43])=[O:2])=[O:8])[CH2:14][CH2:13]2)[CH:20]=[CH:19][CH:18]=1)=[S:23])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)[C@H](CNC(=O)C1CCN(c2cccc(NC(=S)NCc3ccccc3)c2)CC1)NC(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=C(N[C@@H](CNC(=O)C1CCN(c2cccc(NC(=S)NCc3ccccc3)c2)CC1)C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the compound of Example 21 in methanol (2 ml) is added 2M aqueous sodium hydroxide solution (2 ml), and the mixture is stirred at 25° C. overnight. The reaction solution is neutralized with trifluoroacetic acid, and purified by CHP-20 (eluent: gradient, 35% to 100% methanol/0.05% aqueous trifluoroacetic acid solution) to give the title compound (40 mg).