Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:15])[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=[C:4]2[C:3]=1I.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.[C:28]([O-:31])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:7]=[CH:6][N:5]3[C:8](=[O:15])[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=[C:4]3[C:3]=2[C:19]2[CH:24]=[CH:23][C:22]([O:31][CH3:28])=[CH:21][CH:20]=2)=[CH:21][CH:20]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(C)Cn1nc2c(I)c(Br)ccn2c1=O
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2ccn3c(=O)n(CC(C)C)nc3c2-c2ccc(OC)cc2)cc1
Temperature: 200 °C
Yield: 19.2 %

Procedure:
To a stirring, degassed mixture of 7-bromo-8-iodo-2-isobutyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (50 mg, 0.13 mmol), 4-methoxyphenylboronic acid (40 mg, 0.28 mmol), and tetrakis(triphenylphosphine)palladium (7 mg, 0.006 mmol) in dioxane (1.0 mL) at 20° C. was added K2CO3 (40 mg, 0.25 mmol) in water (0.3 mL). The resulting reaction mixture was heated in a microwave reactor at 200° C. for 20 min under argon. Analysis by HPLC/MS indicated that starting material had been consumed. The reaction mixture was brought to room temperature and was concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC (acetonitrile-water-TFA) to isolate the title compound (10 mg, 0.025 mmol) as a pale yellow solid. MS: [M+H]+=404.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5](O)=[O:6].[NH4+:14].[OH-]>S(Cl)(Cl)=O>[CH3:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([NH2:14])=[O:6]
Reactant: [NH4+]
Reactant: Cc1nccc(C(=O)O)c1[N+](=O)[O-]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Product: Cc1nccc(C(N)=O)c1[N+](=O)[O-]

Procedure:
A mixture of 0.5 g 2-methyl-3-nitroisonicotinic acid and 20 ml of thionyl chloride was refluxed gently for 30 min. and the excess thionyl chloride was removed in vacuo to leave an oil, which was treated with conc. NH4OH under cooling for 20 min. and extracted with EtOAc. The extract was washed with water and dried, the solvent was removed to give an oil, which was purified over silica gel to yield 0.2 g of 2-methyl-3-nitroisonicotinamide, mp 203° - 204° C.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:24]([OH:26])=[O:25])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:23])[NH:19][N+:20]([O-:22])=[O:21])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.[NH:28]([C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])[C@@H:29]([C:31](O)=[O:32])[CH3:30]>CN(C=O)C.CCOC(C)=O>[NH:28]([C:34]([O:36][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)=[O:35])[C@@H:29]([C:31]([NH:1][C@H:2]([C:10]([NH:12][C@H:13]([C:24]([OH:26])=[O:25])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:23])[NH:19][N+:20]([O-:22])=[O:21])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:32])[CH3:30]
Reactant: N=C(NCCC[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)O)N[N+](=O)[O-]
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)O

Procedure:
2.69 Grams (5 m moles) of H-Phe-Arg(NO2)-CHA.HCl was dissolved in 10 ml of 1.5N-NEM/DMF, to this solution was added 1.73 g (5 m moles) of Z-D-Ala-SDP at 0° to 5° C., the reacted at room temperature for 18 hours. After the reaction was completed, the reaction mixture was diluted with 150 ml of AcOEt, the washed 3 times with 50 ml of cold 5%-hydrochloric acid and washed twice with 50 ml of an aqueous solution saturated with sodium chloride, then decolored and dried with activated carbon and anhydrous magnesium sulfate. After the drying, magnesium sulfate and activated carbon were removed by filtration, and the solvent was removed from the filtrate by evaporation under reduced pressure to obtain crude product of Z-D-Ala-Phe-Arg(NO2)-CHA, recrystallized from MeOH/AcOEt/n-hexane to obtain 2.8 g (80.0%) of Z-D-Ala-Phe-Arg(NO2)-CHA.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][CH3:20])[C:9](=[O:18])[CH2:10][CH2:11][CH2:12][CH2:13][C:14](OC)=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[BH4-].[Na+].CO>C(O)(C)(C)C>[CH2:1]([N:8]([CH2:19][CH3:20])[C:9](=[O:18])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCN(CC)C(=O)CCCCC(=O)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)(C)O
Product: CCCCCCCN(CC)C(=O)CCCCCO
Yield: 35.8 %

Procedure:
A mixture of a solution of 3.1 gms of the N-heptyl-N-ethyladipamic acid, methyl ester in 40 ml of tert-butanol and 800 mg of sodium borohydride is heated to reflux, following which 7.8 ml of methanol is added dropwise. The reaction mixture is stirred at reflux for 18 hours and then partitioned between water and CH2Cl2. After separation, the organic layer is dried over MgSO4, filtered, and concentrated under vacuum. The residue obtained is flash chromatographed on normal phase silica gel with a 4/1 ratio of hexane and ethyl acetate to yield 1.0 gms of N-heptyl-N-ethyl (6-hydroxy)hexanamide.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[N:8]([CH2:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[C:5]2=[N:6][CH:7]=1.[CH2:22]([SH:24])[CH3:23]>>[C:11]([C:9]1[N:8]([CH2:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:5]2=[N:6][CH:7]=[C:2]([S:24][CH2:22][CH3:23])[CH:3]=[C:4]2[N:10]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1nc2cc(Br)cnc2n1CC1CCOCC1
Reactant: CCS
Product: CCSc1cnc2c(c1)nc(C(C)(C)C)n2CC1CCOCC1

Procedure:
The title compound was prepared according to the procedure described in Step E of Example 32 from 6-bromo-2-tert-butyl-3-(tetrahydro-2H-pyran-4-ylmethyl)-3H-imidazo[4,5-b]pyridine (Step F) and ethanethiol (Wako Pure Chemical Industries, Ltd.).
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]=1[CH3:12])=[O:2].[C:13]1([C:23](Cl)=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.O.CCOC(C)=O>CN(C=O)C.[H-].[Na+]>[CH:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:23]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][CH:14]=2)=[O:24])[C:4]=1[CH3:12])=[O:2]
Reactant: Cc1[nH]c2ccccc2c1C=O
Reactant: O=C(Cl)c1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C=O)c2ccccc2n1C(=O)c1cccc2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 20.1 %

Procedure:
To 3-formyl-2-methylindole (4.30 g; 27.0 mmol) in 70 mL of DMF at r.t. was added NaH 80% (0.861 mg). After 30 min of stirring the solution was cooled to 0° C. and a solution of 1-naphthoyl chloride (5.04 g, 29.3 mmol) in 10 mL of DMF was added dropwise. The mixture was left stirring for 16 h at r.t. and poured into cold water-EtOAc (100mL). The organic phase was washed with H2O (2×25 mL) and brine. The organic phase was dried over Na2SO4 and the solvent removed. Chromatography on silica gel (eluted with 10% EtOAc in toluene) yielded 1.70 g (20%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:7][C:8](=O)[O:9]2)=[CH:4][CH:3]=1.[CH3:19]I.[C:21]([O-:24])([O-])=[O:22].[K+].[K+]>CO.CC(C)=O>[CH3:8][O:9][C:10]1[CH:11]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=1[CH:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:7][C:21]([O:24][CH3:19])=[O:22]
Reactant: O=C([O-])[O-]
Reactant: CI
Reactant: Cc1ccc2c(c1)OC(=O)CC2c1ccccc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CO
Product: COC(=O)CC(c1ccccc1)c1ccc(C)cc1OC
Yield: 92.5 %

Procedure:
7-Methyl-4-phenyl-3,4-dihydrocoumarin (78 g, 0.327 mol) in 150 ml methanol and 150 ml acetone containing methyl iodide (100 g, 0.7 mol) and K2CO3 (55 g, 0.4 mol) was refluxed for 24 h, filtered, and the solvent was evaporated. The residue was dissolved in ether, the solution was washed with water, dried and evaporated giving 86 g (92%) of a viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[C:6]([CH2:8][N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[C@@H:11]([CH2:22][CH3:23])[CH2:10]2)[CH:7]=1.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].C1(C)C=CC=CC=1>ClCCl>[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[C:6]([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][C@@H:11]([CH2:22][CH3:23])[CH2:10]2)[CH:7]=1
Reactant: CC[C@H]1CN(Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@H]1CN(Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)CCN1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of the product from example 69 part e) (2 g) in dichloromethane (100 ml) was added trifluoroacetic acid (100 ml). The mixture was stirred at RT for 24 h. Toluene (100 ml) was added and reaction was concentrated (bath temp <40° C.) in vacuo to give the sub-titled compound as a yellow oil (3.10 g).
Reaction SMILES: [NH2:1][C:2]([O:8][CH2:9][CH3:10])=[C:3]([C:6]#[N:7])[C:4]#[N:5].C(N(CC)CC)C.[SH2:18]>N1C=CC=CC=1>[NH2:1][C:2]([O:8][CH2:9][CH3:10])=[C:3]([C:6]#[N:7])[C:4](=[S:18])[NH2:5]
Reactant: CCOC(N)=C(C#N)C#N
Reactant: S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCOC(N)=C(C#N)C(N)=S
Reaction time: 0.5 h
Yield: 43.8 %

Procedure:
A mixture of 51.2 g of 3-amino-3-ethoxy-2-cyano-2-propenenitrile (above) and 37.8 g of triethylamine in 200 ml of pyridine was continuously stirred and heated to 70° while 60 g of gaseous hydrogen sulfide was bubbled in during 1.5 hours. Heating was continued at 65°-70° for 0.5 hour. Thin-layer chromatographic analysis indicated that no reaction had occurred. The mixture was heated overnight at 55° but still no reaction had occurred. An additional 150 ml of pyridine was added and the mixture was heated to 75°-80° while 17 g of hydrogen sulfide was bubbled in during 0.5 hour. Thin-layer chromatographic analysis indicated that a reaction had occurred, but was incomplete. An additional 18 g of hydrogen sulfide was added during 1 hour at 75°-80°; thin-layer chromatography indicated that the reaction was completed. The reaction mixture was evaporated to dryness under reduced pressure. The residue was recrystallized from ethanol to give a first crop of 28 g of 3-amino-2-cyano-3-ethoxypropenethioamide; m.p. 170°-171°. A second crop of 15 g of this product (m.p. 169°-171°) was obtained by diluting the mother liquor with ice-water. A small sample of crop I was recrystallized again from ethanol (charcoal) to give an analytical sample; m.p. 180°-181°. A total of 43.0 g of 3-amino-2-cyano-3-ethoxypropenethioamide was obtained. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[I:15].[CH3:19]C([O-])(C)C.[K+].CI.ClC1C=C(C=CC=1)OC1C=C2C(=CC=1)N(C)N=C2I>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:14]=[CH:13][C:12]2[C:8](=[C:9]([I:15])[N:10]([CH3:19])[N:11]=2)[CH:7]=1
Reactant: Clc1cccc(Oc2ccc3[nH]nc(I)c3c2)c1
Reactant: CC(C)(C)[O-]
Agent: Cn1nc(I)c2cc(Oc3cccc(Cl)c3)ccc21
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: Cn1nc2ccc(Oc3cccc(Cl)c3)cc2c1I
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 15.9 %

Procedure:
To a solution of 5-(3-chlorophenoxy)-3-iodo-1H-indazole (194 mg, 524 μmol) in THF (5 mL) at 0° C. was added KOtBu (82.2 mg, 733 μmol) and the mixture stirred at 0° C. for 30 min. MeI (104 mg, 45.8 μL, 733 μmol) was added. The reaction mixture was stirred at 0° C. for 30 min then warmed to 25° C. and stirred for 1.5 h. The reaction mixture was quenched with saturated ammonium chloride in water and extracted with dichloromethane. The combined organics were dried over MgSO4 and concentrated to a clear oil, then purified by chromatography (40 g column, 50 μm from Analogix, 0-20% EtOAc in hexanes over 20 min) to afford the desired less polar 5-(3-chlorophenoxy)-3-iodo-1-methyl-1H-indazole (154 mg, 400 mmol, 77%) as a clear yellow oil. MS (M+H)+=384.8; 1H NMR (CDCl3) δ: 7.38 (d, J=9.1 Hz, 1H), 7.17-7.29 (m, 2H), 7.11 (d, J=2.3 Hz, 1H), 7.06 (dt, J=7.9, 0.9 Hz, 1H), 6.94 (t, J=2.3 Hz, 1H), 6.86 (dd, J=8.3, 2.3 Hz, 1H), 4.12 (s, 3H). The regioisomer, 5-(3-chlorophenoxy)-3-iodo-2-methyl-2H-indazole, (32 mg, 83.2 μmol, 16%) was also obtained as a clear yellow oil.
Reaction SMILES: ClCCCl.CN([CH:8]=[O:9])C.P(Cl)(Cl)(Cl)=O.[NH:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20]([O:22][CH3:23])=[O:21]>ClC(Cl)C>[CH:8]([C:19]1[NH:15][C:16]([C:20]([O:22][CH3:23])=[O:21])=[CH:17][CH:18]=1)=[O:9]
Reactant: COC(=O)c1ccc[nH]1
Reactant: CN(C)C=O
Solvent: CC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: COC(=O)c1ccc(C=O)[nH]1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 66.5 %

Procedure:
To 1,2-dichloroethane (40 mL) was added DMF (13.6 mL, 176 mmol). The mixture was cooled to 0° C. and phosphorus oxychloride (16.4 mL, 176 mmol) was added dropwise over 5 min. The resulting solution was stirred for 15 min. To the solution at 0° C. was added dropwise methyl 1H-pyrrole-2-carboxylate (20 g, 160 mmol) in dichloroethane (80 mL) (about 1 h). The cooling bath was removed, and the reaction mixture was heated to reflux for about 1 h and was then cooled to rt. EtOAc (250 mL) in ice water (400 mL) was added and the organic layer was separated. The aqueous layer was neutralized with NaHCO3 solution, and then extracted with EtOAc (4×100 mL). The organic layer and the combined organic extracts were washed with dilute NaHCO3 solution, brine, dried (Na2SO4) and filtered. Silica gel was added, the solvent removed and the silica gel-imbedded material was purified by flash chromatography (0-50% EtOAc/Heptane) to afford a major product, methyl 5-formyl-1H-pyrrole-2-carboxylate (16.3 g) and a minor product, methyl 4-formyl-1H-pyrrole-2-carboxylate (6.94 g). Combined yield: 23.3 g (95%).
Reaction SMILES: C(N(CC)C(C)C)(C)C.CS(C)=O.[OH:14][C@@H:15]([C@@H:26]([NH:31][C:32]([C:34]1([NH:40][C:41]([N:43]2[CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)=[O:42])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)=[O:33])[CH2:27][CH2:28][CH2:29][CH3:30])[C:16]([NH:18][C@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]1[OH:25])=[O:17]>ClCCl>[O:17]=[C:16]([NH:18][C@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C:20]1=[O:25])[C:15](=[O:14])[C@@H:26]([NH:31][C:32]([C:34]1([NH:40][C:41]([N:43]2[CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)=[O:42])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]1)=[O:33])[CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCC[C@H](NC(=O)C1(NC(=O)N2CCOCC2)CCCCC1)[C@H](O)C(=O)N[C@H]1CCCC[C@@H]1O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCCC[C@H](NC(=O)C1(NC(=O)N2CCOCC2)CCCCC1)C(=O)C(=O)N[C@H]1CCCCC1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 86.8 %

Procedure:
Under nitrogen stream, at 0° C., 1.45 g (11.2 mmol) of N,N-diisopropylethylamine was added dropwise to a mixed solution of anhydrous dimethylsulfoxide (5 ml) and anhydrous dichloromethane (5 ml) containing 1.78 g (11.2 mmol) of sulfur trioxide pyridine complex salt. Moreover, to the mixture was added an anhydrous dichloromethane (5 ml) solution containing 465 mg (0.94 mmol) of N-[(2S,3S)-2-hydroxy-1-[N-[(1S,2S)-2-hydroxycyclohexane-1-yl]amino]-1-oxo-3-heptyl]-1-[N-(morpholine-4-carbonyl)amino]cyclohexanecarboxamide, and the resulting mixture was stirred at 0° C. for 3 hours. After completion of the reaction, ice-water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed successively with a 10% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution and a saturated NaCl solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by neutral silica gel column chromatography to obtain 402 mg (Yield: 87%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]([OH:24])([C:20]([F:23])([F:22])[F:21])[CH2:4][NH:5][C:6]([C:8]1[C:13]([NH2:14])=[CH:12][C:11]([C:15]([F:18])([F:17])[F:16])=[C:10](Br)[N:9]=1)=[O:7].[CH3:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][N:29]=1>>[F:1][C:2]([F:26])([F:25])[C:3]([OH:24])([C:20]([F:23])([F:22])[F:21])[CH2:4][NH:5][C:6]([C:8]1[N:9]=[C:10]([C:31]2[CH:30]=[N:29][C:28]([CH3:27])=[CH:33][CH:32]=2)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:12][C:13]=1[NH2:14])=[O:7]
Reactant: Nc1cc(C(F)(F)F)c(Br)nc1C(=O)NCC(O)(C(F)(F)F)C(F)(F)F
Reactant: Cc1ccc(B(O)O)cn1
Product: Cc1ccc(-c2nc(C(=O)NCC(O)(C(F)(F)F)C(F)(F)F)c(N)cc2C(F)(F)F)cn1

Procedure:
This compound was prepared from 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-trifluoromethyl-propyl)-amide (Ex. 1.28) and 2-methylpyridine-5-boronic acid analogously to Example 8. LC-MS Rt 1.28 min; 477 [M+H]+; (Method 2 minLC_v002); 1H NMR (400 MHz, MeOD) δ 8.50 (1H, s), 7.85 (1H, dd), 7.69 (1H, s), 7.40 (1H, d), 4.00 (2H, s), 2.62 (3H, s).
Reaction SMILES: CS(C)=O.[H-].[Na+].[N+:7]([CH3:10])([O-:9])=[O:8].C([C:13]([O:15][CH2:16][CH3:17])=[O:14])#N>C(O)(=O)C>[N+:7]([CH2:10][C:13]([O:15][CH2:16][CH3:17])=[O:14])([O-:9])=[O:8]
Reactant: C[N+](=O)[O-]
Reactant: CCOC(=O)C#N
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CCOC(=O)C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To a 100 ml three-neck round bottom flask, equipped with an addition funnel, a thermometer and a condenser topped with a nitrogen gas inlet tube, was added 20 ml of dimethylsulfoxide, 0.196 g (0.00815 mole) sodium hydride and then 0.5 g (0.00815 mole) of nitromethane was added dropwise at ambient temperature to give a slurry. 1.6 ml (0.0163 mole) of ethyl cyanoformate was then added dropwise forming a homogeneous solution and was then stirred for 2 hours at ambient temperature. The solution was made acidic by adding 30 ml of 1 Normal acetic acid with stirring. The product was extracted with ethyl acetate and dried over magnesium sulfate. Ethyl nitroacetate was formed in 83% yield as determined by gas chromatography.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH:11][CH3:12])[NH:7][C:6](=[O:13])[C:5]2([CH3:15])[CH3:14].[C:16]1(/[CH:22]=[CH:23]/[C:24]([OH:26])=O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH3:27]N(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(CC)CC.C([O-])(O)=O.[Na+]>CN(C)C=O>[C:16]1(/[CH:22]=[CH:23]/[C:24]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][C:10]=2[NH:11][CH3:12])[N:7]([CH3:27])[C:6](=[O:13])[C:5]3([CH3:15])[CH3:14])=[O:26])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)/C=C/c1ccccc1
Reactant: CNc1cc2c(cc1N)C(C)(C)C(=O)N2
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNc1cc2c(cc1NC(=O)/C=C/c1ccccc1)C(C)(C)C(=O)N2C
Temperature: 25 °C
Reaction time: 20 h
Yield: 85.9 %

Procedure:
To a solution of B1 (200 mg) in N,N-dimethylformamide (1.5 ml) is added (E)-3-phenyl-acrylic acid (142 mg; 0.96 mmol), TBTU (308 mg; 0.96 mmol) and NEt3 (97 mg; 0.96 mmol). The mixture is stirred at RT for 20 h. Saturated NaHCO3 solution is added and the aqueous layer is extracted with EtOAc (3×20 ml). The combined organic layer is washed with brine, dried and concentrated in vacuo. The crude material is purified by flash chromatography on silica gel eluting with light petroleum/EtOAc (1:2) to give the compound (288 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1([CH3:40])[CH2:10][CH2:9][CH2:8][CH:7]([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([C:19]3[C:27]4[C:22](=[N:23][CH:24]=[C:25]([Cl:28])[CH:26]=4)[N:21](S(C4C=CC(C)=CC=4)(=O)=O)[CH:20]=3)[N:13]=2)[CH:6]1[OH:39])=[O:4].C1COCC1.[Li+].[OH-]>CO>[Cl:28][C:25]1[CH:26]=[C:27]2[C:19]([C:14]3[N:13]=[C:12]([NH:11][CH:7]4[CH2:8][CH2:9][CH2:10][C:5]([CH3:40])([C:3]([OH:4])=[O:2])[CH:6]4[OH:39])[C:17]([F:18])=[CH:16][N:15]=3)=[CH:20][NH:21][C:22]2=[N:23][CH:24]=1
Reactant: COC(=O)C1(C)CCCC(Nc2nc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ncc(Cl)cc34)ncc2F)C1O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C(=O)O)CCCC(Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1O
Temperature: 25 °C

Procedure:
Racemic methyl-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]-2-hydroxy-1-methyl-cyclohexanecarboxylate, 66f, (0.100 g, 0.170 mmol) was dissolved in MeOH (1 mL) and THF (1 mL) and treated with aqueous LiOH (0.24 mL of 1 M solution, 0.24 mmol) and the reaction was heated to reflux overnight. The reaction was cooled to room temperature and the resulting material directly purified by preparatory HPLC to afford 20 mg of racemic 3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]-2-hydroxy-1-methyl-cyclohexanecarboxylic acid. The enantiomers of the racemic material were separated by chiral SFC purification to afford 6 mg of (1R,2R,3R)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]-2-hydroxy-1-methyl-cyclohexanecarboxylic acid and 6 mg of (1S,2S,3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]-2-hydroxy-1-methyl-cyclohexanecarboxylic acid. LCMS: 420.36 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH3:11])=[CH:9][N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[Li+].[CH3:23]C([N-]C(C)C)C.CI.[Na+].[Cl-]>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH3:11])=[C:9]([CH3:23])[N:8]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)[N-]C(C)C
Reactant: Cc1cn(S(=O)(=O)c2ccc(Br)cc2)c2ncc(Br)cc12
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Solvent: CCOC(C)=O
Product: Cc1c(C)n(S(=O)(=O)c2ccccc2)c2ncc(Br)cc12
Reaction time: 0.5 h

Procedure:
To a suspension of 5-bromo-1-(4-bromophenylsulfonyl)-3-methyl-1H-pyrrolo[2,3-b]pyridine (B-6-2) (0.9 g, 2.56 mmol) in THF (20 mL) was added dropwise LDA (15 mL, 0.2 M in THF) at −40° C. The mixture was stirred at −10˜−20° C. for 0.5 hour. Methyl iodide (0.55 g 3.84 mmol) was added dropwise at −40˜−30° C. The reaction was stirred at room temperature overnight. LC-MS showed that the reaction was complete. Saturated aqueous NaCl (10 mL) and EtOAc (10 mL) were added into the mixture. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated to give 5-bromo-2,3-dimethyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (B-6-3) (0.9 g, 96.3%, containing some starting material (B-6-2) as a light yellow solid.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10].[Br:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1>C1COCC1>[Br:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([O:9][CH3:10])[CH:3]=2)[OH:17])=[CH:14][CH:13]=1
Reactant: COc1ccccc1Br
Reactant: O=Cc1ccc(Br)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1cccc(C(O)c2ccc(Br)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
To a suspension of magnesium (2.4 g, 100 mmmol), in THF (20 mL) at room temperature was added dropwise a solution of bromoanisole (9.1 mL, 71.4 mmol) in THF (30 mL). The reaction mixture was stirred at room temperature for 2 h and at 600C. for 2 h. The mixture was cooled to room temperature and a solution of 4-bromobenzaldehyde (13.2 g, 71.4 mmol) was added over 5 min. The reaction mixture was stirred at room temperature for 3h and was quenched by addition of aqueous saturated ammonium chloride (NH4Cl) (30 mL). The aqueous layer was washed with ether (3x40 mL), dried over Na2SO4 and concentrated. Purification by flash chromatography with hexanes/EtOAc (10 1) afforded 16.95 g of (4-bromo-phenyl)-(3-methoxy-phenyl)-methanol. 1HNMR (400 MHz, CDCl3) δ 7.46-7.41 (comp, 2H), 7.27-7.18 (comp, 3H), 6.916.87 (comp, 2H), 6.816.78 (m, 1H), 5.73 (s, 1H), 3.76 (s, 3H); MS (M+1) 294.2.