Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[F:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1>>[F:15][C:16]1[CH:17]=[C:18]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1
Reactant: COc1cc(F)cc(B(O)O)c1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Product: COc1cc(F)cc(-c2nnc(N)nc2-c2ccccc2)c1
Yield: 32.7 %

Procedure:
6-(3-Fluoro-5-methoxyphenyl)-5-phenyl-1,2,4-triazin-3-amine (193 mg, 32%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.50 g, 1.99 mmol) and 3-fluoro-5-methoxy phenylboronic acid (0.37 g, 2.19 mmol) according to the general procedure of Example 1.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-:4])[CH3:3].[K+].[Br:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](Cl)=[O:12]>C1(C)C=CC=CC=1>[C:2]([O:4][C:11](=[O:12])[C:10]1[CH:14]=[CH:15][CH:16]=[C:8]([Br:7])[CH:9]=1)([CH3:5])([CH3:3])[CH3:1]
Reactant: CC(C)(C)[O-]
Reactant: O=C(Cl)c1cccc(Br)c1
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.2 %

Procedure:
In an oven dried, 1-L, 3-necked round bottom flask equipped with an addition funnel, a glass stopper, a magnetic stirbar, and a reflux condenser connected to a nitrogen inlet, potassium t-butoxide (23.6 g, 209.6 mmol) was combined with toluene (150 mL). A solution of 3-bromobenzoyl chloride (40 g, 182.3 mmol) in toluene (100 mL) was added dropwise to the potassium t-butoxide and the mixture was stirred for 16 h at room temperature. The viscous mixture was transferred to a 1-L separatory funnel, and the reaction flask was rinsed with toluene (50 mL) and added to the separatory funnel. The toluene mixture was extracted with water (200 mL), a potassium carbonate solution (10%, 250 mL), and again with water (3×200 mL). The toluene layer was dried over magnesium sulfate and filtered, and the toluene was removed in vacuo to yield the product as a yellow oil (45.1 g, 96%). HPLC: >99% pure.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[N:10]=[C:11]=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13]([O:15][CH2:16][C:17]1[N:18]([CH2:29][CH2:30][CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[C:19]2[C:24]([CH3:25])=[C:23]([CH3:26])[N:22]=[C:21]([NH2:27])[C:20]=2[N:28]=1)[CH3:14]>>[NH2:27][C:21]1[C:20]2[N:28]=[C:17]([CH2:16][O:15][CH2:13][CH3:14])[N:18]([CH2:29][CH2:30][CH:31]3[CH2:36][CH2:35][N:34]([C:11]([NH:10][C@@H:8]4[CH2:9][C@H:7]4[C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[O:12])[CH2:33][CH2:32]3)[C:19]=2[C:24]([CH3:25])=[C:23]([CH3:26])[N:22]=1
Reactant: O=C=N[C@@H]1C[C@H]1c1ccccc1
Reactant: CCOCc1nc2c(N)nc(C)c(C)c2n1CCC1CCNCC1
Product: CCOCc1nc2c(N)nc(C)c(C)c2n1CCC1CCN(C(=O)N[C@@H]2C[C@H]2c2ccccc2)CC1

Procedure:
Using the method of Examples 54-65, trans-2-phenylcyclopropyl isocyanate was reacted with 2-(ethoxymethyl)-6,7-dimethyl-1-(2-piperidin-4-ylethyl)-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The observed accurate mass was 491.3139.
Reaction SMILES: [C:1]1([CH:7]([OH:10])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1COCC1.[CH3:16][O:17][N:18]=[C:19]([N:27]1[CH:31]=[CH:30][N:29]=[CH:28]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1O.N(C(OCC)=O)=NC(OCC)=O>CCOCC>[CH3:16][O:17][N:18]=[C:19]([N:27]1[CH:31]=[CH:30][N:29]=[CH:28]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:10][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:8][CH3:9]
Reactant: CON=C(c1ccccc1O)n1ccnc1
Reactant: CCC(O)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(Oc1ccccc1C(=NOC)n1ccnc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Thriphenylphosphine (1.05 g), 1-phenylpropyl alcohol 0.54 g) and THF (20 ml) were added to 2-hydroxy-α-(1-imidazolyl)benzaldehyde O-methyloxime (0.43 g), and diethyl azodicarboxylate (0.70 g) was added under ice-cooling over 10 minutes. then the mixture was stirred at room temperature for 2 hours. After completion of the reaction, ether (100 ml) was added, the mixture was washed with water (80 ml) twice, and the ether layer was concentrated under reduced pressure. the resulting crude product was purified by silica gel chromatography to α-(1-imidazolyl)-2-(1-phenylpropyloxy)benzaldehyde O-methyloxime (0.63 g) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([CH3:23])=[C:9]([C:19](OC)=[O:20])[C:10]([O:11][S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])=[C:5]2[CH2:4][CH2:3]1.CC(C[AlH]CC(C)C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>ClCCl>[F:18][C:15]([F:16])([F:17])[S:12]([O:11][C:10]1[C:9]([CH2:19][OH:20])=[C:8]([CH3:23])[N:7]=[C:6]2[N:2]([CH3:1])[CH2:3][CH2:4][C:5]=12)(=[O:14])=[O:13]
Reactant: COC(=O)c1c(C)nc2c(c1OS(=O)(=O)C(F)(F)F)CCN2C
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1nc2c(c(OS(=O)(=O)C(F)(F)F)c1CO)CCN2C
Temperature: 25 °C

Procedure:
To a solution of 169.7 mg of methyl ester 29 in 2 mL of dichloromethane was added 1.43 mL of DIBAL-H (1M in toluene, 3 eq) dropwise at −78° C. under Ar protection. After addition, the reaction mixture was stirred at the same temperature and stirred for additional 2 h then 5 mL of aqueous saturated sodium potassium tartrate was added by syringe. The reaction mixture was allowed to warm to room temperature and stirred for additional 4 h. After separation, the aqueous layer was extracted with three portions of 5 mL of dichloromethane. The combined organic layer was washed with brine and dried over magnesium sulfate. After the solvent was removed, the residue was purified by flash chromatography on a silica gel column (15×2 cm). Elution with 1:2 EtOAc-hexanes gave product 30 as white solid: yield 148 mg, (95%). Silica gel TLC Rf 0.20 (1:1 EtOAc-hexanes); 1H NMR (CDCl3, ppm): δ 1.72 (br s, 1H), 2.52 (s, 3H), 2.96 (s, 3H), 3.08 (t, J=8.4 Hz, 2H), 3.54 (t, J=8.4 Hz, 2H), 4.58 (s, 2H). 13C NMR (CDCl3, ppm): δ 22.01, 23.97, 32.29, 51.78, 76.68, 111.48, 114.08, 149.79, 159.93, 164.67; HRMS (ESI+) calculated for C11H13N2O4SF3 (M+H+) 327.0621. found 327.0622.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][C@@H:15]([OH:18])[CH2:14]3)=[O:12])[S:10][C:3]=12.[CH:19]1([NH:22][C:23]([C:25]2[C:33]3[C:28](=[CH:29][C:30]([OH:34])=[CH:31][CH:32]=3)[N:27]([CH3:35])[C:26]=2[CH3:36])=[O:24])[CH2:21][CH2:20]1.C([O-])([O-])=O.[Cs+].[Cs+]>>[CH:19]1([NH:22][C:23]([C:25]2[C:33]3[C:28](=[CH:29][C:30]([O:34][C:2]4[CH:7]=[CH:6][N:5]=[C:4]5[CH:8]=[C:9]([C:11]([N:13]6[CH2:17][CH2:16][C@@H:15]([OH:18])[CH2:14]6)=[O:12])[S:10][C:3]=45)=[CH:31][CH:32]=3)[N:27]([CH3:35])[C:26]=2[CH3:36])=[O:24])[CH2:20][CH2:21]1
Reactant: Cc1c(C(=O)NC2CC2)c2ccc(O)cc2n1C
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CC[C@@H](O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1c(C(=O)NC2CC2)c2ccc(Oc3ccnc4cc(C(=O)N5CC[C@@H](O)C5)sc34)cc2n1C

Procedure:
This material was prepared by the reaction of (7-chloro-thieno[3,2-b]pyridin-2-yl)-((R)-3-hydroxy-pyrrolidin-1-yl)-methanone 4a with 6-hydroxy-1,2-dimethyl-1H-indole-3-carboxylic acid cyclopropylamide 20b and Cs2CO3 in a manner as previously described for example 1. 1H NMR (300 MHz, CD3OD) δ 8.50 (1H, d, J=5.5 Hz), 7.93 (1H, d, J=17.33 Hz), 7.80 (1H, d, J=8.6 Hz), 7.39 (1H, d, J=2.1 Hz), 7.05 (1H, dd, J=2.1, 8.6 Hz), 6.71 (1H, d, J=5.5 Hz), 4.54 (1H, bs), 4.11–4.00 (2H, m), 3.85–3.72(6H, m), 2.93–2.86(1H, m), 2.66 (3H, s), 2.19–2.07 (2H, m), 0.90–0.84 (2H, m), 0.76–0.68 (2H, m). LCMS (ESI+) [M+H]/z Calc'd 491. found 491.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:4]=1[C:10]1[N:11]=[C:12]2[N:17]([CH:18]=1)[N:16]=[CH:15][N:14]=[CH:13]2.[CH3:19][S:20](Cl)(=[O:22])=[O:21].Cl>[OH-].[Na+].C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][S:20]([CH3:19])(=[O:22])=[O:21])[CH:6]=[CH:5][C:4]=1[C:10]1[N:11]=[C:12]2[N:17]([CH:18]=1)[N:16]=[CH:15][N:14]=[CH:13]2
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(O)ccc1-c1cn2ncncc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1cc(OS(C)(=O)=O)ccc1-c1cn2ncncc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
55 mg (0.227 mmol) of 6-(2-Methoxy-4-hydroxyphenyl)-imidazo[2,1-f][1,2,4]triazine are dissolved in 12 ml of 1N sodium hydroxide solution. 0.2 ml of methanesulphonic acid chloride are added to the clear yellowish-orange solution and the resulting mixture is stirred for 21/2 hours at ambient temperature. The reaction solution is then adjusted to pH 6 with 1N hydrochloric acid and extracted three times, each time with 25 ml of ethyl acetate. The ethyl acetate phase is dried over sodium sulphate and concentrated by evaporation. The residue obtained is dissolved in methylene chloride and applied to a silica gel column, eluting first with methylene chloride and later with methylene chloride/ethanol (50:1). The desired eluates are concentrated by evaporation, then triturated with ether/petroleum ether (1:1) and the crystals obtained are suction filtered.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].[CH3:10][O:11][C:12]([CH3:17])([CH3:16])[C:13](O)=[O:14].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:13](=[O:14])[C:12]([O:11][CH3:10])([CH3:17])[CH3:16])[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: COC(C)(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: COC(C)(C)C(=O)Nc1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.5 %

Procedure:
A stirred solution of 6.1 grams (42 mmole) of 3-chloro-4-fluoroaniline, 5.0 grams (42 mmole) of 2-methoxy-2-methylpropanoic acid, and 10.5 grams (55 mmole) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 120 mL of methylene chloride was cooled to about 0° C., and 7.4 grams (55 mmole) of 1-hydroxybenzotriazole was added. Upon completion of the addition the reaction was slowly warmed to ambient temperature, where it stirred for about 18 hours. After this time the reaction mixture was poured into water, and the resulting mixture was filtered through diatomaceous earth to remove any salts that had precipitated. The organic layer was separated from the aqueous layer, washed with an aqueous saturated sodium chloride solution, dried with sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to a brown oil, which was passed through a silica gel scrub plug, yielding 5.0 grams of N-(3-chloro-4-fluorophenyl)-2-methoxy-2-methylpropionamide. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([OH:13])=O.S(Cl)(Cl)=O.[NH3:18]>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([NH2:18])=[O:13]
Reactant: N
Reactant: O=C(O)CCc1ccc(F)cc1F
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: NC(=O)CCc1ccc(F)cc1F
Temperature: 50 °C
Reaction time: 1 h

Procedure:
27.9 g (0.15 mol) of 3-(2,4-difluorophenyl)propanoic acid are mixed in a sulfation flask with 50 ml (0.69 mol) of thionyl chloride and 0.5 ml of dimethylformamide, and the mixture is stirred at room temperature for one hour, at 50° C. for one hour and under reflux for half an hour. The excess thionyl chloride is then removed by distillation in vacuo. The orange-brown oily residue is dissolved in toluene and then cooled to -15° C. At this temperature, 7.0 g (0.41 mol) of ammonia gas are passed in over about one hour. The temperature is then allowed to rise to room temperature. The partially crystalline reaction mixture is then poured into 500 ml of ice-water. The residue is filtered, washed with a little toluene and dried in vacuo. 21.7 (78% of theory) of white crystals of melting point 107°-108° C. are obtained. After recrystallization from water, the product melts at 109°-110° C.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][CH2:40][OH:41])[CH2:34][CH2:33]2)=[CH:25][C:5]=1[C:6]([NH:8][C:9]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=[CH:15][C:10]=1[C:11]([O:13]C)=[O:12])=[O:7].O.Cl>CO.O1CCOCC1.C(OCC)(=O)C>[OH:3][C:4]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][CH2:40][OH:41])[CH2:34][CH2:33]2)=[CH:25][C:5]=1[C:6]([NH:8][C:9]1[CH:18]=[C:17]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:16]=[CH:15][C:10]=1[C:11]([OH:13])=[O:12])=[O:7]
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OCCN2CCN(CCCO)CC2)ccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1cc(OCCN2CCN(CCCO)CC2)ccc1O
Temperature: 50 °C
Reaction time: 1 h
Yield: 60.7 %

Procedure:
A 2.0 mol/L aqueous solution of sodium hydroxide (0.031 mL) was added to a solution mixture of the obtained methyl 2-(2-hydroxy-5-(2-(4-(3-hydroxypropyl)piperazin-1-yl)ethoxy)benzamido)-4-phenylbenzoate (0.011 g) in methanol (1.0 mL) and dioxane (1.0 mL), followed by stirring at 50° C. for 1 hour. A 2.0 mol/L aqueous solution of sodium hydroxide (0.031 mL) was added to the reaction mixture, followed by stirring at 50° C. for 1 hour. The reaction mixture was cooled to room temperature, and then water was added thereto. After adjusting the pH to 6.5 with 1.0 mol/L hydrochloric acid, ethyl acetate was added thereto. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined. The resulting mixture was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid substance was collected by filtration to obtain 6.5 mg of 2-(2-hydroxy-5-(2-(4-(3-hydroxypropyl)piperazin-1-yl)ethoxy)benzamido)-4-phenylbenzoic acid as a light yellow solid.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:14]([OH:16])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=O)(C)(C)C.N[C@H](C(O)=O)CC(C)C.FC(F)(F)C(O)=O.C(OC([NH:40][C@H:41]([C:49]([OH:51])=[O:50])[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=O)(C)(C)C.CC(N=C=NC(C)C)C>C(N(C(C)C)CC)(C)C.C(Cl)Cl>[NH2:8][C@H:9]([C:14]([OH:16])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12].[NH2:40][C@H:41]([C:49]([OH:51])=[O:50])[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CC(C)C[C@H](N)C(=O)O
Agent: CC(C)N=C=NC(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 2 h

Procedure:
A dipeptide of L-leucine and L-phenylalanine was prepared using the above described resin. N-(tert-butyloxycarbonyl)-L-leucine was coupled using the procedure of Example 1. Amino acid analysis of this resin showed a leucine content of 0.75 meq/g. When treated with 45% trifluoroacetic acid to deprotect and cap the residual sulfide as in Example 1, the leucine content dropped to 0.49 meq/g. A sample of this resin (0.994 g, 0.49 mmol) was washed twice with a solution of 10% diisopropyl ethylamine in methylene chloride, followed by three washes with methylene chloride to neutralize the resin. The resin was coupled with N(tert-butyloxycarbonyl)-L-phenylalanine by suspending the resin in 10 ml methylene chloride and adding 464 mg (1.75 mmol) N-(tert-butyloxycarbonyl)-L-phenylalanine and 0.27 ml (235 mg, 1.86 mmol) N,N-diisopropylcarbodiimide. After shaking for two hours, the resin was washed three times with methylene chloride and dried under vacuum. Amino acid analysis showed the leucine content to be 0.40 meq/g and the phenylalanine content to be 0.40 meq/g.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([CH3:9])[C:5](I)=[CH:4][N:3]=1.O1CCCC1.[B:16]([O:25][CH:26]([CH3:28])[CH3:27])([O:21][CH:22]([CH3:24])[CH3:23])OC(C)C>>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([CH3:9])[C:5]([B:16]2[O:21][C:22]([CH3:23])([CH3:24])[C:26]([CH3:27])([CH3:28])[O:25]2)=[CH:4][N:3]=1
Reactant: Cc1c(I)cnc(Cl)c1F
Reactant: CC(C)OB(OC(C)C)OC(C)C
Solvent: C1CCOC1
Product: Cc1c(B2OC(C)(C)C(C)(C)O2)cnc(Cl)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a −78° C. solution of 2-chloro-3-fluoro-5-iodo-4-methyl-pyridine (498.6 mg; 1.837 mmol) in tetrahydrofuran (6.0 mL; 74 mmol) was added isopropylmagnesium chloride lithium chloride complex (1.3 mol/L) in THF (5.8 mL; 7.5 mmol). The reaction mixture was warmed to room temperature and stirred for 2 hours. The mixture was then re-cooled to −78° C. and triisopropyl borate (2.20 mL; 9.34 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with a few drops of saturated aqueous ammonium chloride solution, and then a few drops of saturated aqueous sodium carbonate solution were added to cleave the boronate ester. The reaction mixture was dried over magnesium sulfate to afford the boronic acid as a THF solution. To this mixture was added pinacol (3.8865 g; 32.230 mmol), and the mixture was then heated at 40° C. for 24 hours. The reaction mixture was concentrated, absorbed onto silica gel and purified by flash chromatography (40 g silica, solvent gradient: 0-50% ethyl acetate in heptane) to yield 0.2622 g (53%) of the title compound. LCMS (ESI): M+H=272.2; 1H NMR (400 MHz, DMSO) δ 8.30 (s, 1H), 2.47 (d, J=2.3 Hz, 3H), 1.32 (s, 12H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[NH:12][C:11]3=[CH:13][C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)=[N:15][C:10]3=[CH:9][N:8]=2)[CH2:3][CH2:2]1.CC[O:24]C(C)=O.[ClH:28]>CO>[OH2:24].[ClH:28].[NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[NH:12][C:11]3=[CH:13][C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)=[N:15][C:10]3=[CH:9][N:8]=2)[CH2:3][CH2:2]1
Reactant: CCOC(C)=O
Agent: Cl
Agent: c1ccc(-c2cc3[nH]c(C4CCNCC4)ncc-3n2)nc1
Solvent: CO
Product: O

Procedure:
Using the method described in Example 30 by employing 2-(1-pyrrolidinylvinyl)-2-pyridine (freshly prepared before use) (2.30 g, 13.2 mmol), 4,6-dichloro-5-nitropyrimidine (Aldrich Chemical Company) (2.55 g, 13.2 mmol), N,N-diisopropylethyl amine (Aldrich Chemical Company) (2.3 mL, 13.2 mmol), piperidine (2.1 mL, 21.1 mmol), NEt3 (Aldrich Chemical Company) (2.0 mL) and SnCl2 (Aldrich Chemical Company) (40 mL of a 2M solution in DMF). The residue was purified by flash chromatography on silica gel with 95:5 CHCl3:MeOH as elutant to give 340 mg (9%) of the free base as a beige colored solid. 1H NMR (DMSO-d6; 400 MHz): δ 1.66 (s, 6), 3.76 (s, 4), 7.13 (br s, 1), 7.41 (t, 1, J=4.8), 7.92 (t, 1, J=7.4), 8.10 (d, 1, J=8.0), 8.26 (br s, 1), 8.70 (br s, 1), 11.24 (s, 1). MS m/z: 280 (M+1). To a solution of 4-piperidyl-6-(2-pyridyl)pyrrolo[3,2-d]pyrimidine (0.34 g, 1.21 mmol) in 15:1 EtOAc:MeOH (30 mL) was added 1N etheral HCl (Aldrich Chemical Company) (1.20 mL, 1.21 mmol). The precipitate was collected by filtration, washed with EtOAc (2×10 mL), ether (3×15 mL) and dried under vacuum to give 300 mg (79%) of the title compound as a tan colored powder. Mp: 279-280° C. 1H NMR (DMSO-d6; 400 MHz): δ 1.72 (s, 6), 4.0 (br s, 4), 7.24 (s, 1), 7.52 (dd, 1, J=7.4, 7.5), 8.01 (dt, 1, J=1.3, 7.7), 8.24 (d, 1, J=8.0), 8.64 (s, 1), 8.77 (d, 1, J=4.4), 12.21 (s, 1), 14.51 (s, 1). MS m/z: 280 (M+1). Anal. Calcd for C16H17N5.1.2HCl.0.7H2O: C, 56.91; H, 5.88; N, 20.75; Cl, 13.01. Found C, 56.91; H, 5.83; N, 20.54; Cl, 12.92.
Reaction SMILES: C([Mg]Br)C.[CH2:5]([C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1)[CH3:6].[CH2:14]=[O:15].CN(C)P(N(C)C)(N(C)C)=O>O1CCCC1.C1(C)C=CC=CC=1>[CH2:5]([C:7]1[CH:12]=[CH:11][C:10]([CH:14]=[O:15])=[C:9]([OH:13])[CH:8]=1)[CH3:6]
Reactant: C=O
Reactant: CCc1cccc(O)c1
Agent: CC[Mg]Br
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCc1ccc(C=O)c(O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
A stirred solution of 200 mL (0.20 mole) of 1.0M of ethylmagnesium bromide (in tetrahydrofuran) in 100 mL of tetrahydrofuran was cooled in an ice-bath and 25.0 grams (0.21 mole) of 3-ethylphenol was added dropwise. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature where it stirred for 30 minutes. After this time, 15.4 grams (0.51 mole) of paraformaldehyde, 36.7 grams (0.21 mole) of hexamethylphosphoramide, and 350 mL of toluene were added. Upon completion of addition, the reaction mixture was heated to 80° C. where it stirred for about 18 hours. The reaction mixture was then cooled and concentrated under reduced pressure to a residue. The residue was taken up in diethyl ether and 200 mL of an aqueous 10% hydrochloric acid solution was added. The aqueous layer was separated and extracted with diethyl ether. The extract was combined with the organic layer, and the combination was washed with water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduce pressure to a residue. The residue was subjected to column chromatography on silica gel, using 1:1 hexane and methylene chloride as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 21.8 grams of 5-ethyl-2-formylphenol. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([N:11]([CH2:22][C:23]2[CH:38]=[CH:37][C:26]([C:27]([NH:29][CH2:30][C@@H:31]([OH:36])[C:32]([O:34]C)=[O:33])=[O:28])=[CH:25][CH:24]=2)[C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=3[N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].O>CO>[C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([N:11]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:27]([NH:29][CH2:30][C@@H:31]([OH:36])[C:32]([OH:34])=[O:33])=[O:28])=[CH:37][CH:38]=2)[C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=3[N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H](O)CNC(=O)c1ccc(CN(c2nc3ccccc3n2C)C2CCC(C(C)(C)C)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1c(N(Cc2ccc(C(=O)NC[C@@H](O)C(=O)O)cc2)C2CCC(C(C)(C)C)CC2)nc2ccccc21
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To a solution of the title compound of Example 7 (0.1 mmol, 50 mg) in 2 mL of MeOH was added LiOH (0.5 mmol, 12 mg). H2O was added dropwise until the reaction became slightly cloudy, then the mixture was sonicated to dissolve the LiOH. The reaction was stirred at 40° C. for 2 h. The reaction was concentrated under reduced pressure and the residue was taken up in dioxane/H2O and acidified with TFA. Purification by reverse-phase HPLC (Condition A), followed by lyophilization, afforded the title compound as a white solid. 1H NMR (500 MHz, CD3OD): δ 7.79 (d, 2H), 7.58 (m, 1H), 7.39-7.52 (overlapping m, 5H), 4.86 (s, 2H), 4.34 (m, 1H), 3.87 (s, 3H), 3.52-3.84 (overlapping m, 3H), 2.16 (m, 2H), 1.99 (m, 2H), 1.84 (m, 2H), 1.31 (m, 2H), 1.14 (m, 1H), 0.92 (s, 9H). MS (ESI): m/z 487 (M+H). MS (ESI): m/z 507 (M+H). HPLC A: 1.84 min.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[C:16]([S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])=[N:17][NH:18]3)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:32]>CO.CCOCC>[ClH:32].[C:26]1([S:23]([C:16]2[C:15]3[C:19](=[CH:20][CH:21]=[CH:22][C:14]=3[N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[NH:18][N:17]=2)(=[O:25])=[O:24])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3[nH]nc(S(=O)(=O)c4ccccc4)c23)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: O=S(=O)(c1ccccc1)c1n[nH]c2cccc(N3CCNCC3)c12
Temperature: 25 °C
Yield: 40 %

Procedure:
A solution of 4-[4-(t-butoxycarbonyl)piperazin-1-yl]-3-(phenylsulfonyl)-1H-indazole (0.022 g, 0.050 mmol) in methanol is treated with a 2 M solution of HCl in ether (0.4 mL), heated at reflux temperature for 1 h, cooled to room temperature and evaporated to dryness. The residue is re-dissolved in methanol and concentrated. Repeating this procedure three more times affords the title product as a white solid, 0.009 g (40% yield), identified by NMR and mass spectral analyses.