Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([CH2:26][N:27]([CH3:37])[CH:28]4[CH2:31][CH:30]([CH2:32][CH2:33][C:34](O)=[O:35])[CH2:29]4)[CH2:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.C(N(CC)C(C)C)(C)C.[Br:53][C:54]1[CH:55]=[C:56]([NH2:61])[C:57]([NH2:60])=[CH:58][CH:59]=1>CN(C)C=O>[NH2:61][C:56]1[CH:55]=[C:54]([Br:53])[CH:59]=[CH:58][C:57]=1[NH:60][C:34](=[O:35])[CH2:33][CH2:32][CH:30]1[CH2:31][CH:28]([N:27]([CH2:26][C@@H:18]2[C@@H:19]3[C@@H:20]([O:21][C:22]([CH3:24])([CH3:25])[O:23]3)[C@H:16]([N:13]3[C:9]4[N:10]=[CH:11][N:12]=[C:7]([NH:6][CH2:5][C:4]5[CH:38]=[CH:39][C:40]([O:42][CH3:43])=[CH:41][C:3]=5[O:2][CH3:1])[C:8]=4[CH:15]=[CH:14]3)[CH2:17]2)[CH3:37])[CH2:29]1
Reactant: Nc1ccc(Br)cc1N
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C)C3CC(CCC(=O)O)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C)C3CC(CCC(=O)Nc4ccc(Br)cc4N)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
N,N,N′,N′-Tetramethyl-0-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (1.20 g, 3.16 mmol) was added to a solution 3-(3-((((3aR,4R,6R,6aS)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)(methyl)amino)cyclobutyl)propanoic acid (1.25 g, 2.10 mmol) and N,N-Diisopropylethylamine (1.21 ml, 6.95 mmol) and 4-bromobenzene-1,2-diamine (0.472 g, 2.53 mmol) in N,N-Dimethylformamide (13.0 ml). The reaction was stirred overnight at RT, partially concentrated to ca. 2 mls and then NaHCO3 (saturated) was added. The mixture was extracted with EtOAc (3×) and the combined organics were dried with MgSO4, filtered and concentrated. The residue was purified by flash chromatography (DCM/7N NH3 in MeOH 95:5) to give the desired compound (1.2 g) as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][CH:11]([C:12]([OH:14])=[O:13])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17](O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][CH:11]([C:12]([O:14][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:13])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)OCc2ccccc2)CC1
Reaction time: 6 h

Procedure:
A mixture of N-tert-butoxycarbonylisonipecotic acid (12.0 g, 52.3 mmol), benzyl alcohol (6.0 mL, 58 mmol), 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (11.04 g, 57.6 mmol), and 4-dimethylaminopyridine (642 mg, 5.25 mmol) in anhydrous dichloromethane (100 mL) was stirred at room temp. for 6 h. The resultant mixture was diluted with dichloromethane and washed successively with water, 10% aqueous citric acid, saturated sodium bicarbonate, and brine. The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentration under vacuum. The residual oil was subjected to column chromatography on silica eluting with 20% ethyl acetate in hexane. Collection and concentration of appropriate fractions afforded the title product as white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=[O:14])[N:11]=[C:10]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([CH3:22])[CH:16]=3)[CH:9]=2)=[C:4]([CH3:23])[CH:3]=1.ClCCCl.C([N:35]1[CH2:40][CH2:39][CH:38]([CH:41]=O)[CH2:37][CH2:36]1)(OC(C)(C)C)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[OH:21][C:18]1[CH:19]=[CH:20][C:15]([C:10]2[CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][CH2:41][CH:38]4[CH2:39][CH2:40][NH:35][CH2:36][CH2:37]4)=[CH:3][C:4]=3[CH3:23])[NH:13][C:12](=[O:14])[N:11]=2)=[CH:16][C:17]=1[CH3:22]
Reactant: Cc1cc(-c2cc(-c3ccc(N)cc3C)[nH]c(=O)n2)ccc1O
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1cc(-c2cc(-c3ccc(NCC4CCNCC4)cc3C)[nH]c(=O)n2)ccc1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59 %

Procedure:
In a round bottom flask was added 6-(4-amino-2-methylphenyl)-4-(4-hydroxy-3-methylphenyl)pyrimidin-2(1H)-one (3) (30 mg, 0.10 mmol), 1,2 dichloroethane (2.0 mL), acetic acid (0.1 mL), and commercially available N-Boc-4-formyl piperidine (29 uL, 0.14 mmol). The reaction was stirred at room temperature for 15 minutes before adding sodium triacetoxy borohydride (30 mg, 0.14 mmol). Stirring was continued at room temperature overnight. The reaction was then quenched with saturated NaHCO3, extracted with EtOAc, dried over Na2SO4 and concentrated to dryness. The resultant oil was then dissolved in 4N HCl/dioxane (1.0 mL) and allowed to sit at RT for 30 min. or until Boc deprotection was complete. The 4N HCl/dioxane was decanted, and the residual solid product was rinsed with EtOAc 4×. The resulting orange solid was then dissolved in MeOH and purified by preparatory HPLC (5-85% gradient of AmAc/ACN, 15 min.) to give the product 4-(4-hydroxy-3-methylphenyl)-6-{2-methyl-4-[(piperidin-4 ylmethyl)amino]phenyl}pyrimidin-2(1H)-one as the acetate salt after lyopholyzation (24 mg, 59% yield).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:13][O:14][C:15]=2[CH2:16][O:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[OH-].[Li+]>O1CCCC1.CO.O>[NH2:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[N:13][O:14][C:15]=2[CH2:16][O:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: COC(=O)c1ccc(OCc2onc(-c3ccccc3)c2-c2ccc(S(N)(=O)=O)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: NS(=O)(=O)c1ccc(-c2c(-c3ccccc3)noc2COc2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Yield: 60.3 %

Procedure:
Methyl 4-[[4-[4-(aminosulfonyl)phenyl]-3-phenylisoxazol-5-yl]methoxy]benzoate (Example 50) (65.0 mg, 0.14 mmol) was dissolved in tetrahydrofuran/methanol/water (5.0 mL 7:2:1) and lithium hydroxide (10 mg, 0.250 mmol) was added. The solution was heated to reflux for 4 hours and cooled to room temperature. The solvent was removed in vacuo and the crude product was purified by preparative high pressure liquid chromatography using a C18 reverse phase column. The appropriate factions were combined and concentrated to afford pure 4-[[4-[4(aminosulfonyl)phenyl]-3-phenylisoxazol-5-yl]methoxy]benozoic acid as a white crystalline material (38 mg, 60%): mp 206.4°-207.9° C. 1H NMR CD3OD 5.29 (S, 2H), 7.01 (d, 2H, 8.4 Hz), 7.25-7.45 (m, 7H), 7.84-7.97 (m, 4H). Mass spectrum calc'd. for C23H18N2O6S: 450. Found: 451 (m+H+).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1.Br[CH2:14][CH3:15]>O1CCCC1>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH2:14][CH3:15])[C:11]#[N:12])=[CH:6][CH:5]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(C#N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 0.42 g (10.5 mmol) NaH (60% dispersion in mineral oil) were added at ambient temperature 1.67 g (11 mmol) 4-chlorophenyl-acetonitrile in 10 ml anhydrous tetrahydrofuran. The reaction mixture was stirred at ambient temperature for 2 hours and then cooled to −20° C. 0.78 ml (10.5 mmol) Bromoethane was added drop-wise to the reaction mixture over 30 minutes. The reaction was warmed to ambient temperature while stirring over 2 hours. The reaction mixture was quenched by addition of 20 ml of saturated ammonium chloride solution. Dichloromethane was added, the organic phase was separated and the aqueous phase washed with dichloromethane. The combined organic phase was dried over MgSO4 and evaporated to afford rac-2-(4-chloro-phenyl)butyronitrile as a brown oil that did not require further purification. NMR (CDCl3, ppm): 0.80 (3H, t), 1.82 (2H, dq), 3.64 (1H, t), 7.30-7.15 (4H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[CH:11]=2)=[C:6]([Cl:18])[C:3]=1[C:4]#[N:5].Cl.Cl[C:21]([NH2:23])=[NH:22]>COCCOCCOC>[NH2:23][C:21]1[N:22]=[C:4]([NH2:5])[C:3]2[C:2](=[CH:9][CH:8]=[C:7]([C:10]3[CH:11]=[C:12]([Cl:17])[CH:13]=[C:14]([Cl:16])[CH:15]=3)[C:6]=2[Cl:18])[N:1]=1
Reactant: N=C(N)Cl
Reactant: N#Cc1c(N)ccc(-c2cc(Cl)cc(Cl)c2)c1Cl
Agent: Cl
Solvent: COCCOCCOC
Product: Nc1nc(N)c2c(Cl)c(-c3cc(Cl)cc(Cl)c3)ccc2n1
Yield: 29.4 %

Procedure:
This compound was prepared in a manner analogous to that of Step E of Example 1, using 1.5 grams (0.005 mole) of 2-amino-6-chloro-5-(3,5-dichlorophenyl)benzonitrile and 0.7 gram (0.006 mole) of chloroformamidine hydrochloride in 10 mL of 2-methoxyethyl ether. The solid was recrystallized from methanol, yielding 0.5 gram of 2,4-diamino-5-chloro-6-(3,5-dichlorophenyl)quinazoline. The NMR spectrum was consistent with the proposed structure; however, methanol was present in the sample.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[N:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:13]=2[C:14]([O:16]C)=[O:15])[N:4]=1.CS(C)=O.[OH-].[Na+]>O>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][C:12]2[N:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:13]=2[C:14]([OH:16])=[O:15])[N:6]=1
Reactant: COC(=O)c1c(-c2ccccc2)ccnc1Oc1nc(OC)cc(OC)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(OC)nc(Oc2nccc(-c3ccccc3)c2C(=O)O)n1
Yield: 44.5 %

Procedure:
2.6 g (0.007 mol) of methyl 2-(4,6-dimethoxypyrimidin-2-yloxy)-4-phenylnicotinate and 50 ml of dimethylsulfoxide were weighed, and 4.6 ml (0.009 mol) of 2N sodium hydroxide aqueous solution was added dropwise thereto at 60° C. After the dropwise addition, the resultant mixture was further stirred for 30 minutes at 60° C. The resultant mixture was poured into water, and was washed twice with ethyl acetate. The aqueous layer was then adjusted to pH 2 with 10% hydrochloric acid aqueous solution, and the precipitated crystal was filtrated out. The crystal thus obtained was washed with water, and was then dried. The dried crystal was recrystallized with ethyl acetate to obtain 1.1 g of a white crystal.
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]([C:8]1[C:13]([Cl:14])=[CH:12][C:11]([Cl:15])=[CH:10][N:9]=1)[CH2:6]Br)[CH3:2].[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.[K].O>CN(C)C=O>[Cl:14][C:13]1[C:8]([C:5](=[N:4][O:3][CH2:1][CH3:2])[CH2:6][N:20]2[C:19](=[O:21])[C:18]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]3[C:16]2=[O:26])=[N:9][CH:10]=[C:11]([Cl:15])[CH:12]=1
Reactant: CCON=C(CBr)c1ncc(Cl)cc1Cl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CCON=C(CN1C(=O)c2ccccc2C1=O)c1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 84.7 %

Procedure:
To 3.00 g of 2-bromo-1-(3,5-dichloropyridin-2-yl)ethanone-O-ethyloxime in 20 ml of N,N-dimethylformamide, 2.32 g of potassium phthalimide was added, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was mixed with 50 ml of water and extracted with ethyl acetate (100 ml×1), the resulting organic layer was washed with water (50 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was washed with 10 ml of diisopropyl ether to obtain 3.08 g of the desired product as white crystals. m.p.: 99.0 to 101.0° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH2:12][C:13]#[N:14])=[CH:5][CH:4]=1.N>CO.[Ni]>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH2:12][CH2:13][NH2:14])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(CC#N)CC2
Agent: [Ni]
Agent: N
Solvent: CO
Product: COc1ccc2c(c1)C(CCN)CC2
Reaction time: 3 h

Procedure:
9.3 g (49 mmol) of crude 2-(6-methoxyindan-1-yl)acetonitrile are dissolved in 100 ml of methanol and, after the addition of 1 g of Raney nickel and 20 g of liquid ammonia, are hydrogenated at 70°-80° and 120 bar pressure. After 3 hours, the catalyst is filtered off from the methanolic solution and is subsequently washed with methanol. The methanolic solutions are combined and rendered acidic with hydrochloric acid. The acidic solution is concentrated to dryness by evaporation in vacuo, and the residue is dissolved in 100 ml of water, rendered alkaline with concentrated sodium hydroxide solution and extracted by shaking with diethyl ether. The ethereal phases are washed with saturated sodium chloride solution and dried over magnesium sulphate. After removing the solvent, crude 2-(6-methoxyindan-1-yl)ethylamine is obtained in the form of a yellow oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[NH3:11]>CO>[NH2:11][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: N
Solvent: CO
Product: N#Cc1ccc(CN)cc1
Yield: 16.8 %

Procedure:
Stir 4-bromomethyl-benzonitrile (2.0 g, 0.010 mmoles) in sealed vessel in a solution of 2N ammonia in methanol at 80° C. until completion. Reduce solvent in volume. Dissolve residue in ethyl acetate and wash with 1N HCl. Basify aqueous layer with 5N NaOH. Extract aqueous layer into dichloromethane. Dry organic layer over MgSO4 and reduce in volume to isolate 0.223 g. Yield=16.8%. Mass Spectrum (m/e): (M−).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[CH:20][C:4]=1[CH2:5][NH:6][CH2:7][CH:8](O)[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1.S(=O)(=O)(O)O>FC(F)(F)C(O)=O>[CH3:25][O:24][C:23]1[C:3]([O:2][CH3:1])=[C:4]2[C:20]([CH:8]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=3)[CH2:7][NH:6][CH2:5]2)=[CH:21][CH:22]=1
Reactant: COc1ccc(C(O)CNCc2cccc(OC)c2OC)cc1OC
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C2CNCc3c2ccc(OC)c3OC)cc1OC
Reaction time: 0.67 h
Yield: 84 %

Procedure:
α-[[(2,3-Dimethoxybenzyl)amino]methyl]-3,4-dimethoxybenzyl alcohol 6.56 g, 18.9 mmol) was dissolved in trifluoroacetic acid (50 ml). Concentrated sulfuric acid was added to the solution under stirring and under cooling with ice and the reaction was conducted under these conditions for 40 minutes. The reaction solution was concentrated. Water was added to the residue and then it was made basic with aqueous ammonia under stirring and under cooling with ice. After extraction with dichloromethane, the dichloromethane layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resultant crystals were washed with isopropyl ether to obtain 5.23 g of 7,8-dimethoxy-4-(3,4-dimethoxyphenyl)-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][C@@:12]([CH2:17][CH3:18])([C:14]([OH:16])=[O:15])[CH:11]=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:10][CH2:11][C@:12]([CH2:17][CH3:18])([C:14]([OH:16])=[O:15])[CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC[C@]1(C(=O)O)C=C[C@@H](NC(=O)OC(C)(C)C)C1
Agent: [Pd]
Solvent: CCO
Product: CC[C@]1(C(=O)O)CC[C@@H](NC(=O)OC(C)(C)C)C1
Reaction time: 18 h
Yield: 107.7 %

Procedure:
To a solution of (1R,4S)-4-[(tert-butoxycarbonyl)amino]-1-ethylcyclopent-2-ene-1-carboxylic acid (1.38 g, 5.41 mmol) in ethanol (40 mL) was added 10% palladium on carbon (200 mg). The mixture was shaken under hydrogen at 50 psi for 18 h and filtered through celite. The filtrate was evaporated in vacuo to afford the desired product (1.5 g). MS calculated for C13H23NO4: (M+H) 258.2; found 158.1 (M+H-Boc).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([CH2:7][CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[CH:6]=1.C([Mg]Cl)(C)C.CO[B:23]1[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]1>C1COCC1>[O:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH:10]1[O:9][CH2:8][CH2:7][N:5]1[CH:6]=[C:2]([B:23]2[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]2)[CH:3]=[N:4]1
Reactant: Ic1cnn(CCOC2CCCCO2)c1
Reactant: COB1OC(C)(C)C(C)(C)O1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
To a solution of 4-iodo-1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazole (1.0 g, 3.1 mmol) in anhydrous THF (8 mL) was added iPrMgCl (2M in THF, 3.10 mL, 6.21 mmol) at 0° C. drop by drop under nitrogen. The reaction was stirred for 1 hour at 0° C. under nitrogen. To the solution was added 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.736 g, 4.66 mmoL) at 0° C. and the resulting yellow solution was allowed to stir for 1 hour at ambient temperature under nitrogen. The reaction was quenched with sat. aqueous solution of NH4Cl (10 mL). EtOAc (50 mL) and sat aqueous NH4Cl solution (10 mL) were added. The organic layer was separated, and the aqueous layer was extracted with EtOAc (3×50 mL), dried over Na2SO4, and concentrated to give the crude product as yellow oil. The oil was purified a silica gel column eluting with EtOAc and hexanes to provide 1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole as clear oil (800 mgs, 80% yield). 1H NMR (300 MHz, DMSO-d6) δ 7.91 (s, 1H) 4.48-4.54 (m, 1H) 4.26-4.33 (m, 2H) 3.86-3.90 (m, 1H) 3.66-3.76 (m, 1H) 3.45-3.57 (m, 1H) 3.33-3.39 (m, 1H) 1.33-1.70 (m, 6H) 1.24 (s, 12H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:16][C@H:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C@@H:14]([NH2:22])[C@H:12]1[OH:13].[C:23]([O:27][C:28]([NH:30][C@H:31]([C:51](O)=[O:52])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][CH2:42][NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[CH:35][CH:34]=1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:16][C@H:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C@@H:14]([NH:22][C:51](=[O:52])[C@H:31]([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([O:39][CH2:40][CH2:41][CH2:42][NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[CH:37][CH:38]=2)[NH:30][C:28]([O:27][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:29])[C@H:12]1[OH:13]
Reactant: CCOC(=O)[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1N
Reactant: CC(C)(C)OC(=O)NCCCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Product: CCOC(=O)[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1NC(=O)[C@H](Cc1ccc(OCCCNC(=O)OC(C)(C)C)cc1)NC(=O)OC(C)(C)C
Yield: 70.5 %

Procedure:
Ethyl 1-(6-amino-9H-purin-9-yl)-1,3-dideoxy-3-[N-tert-butoxycarbonyl-O-(3-tert-butoxycarbonylaminopropyl)-L-tyrosylamino]-β-D-ribofuranuronate (770 mg) was prepared by reacting ethyl 1-(6-amino-9H-purin-9-yl)-1,3-dideoxy-3-amino-β-D-ribofuranuronate (462 mg) prepared in Example 63 with N-tert-butoxycarbonyl-O-(3-tert-butoxycarbonylaminopropyl)-L-tyrosine (906 mg) prepared in Preparation 7 (4) according to a similar manner to that of Example 64, mp. 125°-131° C. (dec.).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[C@H:11]12[N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@H:15]([CH2:16][CH2:17]1)[CH2:14][NH:13][CH2:12]2.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1>C(Cl)Cl>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]([N:13]2[CH2:14][C@@H:15]3[N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@@H:11]([CH2:17][CH2:16]3)[CH2:12]2)=[O:36])=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@H]1CNC2
Reactant: COc1ccc(N=C=O)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(NC(=O)N2C[C@H]3CC[C@@H](C2)N3C(=O)OC(C)(C)C)cc1
Reaction time: 20 h
Yield: 102.4 %

Procedure:
DIPEA (0.53 mL, 3.0 mmol) was added to a suspension of tert-butyl (1S,5R)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate hydrochloride (0.50 g, 2.00 mmol) in DCM (20 mL). To the mixture was added 4-methoxyphenyl isocyanate (0.26 mL, 2.0 mmol) dropwise, and the reaction mixture was stirred for 20 h. The reaction mixture was washed with brine (2×20 mL), then passed through a phase separator and evaporated. The crude material was purified by flash chromatography on silica, with a gradient of 25% increasing to 75% EtOAc/isohexane over 20 column volumes. The title compound (0.74 g, >99%) was obtained as a white solid. LCMS (ES+) 362.8 (M+H)+, RT 2.02 minutes (method 3).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][C:6]=1[F:13])(=[O:3])[CH3:2].[NH2:14][NH:15][C:16]([NH2:18])=[S:17]>>[C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[N:14][NH:15][C:16]([NH2:18])=[S:17])=[CH:7][C:6]=1[F:13])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C=O)cc1F
Reactant: NNC(N)=S
Product: CC(=O)Nc1ccc(C=NNC(N)=S)cc1F

Procedure:
The product was characterized as 4-acetamido-3-fluorobenzaldehyde 15. 4-Acetamido-3-fluorobenzaldehyde 15 reacts with thiosemicarbazide to yield 4-acetamido-3-fluorobenzaldehyde thiosemicarbazone 16. Compound 16 has been tested and shown to be both non-toxic and highly active against M. Tuberculosis.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:12]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH2:5][C:4]1[CH:8]=[CH:9][CH:10]=[CH:2][CH:3]=1)[C:5]([OH:7])=[O:6])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)c1ccc(O)c(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(O)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Temperature: 25 °C

Procedure:
3,4-Dihydroxy benzoic acid, benzyl bromide, and potassium carbonate were dissolved in acetonitrile, and the solution was refluxed for 18 hours. The reaction solution was then cooled to room temperature and filtered. The solution was then concentrated and diluted with hexanes, resulting in a solid that was collected by filtration. The solid was then recrystallized in the mixture of THF and hexanes, giving rise to a pure product.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:10]=1.[CH:25]([C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=1)=O.C[O-].[Na+].Cl>CO.O>[CH3:34][O:33][C:31](=[O:32])[C:30]1[CH:35]=[CH:36][C:27](/[CH:25]=[CH:16]/[C:15]([C:12]2[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][C:11]=2[NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[O:17])=[CH:28][CH:29]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CC(=O)c1ccc(Cl)cc1Nc1ccccn1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(/C=C/C(=O)c2ccc(Cl)cc2Nc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 96.6 %

Procedure:
A mixture of the trifluoroacetic acid salt of 1-[4-chloro-2-(pyridin-2-ylamino)-phenyl]-ethanone (273 mg, 757 μmol) in methanol (3.78 mL) at 25° C. was treated with methyl 4-formylbenzoate (124 mg, 757 μmol) and sodium methoxide in methanol (4.37M, 520 μL, 2.27 mmol). The reaction was stirred at 25° C. for 3 d. At this time, the reaction was diluted with water (50 mL), neutralized with a 1N aqueous hydrochloric acid solution and extracted with methylene chloride (3×50 mL). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo to afford 4-{(E)-3-[4-chloro-2-(pyridin-2-ylamino)-phenyl]-3-oxo-propenyl}-benzoic acid methyl ester (287.3 mg, 96.6%) as an orange solid. The material was used without further purification.