Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](B3OC(C)(C)C(C)(C)O3)[CH:8]=2)[C:3]1=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][N:36]=1>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>[CH3:1][C:2]1([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][N:36]=3)[CH:8]=2)[C:3]1=[O:21]
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Reactant: CCOC(=O)CC1(C)CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc2C1=O
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)CC1(C)CCc2cc(-c3ccc([N+](=O)[O-])cn3)ccc2C1=O
Yield: 101 %

Procedure:
Pd(PPh3)4 (0.248 g, 0.215 mmol) was added to a solution of 3E (1.6 g, 4.3 mmol) in 20 mL of 1,4 dioxane-H2O (3:1) mixture under argon atmosphere, followed by cesium carbonate (4.2 g, 12.89 mmol) and 2-bromo-5-nitropyridine (0.872 g, 4.3 mmol). The mixture was degassed for 5 min. The reaction mixture was refluxed for 3 h, and solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate and water. The separated organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The product was purified by triturating in ethanol to afford the title compound (1.6 g, 69%) as a solid. 1H NMR (400 MHz, CDCl3): δ 9.52 (d, J=2.6 Hz, 1H), 8.57 (dd, J1=2.6 Hz, J2=8.7 Hz, 1H), 8.20 (d, J=8.2 Hz, 1H), 8.02 (s, 1H), 7.97 (dd, J1=3.2 Hz, J2=8.0 Hz, 2H), 4.10 (q, J=7.2 Hz, 2H), 3.19 (m, 1H), 3.06 (dt, J1=17.2 Hz, J2=4.4 Hz, 1H), 2.98 (d, J=15.6 Hz, 1H), 2.56-2.43 (m, 2H), 2.00 (dt, J1=13.5 Hz, J2=4.6 Hz, 1H), 1.31 (s, 3H), 1.22 (t, J=7.2 Hz, 3H). ESI-MS m/z: 369 (M+H)+.
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11]Br)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:13][N:14]=[C:15]([C:21](=[O:23])[CH3:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([O:9][CH2:10][CH2:11][O:13][N:14]=[C:15]([C:21](=[O:23])[CH3:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCCBr)c1ccccc1
Reactant: CCOC(=O)C(=NO)C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=NOCCOC(=O)c1ccccc1)C(C)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.4 %

Procedure:
2-Bromoethyl benzoate (27.5 g.) was added dropwise to a stirred mixture of ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer) (15.7 g.), potassium carbonate (20.7 g.) and N,N-dimethylformamide (25 ml.) under ice cooling over 10 minutes, and stirred at ambient temperature for 4 hours. The resultant mixture was filtred and washed with acetone. The filtrate and washings were combined and concentrated in vacuo. After adding water (100 ml.) to the residue, the solution was extracted with methylene chloride three times. The extracts were washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo to give ethyl 2-(2-benzoyloxyethoxyimino)-3-oxobutyrate (syn isomer) (28 g.).
Reaction SMILES: [I:1][C:2]1[C:3]([C:7]([OH:9])=O)=[N:4][NH:5][CH:6]=1.Cl.Cl.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([NH2:21])[C:17]([NH2:20])=[CH:18][CH:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.CCOC(C)=O>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][C:16]=1[NH:21][C:7]([C:3]1[C:2]([I:1])=[CH:6][NH:5][N:4]=1)=[O:9]
Reactant: O=C(O)c1n[nH]cc1I
Reactant: COc1ccc(N)c(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1ccc(N)c(NC(=O)c2n[nH]cc2I)c1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A suspension of 4-iodo-1H-pyrazole-3-carboxylic acid Compound 1a(500 mg, 2.101 mmol), 4-methoxy-benzene-1,2-diamine dihydrochloride (443 mg, 2.101 mmol), HATU (799 mg, 2.101 mmol), and diisopropyl ethylamine (815 mg, 6.303 mmol) in 15 ml DMF was stirred at 50° C. for 16 hrs. After cooled to rt, the mixture was diluted with 150 ml EtOAc, washed with water (7 times) and brine, then dried with Na2SO4. Evaporation give 4-iodo-1H-pyrazole-3-carboxylic acid (2-amino-5-methoxy-phenyl)-amide Compound 1b (615 mg, 81.7%) as a yellowish powder. NMR (DMSO): δ 3.70 (s, 3H), 6.20 (m, 1H), 6.46 (s, H), 7.12 (d, J=8.0 Hz, 1H), 8.10 (s, 1H). MS m/z 358 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:21]([Cl:22])=[CH:20][C:5]2[N:6]=[C:7]([C:9]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12](Br)=[CH:11][CH:10]=3)[NH:8][C:4]=2[CH:3]=1.C([Li])CCC.CN(C)[CH:30]=[O:31].O>O1CCCC1>[Cl:1][C:2]1[C:21]([Cl:22])=[CH:20][C:5]2[N:6]=[C:7]([C:9]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]([CH:30]=[O:31])=[CH:11][CH:10]=3)[NH:8][C:4]=2[CH:3]=1
Reactant: CN(C)C=O
Reactant: Clc1cc2nc(-c3ccc(Br)c4ccccc34)[nH]c2cc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)c2ccccc12
Reaction time: 0.25 h
Yield: 51.7 %

Procedure:
To a solution of 5,6-dichloro-2-(4-bromo-1-naphthyl)benzimidazole (160 mg, 0.408 mmol) in tetrahydrofuran (6 mL) were added n-butyllithium (1.6 mol/L; 0.64 mL) and dimethylformamide (0.077 mL, 1.0 mmol) sequentially at −78° C. under nitrogen atmosphere, and the mixture was stirred for 15 min. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was combined, washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (2:1 hexane/ethyl acetate) to afford 5,6-dichloro-2-(4-formyl-1-naphthyl)benzimidazole (72 mg, 52%).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[C:6]([C:10]1[CH2:15][C:14](=O)[CH:13]=[CH:12][N:11]=1)([CH3:9])([CH3:8])[CH3:7]>C(Cl)(Cl)Cl>[Cl:3][C:14]1[CH:13]=[CH:12][N:11]=[C:10]([C:6]([CH3:9])([CH3:8])[CH3:7])[CH:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(C)C1=NC=CC(=O)C1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1cc(Cl)ccn1
Reaction time: 48 h

Procedure:
Phosphorous oxychloride (21.8 ml) and 2-tert.butylpyridin-4-one (2.36 g) is heated at reflux in chloroform (15 ml) for 24 hours and then stood at room temperature for 48 hours before pouring onto ice (100 g). Extraction with CH2Cl2 (3 times 250 ml) is followed by drying of the combined organic layers over magnesium sulphate. Evaporation of the organic layers gives the title compound.
Reaction SMILES: [Li]CCCC.[Br:6][C:7]1[N:8]=[C:9]([C:21]([CH3:24])([CH3:23])[CH3:22])[N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:11]=1Br.[Cl:25][C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1>C1COCC1.O=[Mn]=O>[Br:6][C:7]1[N:8]=[C:9]([C:21]([CH3:24])([CH3:23])[CH3:22])[N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:11]=1[C:28]1[CH:29]=[CH:30][N:31]=[C:26]([Cl:25])[N:27]=1
Reactant: CC(C)(C)c1nc(Br)c(Br)n1COCC[Si](C)(C)C
Reactant: Clc1ncccn1
Agent: O=[Mn]=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1nc(Br)c(-c2ccnc(Cl)n2)n1COCC[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 39.2 %

Procedure:
n-BuLi (1.5 M in hexane, 40 mL, 60 mmol) was added dropwise to a cooled solution of 4,5-dibromo-2-tert-butyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (23.6 g, 57.2 mmol) in anhydrous THF (250 mL) at −78° C. After 30 minutes at −78° C., a solution of 2-chloropyrimidine (7.21 g, 63.0 mmol) in anhydrous THF (2 mL) was added dropwise and the reaction was stirred at −78° C. for 1 hour. The reaction was quenched by the addition of saturated aqueous NH4Cl solution and allowed to warm to room temperature. The mixture was partitioned with EtOAc and the layers separated. The aqueous portion was extracted with EtOAc (3×) and the combine organic layers were washed with water, brine, dried (MgSO4), and concentrated. The resulting residue was dissolved in EtOAc, treated with MnO2 (5.2 g, 60 mmol), and heated to reflux for 3 hours. The reaction was allowed to cool to room temperature and filtered through Celite. The filter cake was washed thoroughly with EtOAc and the combine filtrates were concentrated. The remaining residue was purified by flash chromatography (SiO2, 0-10% EtOAc in hexanes) to give 10 g (37%) of 4-(4-bromo-2-tert-butyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloropyrimidine: LCMS (m/z): 445. 0 (MH+), tR=1.35 minutes. 1H NMR (400 MHz, CDCl3) δ 8.64 (d, J=5.3 Hz, 1H), 7.83 (d, J=5.3 Hz, 1H), 5.85 (s, 2H), 3.45 (m, 2H), 1.49 (s, 9H), 0.76 (m, 2H), −0.08 (s, 9H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2([CH3:28])[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19]2)[CH2:14][CH2:13]1.C(N(CC)CC)C>ClCCl>[CH3:28][C:18]1([N:15]2[CH2:16][CH2:17][C:12](=[O:11])[CH2:13][CH2:14]2)[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19]1
Reactant: CCOC(=O)N1CCC(C)(N2CCC(O)CC2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCC(C)(N2CCC(=O)CC2)C1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 98.3 %

Procedure:
2M Oxalyl chloride solution in dichloromethane (617 mg, 4.86 mmol) was taken into a oven dried round bottom flak and cooled to −78° C. under nitrogen atmosphere. Then dimethyl sulfoxide (767 mg, 9.72 mmol) in anhydrous dichloromethane (5 mL) was added dropwise. After 10 minutes, a solution of ethyl 3-(4-hydroxy-1-piperidyl)-3-methyl-pyrrolidine-1-carboxylate (830 mg, 3.24 mmol) in dichloromethane (10 mL) was cannulated into the flask and stirred at −78° C. for another 10 minutes. Triethylamine (1.31 g, 12.96 mmol) was then added and stirred at −78° C. for 30 minutes, allowed to warm to 0° C. over 30 minutes and was quenched with saturated solution of ammonium chloride (10 mL). The product was extracted into dichloromethane (2×50 mL) and the combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo to afford the title compound as a yellow oil (810 mg, 90%). 1H NMR (CDCl3, 400 MHz): δ 4.18 (m, 2H), 3.88 (m, 1H), 3.62-3.35 (m, 3H), 2.92 (m, 1H), 2.85 (brs, 2H), 2.75 (brs, 1H), 2.48-2.39 (m, 4H), 2.05-1.89 (m, 1H), 1.41 (m, 1H), 1.26 (t, 3H), 1.08 (s, 3H) MS (M+1): 255.12.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:25])=[C:4]([CH:9]=[C:10]([Cl:24])[C:11]=1[O:12][C:13]1[CH:18]=[C:17]([CH:19]([CH3:21])[CH3:20])[C:16]([OH:22])=[C:15]([CH3:23])[CH:14]=1)[C:5]([O:7]C)=[O:6].O[Li].O>C1COCC1.O>[Cl:1][C:2]1[C:3]([CH3:25])=[C:4]([CH:9]=[C:10]([Cl:24])[C:11]=1[O:12][C:13]1[CH:18]=[C:17]([CH:19]([CH3:21])[CH3:20])[C:16]([OH:22])=[C:15]([CH3:23])[CH:14]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(Cl)c(Oc2cc(C)c(O)c(C(C)C)c2)c(Cl)c1C
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Oc2c(Cl)cc(C(=O)O)c(C)c2Cl)cc(C(C)C)c1O
Yield: 93.6 %

Procedure:
A solution of methyl 3,5-dichloro-2-methyl-4-(3-methyl-4-hydroxy-5-isopropylphenoxy)benzoate (125 mg, 0.33 mmol) and LiOH H2O (68 mg, 1.63 mmol) in a 5:1 THF/H2O (6 mL) was stirred overnight at 20° C. under N2. The solution was concentrated under vacuum and acidified to pH 1 with 1N HCl. The resulting tan solid was collected by filtration, washed with H2O and air dried to yield 114 mg of 3,5-dichloro-2-methyl-4-(3-methyl-4-hydroxy-5-isopropylphenoxy)benzoic acid.
Reaction SMILES: O=[CH:2][C@@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[CH:11]1([CH2:14][NH2:15])[CH2:13][CH2:12]1.[Cl:16][CH2:17][CH2:18][N:19]=[C:20]=[O:21]>>[Cl:16][CH2:17][CH2:18][NH:19][C:20]([N:15]([CH2:14][CH:11]1[CH2:13][CH2:12]1)[CH:2]1[O:8][C@H:7]([CH2:9][OH:10])[C@@H:5]([OH:6])[C@H:3]1[OH:4])=[O:21]
Reactant: O=C[C@H](O)[C@H](O)[C@H](O)CO
Reactant: O=C=NCCCl
Reactant: NCC1CC1
Product: O=C(NCCCl)N(CC1CC1)C1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 68.1 %

Procedure:
3.0 g of D-ribose, 2.2 g of cyclopropylmethylamine and 2.5 g of 2-chloroethyl isocyanate are treated in the same manner as described in Example 31-(1). 4.2 g of 1-(2-chloroethyl)-3-cyclopropylmethyl-3-(D-ribofuranosyl)urea are thereby obtained as colorless caramel.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:29])=[C:4]([NH:10][C@H:11]([C@H:26]([OH:28])[CH3:27])[C:12]([NH:14][NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=2)=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].S(Cl)(C1C=CC(C)=CC=1)(=O)=O.CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:29])=[C:4]([NH:10][C@@H:11]([C:12]2[O:25][C:16]([C:17]3[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[CH:21][CH:22]=3)=[N:15][N:14]=2)[C@H:26]([OH:28])[CH3:27])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(C#N)cc2)[C@@H](C)O)ccc(C#N)c1Cl
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(C#N)cc3)o2)[C@@H](C)O)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 14.6 %

Procedure:
To a 250 mL, round-bottomed flask equipped with a magnetic stir bar and septum was added N′-((2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoyl)-4-cyanobenzohydrazide (0.6871 g, 2.4 mmol) followed by addition of anhydrous THF (200 mL) under an atmosphere of nitrogen. To this was then added tosyl chloride (318 mg, 1.7 mmol) followed by addition of polystyrene bound (2-tert-butylimino-2-diethylamino-1,3-d methylperhydro-1,3,2-diazaphosphorine (PS-BEMP) (2.2 mmol/g loading) 2.29 g, 5.0 mmol). This mixture was allowed to stir at room temperature for a period of 16 h. The solids were then filtered off and washed with additional THF (100 mL). The filtrate was then concentrated under reduced pressure to reveal a yellow solid. This was purified via silica gel chromatography eluted with 50% EtOAc/hexanes to provide product as a white solid (138 mg, 21%). 1H NMR (500 MHz, acetone-d6, δ in ppm) 8.19 (AA′XX′, J=8.4 Hz, 2H), 7.98 (AA′XX′, J=8.5 Hz, 2H), 7.48 (d, J=8.6 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 5.89 (d, J=8.8 Hz, 1H), 5.11 (dd, J=5.6, 8.8 Hz, 1H), 4.71 (d, J=5.9 Hz, 1H), 4.55 (m, 1H), 2.36 (s, 3H), 1.43 (d, J=6.3 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[C:21]([NH:22][CH3:23])=[CH:20][CH:19]=[CH:18][N:13]3[C:14](=[O:17])[C:15]=2[OH:16])=[O:9])=[CH:4][CH:3]=1.[CH3:26][S:27]([CH2:30][C:31](Cl)=[O:32])(=[O:29])=[O:28].C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[C:21]([N:22]([CH3:23])[C:31](=[O:32])[CH2:30][S:27]([CH3:26])(=[O:29])=[O:28])=[CH:20][CH:19]=[CH:18][N:13]3[C:14](=[O:17])[C:15]=2[OH:16])=[O:9])=[CH:24][CH:25]=1
Reactant: CNc1cccn2c(=O)c(O)c(C(=O)NCc3ccc(F)cc3)nc12
Reactant: CS(=O)(=O)CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)CS(C)(=O)=O)c1cccn2c(=O)c(O)c(C(=O)NCc3ccc(F)cc3)nc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
N-(4-fluorobenzyl)-3-hydroxy-9-(methylamino)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide was dissolved in dichloromethane. Methylsulfonylacetyl chloride (1.2 eqs.) and triethylamine (2 eqs.) were added and the solution was stirred at room temperature. After 5 hours a further 2 eqs. of methylsulfonylacetyl chloride and 2 eqs. of triethylamine were added. The solvent was removed under vacuum and the residue was suspended in methano/0.1 M NaOH. The suspension was sonicated for 2 minutes and left stirring at room temperature for 30 minutes. The product was purified by preparative RP-HPLC, using water (0.1% TFA) and acetonitrile (0.1% TFA) as eluants (column: C18). The product was obtained after lyophilization of the pooled product fractions as bright yellow fluffy material.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]2)=[C:4]([N+:14]([O-])=O)[C:3]=1[CH3:17].O.O.[Sn](Cl)Cl>C(O)C>[NH2:14][C:4]1[C:3]([CH3:17])=[C:2]([Cl:1])[CH:11]=[C:10]2[C:5]=1[NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]2
Reactant: Cc1c(Cl)cc2[nH]c(=O)c(=O)[nH]c2c1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Cc1c(Cl)cc2[nH]c(=O)c(=O)[nH]c2c1N
Temperature: 25 °C

Procedure:
A suspension of 7-chloro-1,4-dihydro-6-methyl-5-nitroquinoxaline-2,3-dione (0.050 g, 0.20 mmol) and tin (II) chloride dihydrate (0.133 g, 0.60 mmol) in ethanol (1.0 mL) was refluxed for 6 h. The suspension was then cooled to room temperature and the solid was collected by vacuum filtration, washed with ethanol (1 mL), and dried further under vacuum to obtain 0.036 g (82%) pure (HPLC) title compound as an off-white solid; mp-darkens at 323° C.; 1H NMR (DMSO-d6) δ 2.09 (s, 3H), 5.47 (s, 2H), 6.46 (s, 1H), 11.15 (s, 1H), 11.72 (s, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C@H:15]1[CH2:45][CH2:44][C:18]2[N:19]=[C:20]([NH:22][C:23](=[O:43])[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][C:32](=[O:42])[NH:33][C:34]4[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=4)[CH:25]=3)[S:21][C:17]=2[CH2:16]1)(C)(C)C>C(Cl)Cl>[NH2:14][C@H:15]1[CH2:45][CH2:44][C:18]2[N:19]=[C:20]([NH:22][C:23](=[O:43])[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][C:32](=[O:42])[NH:33][C:34]4[CH:35]=[CH:36][C:37]([C:40]#[N:41])=[CH:38][CH:39]=4)[CH:25]=3)[S:21][C:17]=2[CH2:16]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2nc(NC(=O)c3cccc(OCC(=O)Nc4ccc(C#N)cc4)c3)sc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(NC(=O)COc2cccc(C(=O)Nc3nc4c(s3)C[C@@H](N)CC4)c2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 60.2 %

Procedure:
Add trifluoroacetic acid (1.0 mL, 14 mmol) to a solution of ((S)-2-{3-[(4-cyano-phenylcarbamoyl)-methoxy]-benzoylamino}-4,5,6,7-tetrahydro-benzothiazol-6-yl)-carbamic acid tert-butyl ester (0.14 g, 0.26 mmol) in methylene chloride (10 mL). Stir the mixture at room temperature for 15 h then concentrate under reduced pressure. Purify the residue by preparative reverse phase HPLC using acetonitrile/water with 0.1% trifluoroacetic acid additive as the eluent to provide 0.07 g of the title compound as a white powder. MS, electrospray 448.75 (M+H), rt. 1.21 min.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:23][C:24]1[C:28]([C:29]([OH:31])=O)=[C:27]([CH2:32][C:33](=[O:40])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:26][N:25]=1.C(N(C(C)C)C(C)C)C.[C:50]([N:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1)(=[O:52])[CH3:51]>CN(C=O)C.C(Cl)(Cl)Cl>[C:50]([N:53]1[CH2:58][CH2:57][N:56]([C:29]([C:28]2[C:24]([CH3:23])=[N:25][O:26][C:27]=2[CH2:32][C:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:40])=[O:31])[CH2:55][CH2:54]1)(=[O:52])[CH3:51]
Reactant: Cc1noc(CC(=O)c2ccccc2)c1C(=O)O
Reactant: CC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCN(C(=O)c2c(C)noc2CC(=O)c2ccccc2)CC1
Temperature: 25 °C

Procedure:
A solution of TBTU (0.48 g, 1.5 mmol, 1,5 eq.) in DMF (2 mL) was added to a mixture of 3-methyl-5-(2-oxo-2-phenylethyl)isoxazole-4-carboxylic acid (0.24 g, 1 mmol, 1 eq), N-ethyl-N-isopropylpropan-2-amine (0.18 mL, 1 eq) and 1-acetylpiperazine (0.13 g, 1 eq) in DMF (1 mL). The resulting solution was stirred at room temperature. Chloroform (25 mL) was added and the solution was washed with water and 1 M HCl, dried (Na2SO4) and evaporated. The residue was purified by flash chromatography (SiO2 1:2 heptane/EtOAc) to afford the title compound. MS (ESI, POS. ION) M/Z Calcd for C19H21N3O4: 355.1532, found 355.1538.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:37]([O:41][C:42]([NH:44][C@@H:45]1[CH2:50][CH2:49][CH2:48][CH2:47][C@H:46]1[NH2:51])=[O:43])([CH3:40])([CH3:39])[CH3:38]>CN(C)C=O>[C:37]([O:41][C:42]([NH:44][C@@H:45]1[CH2:50][CH2:49][CH2:48][CH2:47][C@H:46]1[NH:51][C:11]([C:6]1[NH:7][C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)=[O:13])=[O:43])([CH3:40])([CH3:38])[CH3:39]
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 72 h
Yield: 95 %

Procedure:
5-Chloroindole-2-carboxylic acid (2.88 g), 1-hydroxybenzotriazole monohydrate (2.08 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.95 g) were added to a solution of (±)-trans-N-tert-butoxycarbonyl-1,2-cyclohexanediamine (3.00 g) in N,N-dimethylformamide (10 ml) at room temperature. After stirring for 3 days, the reaction mixture was concentrated under reduced pressure, and dichloromethane (30 ml), a saturated aqueous solution (150 ml) of sodium hydrogencarbonate and water (150 ml). were added to the residue. After collecting colorless precipitate formed was collected by filtration and dried to obtain the title compound (5.21 g) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:21]([Cl:22])=[CH:20][C:5]2[N:6]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][CH2:18]O)=[CH:13][CH:12]=3)[C:7]([CH2:9][CH3:10])=[N:8][C:4]=2[CH:3]=1.[C:23]([O:27][C:28]([NH:30][O:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:23]([O:27][C:28]([N:30]([O:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:18][CH2:17][C:14]1[CH:13]=[CH:12][C:11]([N:6]2[C:5]3[CH:20]=[C:21]([Cl:22])[C:2]([Cl:1])=[CH:3][C:4]=3[N:8]=[C:7]2[CH2:9][CH3:10])=[CH:16][CH:15]=1)=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)NOC(=O)OC(C)(C)C
Reactant: CCc1nc2cc(Cl)c(Cl)cc2n1-c1ccc(CCO)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1nc2cc(Cl)c(Cl)cc2n1-c1ccc(CCN(OC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirred mixture of 2-[4-(5,6-dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethanol (Example 96, 100 mg, 0.3 mmol), N,O-Bis-tert-butoxycarbonylhydroxylamine (Baillie, L. C.; Batsanov, A.; Bearder, J. R.; Whiting, D. A. J. Chem. Soc. Perkin Trans. 1, 1998, 20, 3471., 140 mg, 0.6 mmol) and triphenylphosphine (158 mg, 0.6 mmol) in THF (10 mL) was added diethyl azodicarboxylate (DEAD) (0.1 mL, 0.6 mmol). The mixture was stirred under nitrogen atmosphere at room temperature for 2.5 h. The solvent was removed and the residue was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (1:1) to afford 174 mg (quant.) of the title compound as yellow amorphous: 1H-NMR (CDCl3) δ 7.84 (1H, s), 7.46 (2H, d, J=8.4 Hz), 7.25 (2H, d, J=8.4 Hz), 7.16 (1H, s), 3.92 (2H, t, J=6.7 Hz), 3.05 (2H, t, J=6.7 Hz), 2.76 (2H, q, J=7.6 Hz), 1.56 (9H, s), 1.46 (9H, s), 1.33 (3H, t, J=7.6 Hz).
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[CH2:10][C:9](=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]2=[N:18][NH:19][CH:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:7]2[CH2:6]1)=[O:4].[C:27](OC(=O)C)(=[O:29])[CH3:28]>>[C:27]([N:19]1[CH:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:7]2[CH2:6][N:5]([C:3]([NH:2][CH3:1])=[O:4])[CH2:10][C:9](=[CH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]2=[N:18]1)(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: CNC(=O)N1CC(=Cc2ccccc2)C2=NNC(c3ccccc3)C2C1
Product: CNC(=O)N1CC(=Cc2ccccc2)C2=NN(C(C)=O)C(c3ccccc3)C2C1
Temperature: 0 °C

Procedure:
A suspension of 5 g of 2,3,3a,4,6,7-hexahydro-N-methyl-3-phenyl-7-(phenylmethylene)-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (the product of Example 55) in 50 ml of acetic anhydride is refluxed for four hours. The mixture is cooled and poured onto 250 ml of ice-water. The product is filtered and dried.