Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH:3]([C:5]1[CH:19]=[CH:18][C:8]2[N:9]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[CH:10]=[N:11][C:7]=2[CH:6]=1)[CH3:4].Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[NH:32][N:31]=[C:30]([CH:33]3[CH2:35][CH2:34]3)[CH:29]=2)[CH:24]=[CH:23][N:22]=1.CCN(C(C)C)C(C)C>CC(O)C>[CH:33]1([C:30]2[NH:31][N:32]=[C:28]([NH:27][C:25]3[CH:24]=[CH:23][N:22]=[C:21]([N:2]([CH3:1])[CH:3]([C:5]4[CH:19]=[CH:18][C:8]5[N:9]([CH:12]6[CH2:17][CH2:16][CH2:15][CH2:14][O:13]6)[CH:10]=[N:11][C:7]=5[CH:6]=4)[CH3:4])[N:26]=3)[CH:29]=2)[CH2:35][CH2:34]1
Reactant: Clc1nccc(Nc2cc(C3CC3)n[nH]2)n1
Reactant: CNC(C)c1ccc2c(c1)ncn2C1CCCCO1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(c1ccc2c(c1)ncn2C1CCCCO1)N(C)c1nccc(Nc2cc(C3CC3)[nH]n2)n1
Temperature: 120 °C
Reaction time: 8 h
Yield: 19.3 %

Procedure:
A tube was charged with mixture of 84 (200 mg, 0.77 mmol), 53 (181 mg, 0.77 mmol) and DIPEA (200 mg, 1.5 mmol) in IPA (5 mL), sealed and stirred at 120° C. overnight. The reaction mixture was cooled to RT and concentrated under reduced pressure. The crude residue was purified by SiO2 chromatography eluting with a MeOH/DCM gradient (5% to 15% MeOH) to afford 68 mg (19%) of (±)-N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-methyl-N2-(1-(1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-5-yl)ethyl)pyrimidine-2,4-diamine (86) as white solid: MS (ESI) m/z=459.2 (M+1).
Reaction SMILES: CC([O-])(C)C.[K+].C1COCC1.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH2:21][C:22]([NH2:24])=[O:23])=[CH:13]1.C[O:26][C:27](=O)[C:28]([C:30]1[CH:31]=[CH:32][CH:33]=[C:34]2[C:38]=1[N:37]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[CH:36]=[CH:35]2)=O>CN(C=O)C>[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21]2[C:22](=[O:23])[NH:24][C:27](=[O:26])[C:28]=2[C:30]2[CH:31]=[CH:32][CH:33]=[C:34]3[C:38]=2[N:37]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[CH:36]=[CH:35]3)=[CH:13]1
Reactant: NC(=O)Cc1c[nH]c2ccccc12
Reactant: COC(=O)C(=O)c1cccc2ccn(COCC[Si](C)(C)C)c12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc2cccc(C3=C(c4c[nH]c5ccccc45)C(=O)NC3=O)c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 13.3 %

Procedure:
A 1.0 M solution of KOtBu in THF (8.1 mL, 8.1 mmol) was added to a solution of 2-(1H-indol-3-yl)-acetamide (417 mg, 2.4 mmol) and {1-(2-trimethylsilanyl-ethoxymethyl)-1H-indol-7-yl}-oxo-acetic acid methyl ester (774 mg, 2.32 mmol) in DMF (50 mL). The deep red-orange solution was stirred 16 h at room temperature and then 1 h at 65° C. The heating bath was removed and pH 7.0 buffer added. The mixture was poured into EtOAc, the layers separated and the EtOAc solution washed with 0.1 N HCl, water (3×), saturated aq NaHCO3 and brine (3×), dried (MgSO4), filtered and concentrated onto SiO2. Flash chromatography afforded 3-(1H-Indol-3-yl)-4-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-indol-7-yl]-pyrrole-2,5-dione (141 mg, 13%) as a bright orange solid which was dried under vacuum overnight at 70° C., and 3-(1H-Indol-7-yl)-4-(1H-indol-3-yl)-pyrrole-2,5-dione (165 mg, 22%) as a bright red solid which was dried under vacuum overnight at 70° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][CH2:11][CH2:12][C:13]([OH:15])=O)([CH3:3])[CH3:2].FC(F)(F)C(OC(=O)C(F)(F)F)=O>FC(F)(F)C(O)=O>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:5]=1[S:10][CH2:11][CH2:12][C:13]2=[O:15])([CH3:2])[CH3:3]
Reactant: CC(C)c1ccccc1SCCC(=O)O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1cccc2c1SCCC2=O
Temperature: 25 °C
Reaction time: 64.2 h
Yield: 17 %

Procedure:
3-(2-Isopropylphenylthio)propanoic acid from Step 1 (6.85 g, 30 mmol) was dissolved in trifluoroacetic acid (20 mL), treated with trifluoroacetic anhydride (12 mL) and stirred at room temperature (64.2 hours). The reaction was concentrated in vacuo, and the residue dissolved in ethyl acetate, extracted with 5% NaOH, washed with brine, dried over MgSO4, and concentrated in vacuo to give a brown oil which was passed through a column of silica gel eluted with 12% ether/hexane to give 8-isopropylthiochroman-4-one as a brown oil (1.05 g, 17%): 1H NMR (CDCl3) 300 MHz 8.01 (d, J=7.0 Hz, 1H) 7.38 (d, J=7.5 Hz, 1H) 7.17 (t, J=7.8 Hz, 1H) 3.19 (m, 3H) 2.96 (m, 2H) 1.25 (d, J=7.0 Hz 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([OH:22])=[N:11][C:12]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=2)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([O-])([O-])=O.[Cs+].[Cs+].COS(OC)(=O)=O.CCOC(C)=O>O1CCOCC1.O>[CH2:1]([O:8][C:9]1[C:10](=[O:22])[N:11]([CH3:23])[C:12]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=2)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1nc(-c2ccnc(Cl)c2)ncc1OCc1ccccc1
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1c(-c2ccnc(Cl)c2)ncc(OCc2ccccc2)c1=O
Temperature: 25 °C
Yield: 10.9 %

Procedure:
To a mixture of 5-(benzyloxy)-2-(2-chloropyridin-4-yl)pyrimidin-4-ol (14.2 g, 112 mmol), Cs2CO3(36.6 g, 112 mmol) in 300 mL of 1,4-dioxane, was added Me2SO4 (17.6 g, 56 mmol) and the resulting mixture was refluxed for 5 min. After cooling to rt, EtOAc (300 mL) and water (200 mL) were added. The organic layer was separated, the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic layer was washed with water, brine, and dried over Mg2SO4, filtered, and concentrated to give 25 g of crude compound, which was purified by silica gel to afford 5-(benzyloxy)-2-(2-chloropyridin-4-yl)-3-methylpyrimidin-4(3H)one (4.0 g, 22%). 1H-NMR δ (400 MHz, d6-DMSO): 8.53 (dd, J=5.2, 0.4 Hz, 1H), 7.51 (s, 1H), 7.44 (m, 3H), 7.42-7.29 (m, 4H), 5.19 (s, 2H), 3.33 (s, 3H); MS (ESI) m/z (M+H)+ 328.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([CH2:22][O:23][CH2:24][CH3:25])[N:14]([CH2:15][C:16]3[O:20][N:19]=[C:18]([CH3:21])[CH:17]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:26]>CO>[CH2:24]([O:23][CH2:22][C:13]1[N:14]([CH2:15][C:16]2[O:20][N:19]=[C:18]([CH3:21])[CH:17]=2)[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:26])[C:11]=2[N:12]=1)[CH3:25]
Reactant: N
Reactant: CCOCc1nc2c(Cl)nc3ccccc3c2n1Cc1cc(C)no1
Solvent: CO
Product: CCOCc1nc2c(N)nc3ccccc3c2n1Cc1cc(C)no1

Procedure:
A slurry of 4-chloro-2-(ethoxymethyl)-1-[(3-methylisoxazol-5-yl)methyl]-1H-imidazo[4,5-c]quinoline (4.21 g, 11.8 mmol) in a solution of 7 M ammonia in methanol (50 mL) was heated at 150° C. for 22 hours in a Parr pressure vessel. The volatiles were removed under reduced pressure and the resulting solid was triturated with water. A tan solid was isolated and purified by flash chromatography (silica gel, gradient elution from 9:1 to 1:1 chloroform/CMA) to yield 43.2 mg of pure 2-(ethoxymethyl)-1-[(3-methylisoxazol-5-yl)methyl]-1H-imidazo[4,5-c]quinolin-4-amine as a white powder, mp 178.0-180.0° C.
Reaction SMILES: C[Si]([C:5]#[C:6][Si:7]([CH:12]([CH3:14])[CH3:13])([CH:9]([CH3:11])[CH3:10])Br)(C)C.[CH2:15]([Mg]Cl)[CH:16]=[CH2:17]>C1COCC1>[CH2:15]([Si:7]([C:6]#[CH:5])([CH:12]([CH3:14])[CH3:13])[CH:9]([CH3:11])[CH3:10])[CH:16]=[CH2:17]
Reactant: C=CC[Mg]Cl
Reactant: CC(C)[Si](Br)(C#C[Si](C)(C)C)C(C)C
Solvent: C1CCOC1
Product: C#C[Si](CC=C)(C(C)C)C(C)C
Temperature: 45 °C
Reaction time: 1.5 h

Procedure:
The (trimethylsilylethynyl)diisopropylbromosilane intermediate was transferred to an oven-dried flask, dissolved in anhydrous THF, treated with 1.2 equivalents of allylmagnesium chloride (2.0 M in THF) dropwise, and heated to 45° C. for 12 hrs. The reaction was quenched by the slow addition of ice water, then dilute sulfuric acid to dissolve magnesium salts, followed by the addition of pentane. The organic layer was separated, and the aqueous layer was extracted with pentane one additional time. Organic layers were combined, washed with water and brine, dried over magnesium sulfate, filtered, and concentrated under rotary evaporation. Removal of the trimethylsilyl substituent is effected by treatment with 6-8 drops of 15% NaOH in 1:1 THF:MeOH, followed by stirring for 1-2 hours. Analysis by GC-MS was helpful to ascertain completion of the deprotection, since thin layer chromatography (hexanes, visualization by potassium permanganate stain) revealed no appreciable difference between the trimethylsilyl-protected and deprotected acetylene. The product was isolated by extraction into hexanes (2×50 mL). The organic layer was washed with 10% HCl (10 mL) and water (2×10 mL), then dried over magnesium sulfate, filtered, and concentrated under rotary evaporation to yield 11.3 g of crude (allyldiisopropylsilyl)acetylene.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([NH2:11])[CH:3]=1.[F:12][C:13]1[CH:14]=[C:15]([C:19]2[N:24]=[C:23]([CH3:25])[C:22]([C:26](O)=[O:27])=[CH:21][N:20]=2)[CH:16]=[CH:17][CH:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C.O>[CH3:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([NH:11][C:26]([C:22]2[C:23]([CH3:25])=[N:24][C:19]([C:15]3[CH:16]=[CH:17][CH:18]=[C:13]([F:12])[CH:14]=3)=[N:20][CH:21]=2)=[O:27])[CH:3]=1
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)O
Reactant: Cc1cn(N)c2ccncc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1cc(C)c2cnccc21
Reaction time: 1 h
Yield: 36 %

Procedure:
A mixture of 3-methyl-pyrrolo[3,2-c]pyridin-1-ylamine (224 mg, 1.52 mmol), 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (354 mg, 1.52 mmol), HATU (693 mg, 1.82 mmol) and DIPEA (593 mg, 4.59 mmol) in DMF (8 mL) is heated at 1500 C. for 1 h. The reaction is quenched with water, NaHCO3 (168 mg, 2 mmol) is added and the mixture is extracted with EtOAc. The organic layer is separated, dried (Na2SO4), filtered and concentrated. The residue is first purified by silica gel column chromatography eluting with 10% MeOH in DCM and then recrystallized from EtOAc to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (3-methyl-pyrrolo[3,2-c]pyridin-1-yl)-amide (198 mg). MS: 362 (M+H); 1H NMR (300 MHz, CD3OD): δ 9.12 (s, 1H), 8.86 (s, 1H), 8.35 (d, 1H), 8.15-8.31 (m, 2H), 7.47-7.60 (m, 2H), 7.35 (s, 1H), 7.29 (t, 1H), 2.84 (s, 3H), 2.44 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1([O:9][CH3:10])[CH2:6][CH:5]([CH2:7][OH:8])[CH2:4]1.CC(C)([O-])C.[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1>[CH3:1][O:2][C:3]1([O:9][CH3:10])[CH2:6][CH:5]([CH2:7][O:8][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:4]1
Reactant: BrCc1ccccc1
Reactant: COC1(OC)CC(CO)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC1(OC)CC(COCc2ccccc2)C1
Reaction time: 0.5 h
Yield: 68.5 %

Procedure:
To a stirring solution of crude (3,3-dimethoxy-cyclobutyl)-methanol (11.9 g, 81.5 mmol) in 100 mL of tetrahydrofuran at room temperature was added a solution of potassium t-butoxide (163 mL, 1M tetrahydrofuran). The reaction was allowed to stir for 30 minutes and then benzyl bromide (10.2 mL, 85.6 mmol) was added. After 30 minutes TLC analysis indicated complete consumption of starting material. The reaction was quenched with water and diluted with methylene chloride. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification of this material was accomplished by flash column chromatography using a Biotage Column 75 medium, eluting with a gradient of hexanes through 5% EtOAc/hexanes. The product containing fractions were collected and concentrated under reduced pressure to give the title compound (13.2 g, 69% yield), as a colorless oil.
Reaction SMILES: [CH3:1][N:2]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:24]=1[N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[CH3:31])C(=O)C1C=C(C(F)(F)F)C=C(C(F)(F)F)C=1.[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]>C(Cl)Cl>[OH:38][C:32]([C:34]([F:37])([F:36])[F:35])=[O:33].[CH3:1][NH:2][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:24]=1[N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[CH3:31]
Reactant: CC1CCCCN1c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNc1cnccc1N1CCCCC1C

Procedure:
Methyl-(2-methyl-3,4,5,6-tetrahydro-2H-[1,4]bipyridinyl-3′-yl)-carbamic acid tert-butyl ester (60 mg, 0.20 mmol, example 20, intermediate b) was stirred in a solution of TFA (300 μL) and CH2Cl2 (2 mL) for 1 h after which all volatiles were removed under reduced pressure to give crude methyl-(2-methyl-3,4,5,6-tetrahydro-2H-[1,4]bipyridinyl-3′-yl)-amine TFA salt. The crude TFA salt was dissolved in CH2Cl2 (2 mL) and treated with DIPEA (100 μL, 590 mmol) and 3,5-dichlorobenzoyl chloride (54 mg, 0.26 mmol, CAS RN 2905-62-6). The reaction mixture was loaded directly on a silica gel column and elution with 66% EtOAc in n-hexane gave the title product (12 mg, 16%). MS (ESI): m/z=378.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6](NN)[C:5]([Cl:11])=[CH:4][N:3]=1.Cl[O-].[Na+]>O1CCCC1.O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:11])=[CH:4][N:3]=1
Reactant: NNc1c(Cl)cnc(Cl)c1Cl
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Solvent: C1CCOC1
Product: Clc1cnc(Cl)c(Cl)c1
Reaction time: 1 h

Procedure:
A solution was prepared by dissolving 2.5 grams of 2,3,5-trichloro-4-hydrazinopyridine in 25 milliliters of tetrahydrofuran. To this mixture was added ~10 milliliters of 5.25 percent sodium hypochlorite. The mixture was stirred at ~30° C. for about one hour. The mixture was diluted with water and extracted with methylene chloride. The extract was washed with water and the methylene chloride removed by evaporation. The residue, a dark brown oil, was recovered in a yield of 2.1 grams. The crude 2,3,5-trichloropyridine product was sublimed at ~1 millimeter of mercury and ~50° C. The purified product was obtained in a yield of 1.52 grams (72 percent of theoretical). The structure was confirmed by N.M.R.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[N+:11]([O-:14])([OH:13])=[O:12].[NH2:15][NH:16][C:17]([NH:19][NH2:20])=[NH:18].[N+]([O-])(O)=O>C(O)C.O>[N+:11]([O-:14])([OH:13])=[O:12].[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[N:15][NH:16][C:17]([NH:19][N:20]=[CH:7][C:6]2[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[NH:18])=[CH:5][CH:4]=1)#[N:2]
Reactant: N=C(NN)NN
Reactant: N#Cc1ccc(C=O)cc1
Solvent: O
Solvent: CCO
Solvent: O=[N+]([O-])O
Product: N#Cc1ccc(C=NNC(=N)NN=Cc2ccc(C#N)cc2)cc1

Procedure:
A boiling solution of 13.1 grams of 4-cyanobenzaldehyde in 250 milliliters of ethanol is stirred vigorously as a solution of 6.1 grams of 1,3-diaminoguanidine nitrate and 0.5 milliliters of concentrated nitric acid in 50 milliliters of water is added in one portion. The reaction mixture is stirred as the temperature recedes to room temperature. The reaction mixture is then allowed to stand for several hours. The precipitate which forms is collected, washed with hot ethanol, air dried and finally dried at 60°C. under reduced pressure. The yield is 15.1 grams of product and the melting point is 205°-210°C. with decomposition.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[F:21][C:22]1[CH:23]=[C:24]([C:34](=[O:36])[CH3:35])[CH:25]=[CH:26][C:27]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>O1CCOCC1>[F:21][C:22]1[CH:23]=[C:24]([C:34](=[O:36])[CH3:35])[CH:25]=[CH:26][C:27]=1[N:28]1[CH2:33][CH2:32][N:31]([C:4](=[O:5])[C:3]2[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:2]=2[F:1])[CH2:30][CH2:29]1
Reactant: CC(=O)c1ccc(N2CCNCC2)c(F)c1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1F
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(=O)c1ccc(N2CCN(C(=O)c3cc([N+](=O)[O-])ccc3F)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.9 %

Procedure:
A solution of 2-Fluoro-5-nitro-benzoyl chloride (CAS: 7304-32-7; Feng, Y.; Burgess, K.; Chem.Europ.J.; EN; 5; 11; 1999; 3261-3272) (0.054 g, 0.261 mmol) in dioxane (1 ml) was treated with triethylamine (0.073 ml, 0.522 mmol) and then with a solution of 1-(3-Fluoro-4-piperazin-1-yl-phenyl)-ethanone (CAS: 189763-57-3; WO9714690) (58 mg, 0.261 mmol) in dioxane (1 ml). The mixture was stirred at room temperature for 30 minutes. The solvent was removed in vacuo. The crude oil was taken in water. The aqueous layer was extracted 3 times with CH2Cl2. The combined extracts were dried over Na2SO4, filtered and the solvent was removed in vacuo. The crude gum was purified on a SiO2 (Heptane/AcOEt 0%-20% (10 minutes, then 20% (5 minutes) to provide 1-{3-Fluoro-4-[4-(2-fluoro-5-nitro-benzoyl)-piperazin-1-yl]-phenyl}-ethanone (69 mg, 68%) as a light yellow solid (M+H+: 390.2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[S:10][C:11]2[CH:12]=[N:13][CH:14]=[C:15]([F:18])[C:16]=2[N:17]=1.C1C=C(Cl)C=C(C(OO)=[O:27])C=1>C(Cl)Cl>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[S:10][C:11]2[CH:12]=[N+:13]([O-:27])[CH:14]=[C:15]([F:18])[C:16]=2[N:17]=1
Reactant: Fc1cncc2sc(-c3c(Cl)cccc3Cl)nc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [O-][n+]1cc(F)c2nc(-c3c(Cl)cccc3Cl)sc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 120.6 %

Procedure:
To an ice-cooled solution of 2-(2,6-dichlorophenyl)-7-fluorothiazolo[5,4-c]pyridine (5.1 g, 17.1 mmol) in DCM (70 mL), was added m-CPBA (11.77 g, 68.2 mmol) over 3 minutes, at 0° C. under argon. The reaction mixture was slowly warmed to room temperature over 1 hour and then stirred at room temperature for 4 hours. The resultant mixture was diluted with DCM (150 mL) and washed with a saturated solution of potassium carbonate (100 mL). Additional amounts of DCM and water were added, followed by MeOH (50 mL). The organic layer was separated, washed with water (300 mL), dried (Na2SO4) and concentrated under reduced pressure. The resultant residue was triturated with water, dried under reduced pressure to afford the title compound as a white solid (6.50 g, quantitative). LCMS (Method F): RT=2.76 min, m/z: 315 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[CH3:14][CH2:15][O:16][C:17]([C:19]([CH2:21]Br)=O)=[O:18]>CCO.CCOC(C)=O>[CH2:15]([O:16][C:17]([C:19]1[N:8]=[C:6]([C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=2[N+:11]([O-:13])=[O:12])[S:7][CH:21]=1)=[O:18])[CH3:14]
Reactant: Cc1ccc(C(N)=S)c([N+](=O)[O-])c1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1csc(-c2ccc(C)cc2[N+](=O)[O-])n1
Temperature: 70 °C

Procedure:
4-Methyl-2-nitro-thio benzamide (60 mgs, 0.30 mmol, prepared as described in compound 5, Step 2, was stirred in 1 mL absolute EtOH at room temperature under N2. Ethyl bromo pyruvate (65 mgs, 0.33 mmol) was added, and the resulting solution was heated to 70° C. for 3 h. The reaction was diluted to 30 mL with EtOAc and washed with saturated NaHCO3, and saturated NaCl. The organic layer was dried over MgSO4, filtered and concentrated to a yellow oil, which was used as is in the next step.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([NH:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:4][CH2:3]1.C([O:36][C@@H:37]([CH3:41])[C:38](Cl)=[O:39])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([NH:26][CH:27]4[CH2:28][CH2:29][N:30]([C:38](=[O:39])[C@@H:37]([OH:36])[CH3:41])[CH2:31][CH2:32]4)=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:4][CH2:3]1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ccnc2c1C(=O)NC1CCNCC1
Agent: Cl
Product: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ccnc2c1C(=O)NC1CCN(C(=O)[C@H](C)O)CC1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-fluorophenyl]-2-methyl-N-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f4) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:22]=[CH:21][C:15]([O:16][CH2:17][C:18]([OH:20])=O)=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:24][C@H:25]([C:30]([NH:32][C@@H:33]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C@H:34]([OH:49])[C:35]([N:37]1[CH2:48][CH2:47][CH2:46][C@H:38]1[C:39]([NH:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[O:36])=[O:31])[CH2:26][C:27](=[O:29])[NH2:28].C(OC(N[C@H](C(N[C@@H](CC1C=CC=CC=1)[C@H](O)C(N1CCC[C@H]1C(NC(C)(C)C)=O)=O)=O)CC(=O)N)=O)(C)(C)C.Cl>O1CCOCC1>[CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([O:16][CH2:17][C:18]([NH:24][C@H:25]([C:30]([NH:32][C@@H:33]([CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C@H:34]([OH:49])[C:35]([N:37]2[CH2:48][CH2:47][CH2:46][C@H:38]2[C:39]([NH:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[O:36])=[O:31])[CH2:26][C:27](=[O:29])[NH2:28])=[O:20])=[CH:21][CH:22]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(N)=O
Reactant: O=C(O)COc1ccc(NC(=O)OCc2ccccc2)cc1
Agent: CC(C)(C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)COc1ccc(NC(=O)OCc2ccccc2)cc1
Yield: 73.4 %

Procedure:
Following a procedure similar to that described in Example 14, but using 99.8 mg (0.33 mmol) of 4-(benzyloxycarbonylamino)phenoxyacetic acid (prepared as described in Preparation 15) and 150 mg (0.30 mmol) of 1-[(2S,3S)-3-(L-asparaginylamino)-2-hydroxy-4-phenylbutyryl]-N-t-butyl-L-prolinamide hydrochloride {prepared by treating 1-[(2S,3S)-3-(N2 -t-butoxycarbonyl-L-asparaginyl)amino-2-hydroxy-4-phenylbutyryl]-N-t-butyl-L-prolinamide, the compound prepared as described in Example 15, with a 4N solution of hydrogen chloride in dioxane), 164 mg of the title compound were obtained as a white powder, melting at 103°-105° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2].[CH3:16][O:17][CH2:18][CH:19](O)[CH3:20]>C1(C)C=CC=CC=1.C1(C)C(S(O)(=O)=O)=CC=CC=1>[CH3:16][O:17][CH2:18][CH:19]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:4]=1[N+:1]([O-:3])=[O:2])[CH3:20]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: COCC(C)O
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Product: COCC(C)OC(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 53.5 %

Procedure:
To a mixture of 212.0 g of 2,4-dinitrobenzoic acid in 300 ml of toluene were added 4.0 g of toluenesulfonic acid and 180.2 g of 1-methoxy-2-propanol. The mixture was refluxed for 48 hrs and the resulting water removed by azeotropic distillation. After this period the mixture was cooled to room temperture and washed with 500 ml of an aqueous 5% NaHCO3 solution followed by two 150 ml water washings. The toluene was removed at reduced pressure and the resulting oil was washed with hexane to give 152 g (1-methoxy-2-propyl)-2,4-dinitrobenzoate, a tan solid, mp 42° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.[C:11](OC(=O)C)(=[O:13])[CH3:12]>O1CCOCC1.O>[C:11]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2)(=[O:13])[CH3:12]
Reactant: Nc1ccc2c(c1)CCC2
Reactant: CC(=O)OC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)Nc1ccc2c(c1)CCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.9 %

Procedure:
To a solution of 5.2 g (39 mmol) of 5-aminoindan in 15 mL of dioxane kept in an ice-bath was added dropwise 8 mL (8.6 g, 84 mmol) of acetic anhydride. The solution was stirred at room temperature for 16 h. It was diluted with 70 mL of water. The mixture was filtered, washed with water, and dried to leave a gray solid 6.21 g (91%). 1H NMR (CDCl3), 2.069 (m, 2), 2.165 (s, 3), 2.879 (m, 4), 7.20 (mb, 1), 7.145 (s, 2), 7.441 (s, 1).