Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[C:12]2[C:13](=O)[NH:14][S:15][C:11]=2[CH:10]=[CH:9][CH:8]=1>>[Cl:3][C:13]1[C:12]2[C:7]([Cl:6])=[CH:8][CH:9]=[CH:10][C:11]=2[S:15][N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]sc2cccc(Cl)c12
Product: Clc1cccc2snc(Cl)c12

Procedure:
Phosphorus oxychloride was added slowly to 4-chlorobenzo[d]isothiazol-3(2H)-one (2.34 g). The reaction mixture was heated at reflux overnight. After normal aqueous work-up, the product was purified by column chromatography, on silica gel, eluted with a mixture of 5% ethyl acetate in hexanes to provide 3,4-dichlorobenzo[d]isothiazole. (This method can be used to 1,2-benzisothiozal-3-ones). 1H NMR (300 MHz, DMSO-d6): 8.23-8.31 (m, 1H), 7.62 ppm (d, 2H). MW=204 confirmed by LC-MS, tr=2.38 min (Method B) MH+=205.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7](=[O:10])(=[O:9])[NH2:8])=[C:5]([C:11]([O:13]CC)=O)[CH:4]=[N:3]1.O.[NH2:17][NH2:18]>>[CH3:1][N:2]1[C:6]([S:7](=[O:10])(=[O:9])[NH2:8])=[C:5]([C:11]([NH:17][NH2:18])=[O:13])[CH:4]=[N:3]1
Reactant: NN
Reactant: CCOC(=O)c1cnn(C)c1S(N)(=O)=O
Solvent: O
Product: Cn1ncc(C(=O)NN)c1S(N)(=O)=O
Yield: 90 %

Procedure:
Ethyl 1-methyl-5sulfamoylpyrazole-4-carboxylate (1.0 g), prepared according to Bellemin and Festal, J. Heterocycl. Chem. 1984, 21, 1017, was stirred with 1 ml of hydrazine monohydrate at room temperature for 3 h and then evaporated to dryness. The residue was taken up in 5 ml of water and extracted with 25 ml of dichloromethane. The aqueous phase was evaporated to give 0.85 g (90%) of the title compound as a slowly crystallizing oil. Trituration with 5 ml of a 2:1 mixture of methanol and ethyl acetate gave a pure product: m.p. 172°-173° C.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])=[CH:6][C:5]=1[CH3:18])([O-])=O.CCO.C(OCC)(=O)C>[Pd].C(O)(=O)C>[NH2:1][C:4]1[CH:17]=[CH:16][C:7]([C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])=[CH:6][C:5]=1[CH3:18]
Reactant: Cc1cc(C(=O)Nc2nccs2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)Nc2nccs2)ccc1N
Yield: 95 %

Procedure:
4-Nitro-3-methyl-N-thiazol-2-yl-benzamide (63 mmol) was suspended in abs. EtOH (200 mL) and ethyl acetate (100 mL) and glacial acetic acid (10 mL) was added followed by 10% Pd/C (1 g). The mixture was hydrogenated over night at 3 bar H2. The hydrogenation mixture was filtered and the solvent was removed under reduced pressure. The crude product was added NaHCO3 (sat.) and ethyl acetate, the remaining solid fraction was removed by filtration and dried in vacuo. The liquid phases were separated, the organics were washed with brine, dried over MgSO4, filtered and evaporated to yield the product as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:17]O>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:17])=[O:10])=[CH:6][CH:7]=1
Reactant: CO
Reactant: Nc1ccc(CC(=O)O)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(N)cc1

Procedure:
To a suspension of 4-aminophenylacetic acid (7.4 g; 59.0 mmol) in ca. 90 ml of methanol, was added ca. 6.0 ml of concentrated sulfuric acid. After refluxing the brown solution for 2.5 hrs, it was concentrated to a dark oil. The oil was diluted with water and basified with 10 wt % NaHCO3 to pH 9 and extracted with ethyl acetate. The organic layer was washed with water, brine and dried with Na2SO4. Evaporation in vacuo afforded 5.0 g of methyl 4-aminophenylacetate as a dark oil.
Reaction SMILES: [OH-].[Na+].[ClH:3].[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[C:12](=[C:18]([S:21][CH2:22][CH:23]([O:31]C(=O)C)[CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)[C:19]#[N:20])[NH:11][CH2:10][CH2:9]2>C(O)C>[ClH:3].[ClH:3].[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[C:12](=[C:18]([S:21][CH2:22][CH:23]([OH:31])[CH2:24][N:25]1[CH2:26][CH2:27][O:28][CH2:29][CH2:30]1)[C:19]#[N:20])[NH:11][CH2:10][CH2:9]2
Reactant: COc1cc2c(cc1OC)C(=C(C#N)SCC(CN1CCOCC1)OC(C)=O)NCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc2c(cc1OC)C(=C(C#N)SCC(O)CN1CCOCC1)NCC2
Yield: 182.5 %

Procedure:
After adding 4 ml of 10% sodium hydroxide solution and 6 ml of ethanol to 0.48 g of 2-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-[2-acetoxy-3-(4-morpholinyl)propyl]mercaptoacetonitrile hydrochloride (product of Example 23), the reaction mixture is refluxed for 30 minutes, then ethanol is evaporated under reduced pressure. The oily residue crystallizes out, it is filtered, washed with water and dried. The product obtained is dissolved in 5 ml of abs. ethanol under heating and the solution is acidified by abs. ethanolic hydrogen chloride solution to give 0.4 g of the named hydrochloride which is identical to the product of Example 17, m.p.: 210° C.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([CH2:9][CH:10]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=2[NH:24]C(=O)OC(C)(C)C)[C:11]([CH:13]2[CH2:15][CH2:14]2)=O)[CH:6]=[CH:5][CH:4]=1)#[N:2].FC(F)(F)C(O)=O>C(#N)C.ClCCl>[CH:13]1([C:11]2[NH:24][C:17]3[C:16]([C:10]=2[CH2:9][C:7]2[N:8]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][CH:6]=2)=[CH:21][CH:20]=[C:19]([O:22][CH3:23])[CH:18]=3)[CH2:15][CH2:14]1
Reactant: COc1ccc(C(Cc2cccc(C#N)n2)C(=O)C2CC2)c(NC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COc1ccc2c(Cc3cccc(C#N)n3)c(C3CC3)[nH]c2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 90.6 %

Procedure:
To a solution of tert-butyl {2-[1-(6-cyanopyridin-2-ylmethyl)-2-cyclopropyl-2-oxoethyl]-5-methoxyphenyl}carbamate (290 mg) in acetonitrile/dichloromethane (2.3 mL/2.3 mL) was added trifluoroacetic acid (2.3 mL) under ice-cooling, and the mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the resulting mixture was washed with a saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, washed with water and saturated brine successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (189 mg). 1H-NMR (CDCl3) δ ppm: 0.67-0.76 (2H, m), 0.92-1.02 (2H, m), 1.95-2.08 (1H, m), 3.82 (3H, s), 4.35 (2H, s), 6.71 (1H, dd, J=2.3, 8.5 Hz), 6.80 (1H, d, J=2.3 Hz), 7.18-7.29 (2H, m), 7.46-7.52 (1H, m), 7.55-7.68 (2H, m).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[C@@H:10]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([N:28]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C@H:29]([C:34](O)=[O:35])[CH2:30][CH2:31][CH2:32][NH2:33])([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C.ON1C(=O)CCC1=O>[CH2:1]([O:8][C:9](=[O:20])[C@@H:10]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:11][C:34](=[O:35])[C@H:29]([CH2:30][CH2:31][CH2:32][NH2:33])[N:28]([C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])[C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@H](CCc1ccccc1)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H](CCCN)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H](CCCN)C(=O)N[C@H](CCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 30 h

Procedure:
D-Homophenylalanine Benzyl ester Tosylate (2.48 g, 5.6 mmol) was suspended in ethyl acetate (25 mL) and a saturated solution of sodium bicarbonate in water was added in portions (25 mL) with stirring at 25° C. The water layer was extracted with ethyl acetate (3×10 mL). The combined organic extract was dried over anhydrous sodium sulfate, filtered and concentrated to dryness to afford D-Homophenylalanine Benzyl ester. The ester was dissolved in acetonitile (25 mL). NaNd-bis-Boc-L-Ornithine (2.0 g, 6.0 mmol) was then added followed by N-hydroxysuccinimide (50 mg) and dicyclohexylcarbodiimide (1.28 g, 6.2 mmol). The reaction was stirred at 25° C. for 30 hr, filtered and the filtrate concentrated to dryness to afford crude product. It was purified by column chromatography on silica gel (hexane:ethyl acetate=3:1), which gave the title product (2.80 g) as white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:37]=[CH:36][CH:35]=[CH:34][C:26]=1[C:27]([NH:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[C:26]([C:27]([NH:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:34][CH:35]=[CH:36][CH:37]=3)=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CC(C)(C)NC(=O)c1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: CC(C)(C)NC(=O)c1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared using methods analogous to those described in Example 369 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and 2-bromo-N-(tert-butyl)benzamide. MS (ESI): mass calcd. for C21H21FN4O, 364.17; m/z found, 365.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.55-8.50 (m, 1H), 8.13 (d, J=1.4, 1H), 8.04-7.95 (m, 1H), 7.64-7.58 (m, 1H), 7.51-7.44 (m, 1H), 7.43-7.37 (m, 2H), 7.36-7.31 (m, 1H), 7.29-7.22 (m, 1H), 5.69 (s, 1H), 5.45 (s, 2H), 2.65-2.54 (m, 1H), 1.24 (m, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][NH2:11])[CH:5]=[CH:6][CH:7]=1.C[O:13][C:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21]Br.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:21][C:16]3[C:15](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:14]2=[O:13])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccccc1CBr
Reactant: NCCCc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2CN1CCCc1cccc(Br)c1
Reaction time: 1.5 h
Yield: 72.7 %

Procedure:
A mixture of 3-(3-bromophenyl)-propylamine (7.86 g, 36.7 mmol), 2-bromomethyl-benzoic acid methyl ester (8.45 g, 36.7 mmol), and K2CO3 (6.91 g, 50 mmol) in toluene (100 mL) was heated at reflux with stirring for 1.5 h. Workup and silica gel column chromatography using a gradient of hexanes to 50% ethyl acetate in hexanes afforded 2-[3-(3-bromophenyl)-propyl]-2,3-dihydroisoindol-1-one (8.81 g, 73%). GC/MS gave: m/z (rel.int.) 331 (M+, 10), 329 (M+, 10), 147-(100), 146 (72) 119 (25), and 91 (38). 1H NMR (300 MHz, CDCl3): δ 2.00 (dt, 2H), 2.67 (t, 2H), 3.67 (t, 2H), 4.36 (s, 2H), 7.14 (dd, 2H), 7.31 (m, 1H), 7.35 (br s, 1H), 7.45 (m, 2H), 7.51 (dt, 1H), 7.85 (d, 1H). 13C NMR (300 MHz, CDCl3): δ 29.9, 32.8, 42.0, 49.9, 122.4, 122.7, 123.6, 127.1, 128.0, 129.1, 130.0, 131.2, 131.3 132.8, 141.1, 143.7, 168.6.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]#N)=[C:4]1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH3:2].CC(C[AlH]CC(C)C)C.[Cl-].[CH2:30]([O:32][CH2:33][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:31].CC(C)([O-])C.[K+].C(N1C2C(=CC=CC=2)C(C=O)=C1C1C=NC=CC=1)C>C1(C)C=CC=CC=1.C1COCC1.[Pd]>[CH2:30]([O:32][CH2:33][CH2:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:3]([CH2:1][CH3:2])[C:4]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH3:31]
Reactant: CCOC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCn1c(-c2cccnc2)c(C#N)c2ccccc21
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOCCc1c(-c2cccnc2)n(CC)c2ccccc12
Reaction time: 1 h

Procedure:
To a solution of 1-ethyl-2-pyridin-3-yl-1H-indole-3-carbonitrile (Example 84, 590 mg, 2.4 mmol) in toluene (20 mL) at −60° C. is added a 1 M solution of DIBAL-H (3.6 mL, 3.6 mmol). The reaction is stirred for 1 h and kept below −40° C. The reaction is then quenched with water (1 mL) and brought to room temperature. Anhydrous sodium sulfate (ca. 2 g) is then added to the reaction mixture. The reaction mixture is filtered through a plug of celite. Sulfuric acid (2M, ca. 5 mL) is added and upon complete conversion to the desired aldehyde, the reaction mixture is brought to pH 8 with the addition of Na2CO3, and extracted with ethyl acetate. The organic extract is washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting 1-ethyl-2-pyridin-3-yl-1H-indole-3-carbaldehyde is used without further purification. To a solution of ethoxymethyltriphenylphosphonium chloride (0.32 g, 0.9 mmol) in THF (3 mL) is added potassium tert-butoxide (1 M in THF, 0.93 mL, 0.93 mmol). The resulting red solution is permitted to stir for 15 min, at which time a solution of 1-ethyl-2-pyridin-3-yl-1H-indole-3-carbaldehyde (75 mg, 0.3 mmol) in THF (3 mL) is added. The reaction is stirred for 1 h, quenched with saturated aqueous NH4Cl, diluted with water and extracted with ethyl acetate. The organic extract is dried over Na2SO4, filtered, and concentrated. The resulting E/Z mixture of 3-(2-ethoxy-vinyl)-1-ethyl-2-pyridin-3-yl-1H-indole is then dissolved in methanol (5 mL) and 10% Pd/C (32 mg, 0.03 mmol) is added. The reaction mixture is stirred under an atmosphere of H2 gas (balloon) for 2 h. The reaction is then filtered through a plug of celite and concentrated to dryness. The resulting residue is purified by silica gel flash chromatography (ethyl acetate-heptane, 0:1 to 2:5) to afford 3-(2-ethoxy-ethyl)-1-ethyl-2-pyridin-3-yl-1H-indole. 1H NMR (400 MHz, CDCl3) δ ppm 1.17 (t, J=7.0 Hz, 3H), 1.23 (t, J=7.2 Hz, 3H), 2.94 (t, J=7.3 Hz, 2H), 3.43 (q, J=7.1 Hz, 2H), 3.61 (t, J=7.3 Hz, 2H), 4.05 (q, J=7.3 Hz, 2H), 7.19 (t, J=7.4 Hz, 1H), 7.30 (t, J=7.1 Hz, 1H), 7.40 (d, J=8.3 Hz, 1H), 7.53 (dd, J=7.6, 5.1 Hz, 1H), 7.69 (d, J=7.8 Hz, 1H), 7.92 (d, J=7.8 Hz, 1H), 8.72 (dd, J=4.9, 1.6 Hz, 1H), 8.77 (d, J=1.5 Hz, 1H). HRMS (ESI) m/z 295.1805 [(M+H)+ Calcd for C19H23N2O: 295.1810].
Reaction SMILES: [NH:1]([CH2:3][C:4]([OH:6])=[O:5])[CH3:2].Cl[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]>[OH-].[Na+]>[C:12]1([CH2:11][O:10][C:8]([N:1]([CH2:3][C:4]([OH:6])=[O:5])[CH3:2])=[O:9])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CNCC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CN(CC(=O)O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.4 %

Procedure:
This material was prepared following the method of R. S. Tipton and B. A. Pawson [J. Org. Chem., 26, 4648 (1961)]. Sarcosine (8.90 g, 1.0 mole) was dissolved in 500 ml of 2 N sodium hydroxide with cooling in an ice bath. Simultaneously, 550 ml of 2 N sodium hydroxide and benzyl chloroformate [196 g (95%), 1.095 moles] were added over a period of one hour with rapid stirring. The resulting reaction mixture was stirred for about 18 hours at ambient temperature, after which time it was extracted with three 250 ml portions of diethyl ether. Ethyl acetate (500 ml) was then added to the aqueous phase, followed by the careful addition of 200 ml of concentrated hydrochloric acid. The organic layer was separated, washed with two 500 ml portions of water followed by 300 ml of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure after removal of the drying agent by filtration gave 213 g (95%) of N-phenylmethoxycarbonyl-sarcosine as an oil which was identified by nmr spectroscope and used without further purification.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[N:12]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH:14]2CCC(O)=O)[C:11]2[CH:31]=[CH:32][C:33]([CH3:35])=[CH:34][C:10]=2[N:9]=1.C1C[O:39][CH2:38]C1>>[CH3:7][C:8]1[N:12]([C@@H:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:15][C@H:14]2[CH2:38][OH:39])[C:11]2[CH:31]=[CH:32][C:33]([CH3:35])=[CH:34][C:10]=2[N:9]=1
Reactant: Cc1ccc2c(c1)nc(C)n2C1CCN(C(=O)OC(C)(C)C)CC1CCC(=O)O
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cc1ccc2c(c1)nc(C)n2[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1CO
Reaction time: 1 h

Procedure:
Lithium aluminum hydride (76 mg; 2 mmol) was added to a stirring solution of 4-(2,5-dimethylbenzimidazol-1-yl)-3-carboxyethyl-N-Boc piperidine (310 mg; 0.77 mmol) in THF (5 mL) under Ar at 0° C. After one hour, Na2SO4 decahydrate (500 mg; 1.55 mmol) was added carefully portionwise. The reaction mixture was stirred 2 h and the grey solid that formed during this time was removed by filtration through Celite®. Volatiles were removed under reduced pressure and the product racemic trans-4-(2,5-dimethylbenzimidazol-1-yl)-3-hydroxymethyl-N-Boc piperidine was isolated by flash chromatography (258 mg; 93%) as a white powder.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:13]=[CH:12][N:11]3[CH:14]=[CH:15][N:16]=[C:10]3[CH:9]=2)[CH2:3][CH2:2]1.Cl[C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[C:21]([O:28][C@@H:29]3[CH2:34][CH2:33][N:32]([C:35]([O:37][CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[O:36])[CH2:31][C@H:30]3[F:45])[CH:22]=[CH:23][CH:24]=2)[N:19]=1>>[F:45][C@H:30]1[C@H:29]([O:28][C:21]2[CH:22]=[CH:23][CH:24]=[C:25]3[C:20]=2[N:19]=[C:18]([C:14]2[N:11]4[CH:12]=[CH:13][C:8]([O:7][CH:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)=[CH:9][C:10]4=[N:16][CH:15]=2)[CH:27]=[CH:26]3)[CH2:34][CH2:33][N:32]([C:35]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:36])[CH2:31]1
Reactant: c1cn2ccc(OC3CCOCC3)cc2n1
Reactant: O=C(OCc1ccccc1)N1CC[C@@H](Oc2cccc3ccc(Cl)nc23)[C@H](F)C1
Product: O=C(OCc1ccccc1)N1CC[C@@H](Oc2cccc3ccc(-c4cnc5cc(OC6CCOCC6)ccn45)nc23)[C@H](F)C1

Procedure:
Prepared according to the procedure used for Example 1, Step D, using 7-(tetrahydro-2H-pyran-4-yloxy)imidazo[1,2-a]pyridine in place of 7-(2-methoxyethoxy)imidazo[1,2-a]pyridine and (trans)-benzyl 4-(2-chloroquinolin-8-yloxy)-3-fluoropiperidine-1-carboxylate in place of 2,8-dibromoquinoline. MS APCI (+) m/z 597 (M+1) detected.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:8])[CH:5]=[CH:6][CH:7]=1.[N:9]1([C:15]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(O[Na])(C)(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)C=CC=CC=1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:18]([O:17][C:15]([N:9]1[CH2:14][CH2:13][N:12]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[CH:3]=2)[CH2:11][CH2:10]1)=[O:16])[CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)COC(=O)N1CCNCC1
Reactant: Clc1cccc(Br)c1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)COC(=O)N1CCN(c2cccc(Cl)c2)CC1
Temperature: 140 °C

Procedure:
3-bromo chlorobenzene (434 mg, 2.3 mmol), isobutyl piperazine-1-carboxylate 6 (324 mg, 1.7 mmol), Pd2(dba)3 (32 mg, 0.035 mmol), t-BuONa (251 mg, 2.6 mmol), and Xantphos (60 mg, 0.11 mmol) in dry toluene (5 mL) were sealed in a microwave vessel and heated by microwave irradiation at 140° C. for 40 seconds. The reaction mixture was cooled and diluted with 10 mL of CH2Cl2, washed with water (5 mL), dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by reverse phase HPLC (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)); LC/MS: m/z 297.4 (M+H)+, r.t: 3.84 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), to give 13.
Reaction SMILES: [OH:1][CH:2]([C:6]1[C:7]([CH3:28])=[N:8][C:9]2[N:10]([N:19]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:21]=2)[C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)[C:3]([OH:5])=[O:4].[CH3:29]O>>[OH:1][CH:2]([C:6]1[C:7]([CH3:28])=[N:8][C:9]2[N:10]([N:19]=[C:20]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:21]=2)[C:11]=1[C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=1)[C:3]([O:5][CH3:29])=[O:4]
Reactant: CO
Reactant: Cc1ccc(-c2c(C(O)C(=O)O)c(C)nc3cc(-c4ccccc4)nn23)cc1
Product: COC(=O)C(O)c1c(C)nc2cc(-c3ccccc3)nn2c1-c1ccc(C)cc1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
To a solution of 2-hydroxy-2-(5-methyl-2-phenyl-7-p-tolylpyrazolo[1,5-a]pyrimidin-6-yl)acetic acid (6 mg, 0.016 mmol) in methanol (2 mL) was added thionyl chroride (0.0023 mL, 0.032 mmol). The reaction mixture was stirred at 40° C. for 16 hrs. The solvent was evaporated to give the title compound. The crude product was used directly for next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][C:5]=1[O:11][C:12]1[C:20]2[N:19]=[N:18][N:17]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:16]=2[CH:15]=[CH:14][CH:13]=1.[NH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.ClCCl>CS(C)=O>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:6][C:5]=1[O:11][C:12]1[C:20]2[N:19]=[N:18][N:17]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:16]=2[CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccc(F)cc1Oc1cccc2c1nnn2Cc1ccc(OC)cc1
Reactant: C1CNCCN1
Solvent: ClCCl
Solvent: CS(C)=O
Product: COC(=O)c1ccc(N2CCNCC2)cc1Oc1cccc2c1nnn2Cc1ccc(OC)cc1
Temperature: 100 °C

Procedure:
To a solution of EXAMPLE 342D (650 mg) in dimethylsulfoxide (12 mL) was added piperazine (618 mg). The solution was heated at 100° C. for one hour, cooled, added to dichloromethane, extracted with water three times, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under vacuum.
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[S:19](=[O:27])(=[O:26])[NH:18]2)=[C:9]1[CH3:28])(C)(C)C.[CH2:30](Br)[CH:31]=[CH2:32]>>[CH2:32]([N:18]1[CH:17]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]([CH2:7][C:6]([OH:5])=[O:29])[C:9]=2[CH3:28])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[S:19]1(=[O:26])=[O:27])[CH:31]=[CH2:30]
Reactant: C=CCBr
Reactant: Cc1c(C2NS(=O)(=O)c3ccccc32)c2ccccc2n1CC(=O)OC(C)(C)C
Product: C=CCN1C(c2c(C)n(CC(=O)O)c3ccccc23)c2ccccc2S1(=O)=O

Procedure:
The title compound was prepared by the method described for example 14 using the product from example 3, step c) and allyl bromide. MS: ESI (negative): 395 (M−H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C@H:7]2[O:19][C@@H:18]([CH2:20][O:21]C(=O)C)[C@H:13]([O:14]C(=O)C)[C@@H:8]2[O:9]C(=O)C)[N:5]=[N:4][C:3]=1[C:25]([NH2:27])=[O:26]>N>[NH2:1][C:2]1[N:6]([C@H:7]2[O:19][C@@H:18]([CH2:20][OH:21])[C@H:13]([OH:14])[C@@H:8]2[OH:9])[N:5]=[N:4][C:3]=1[C:25]([NH2:27])=[O:26]
Reactant: CC(=O)OC[C@@H]1O[C@H](n2nnc(C(N)=O)c2N)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: N
Product: NC(=O)c1nnn([C@H]2O[C@@H](CO)[C@H](O)[C@@H]2O)c1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Compound 36 (0.5 g, 1.29 mmol) was dissolved in methanolic ammonia (50 mL, sat. at 0° C.). The reaction mixture was stirred at room temperature for 16 h and evaporated to dryness. The residue was triturated thrice with EtOAc and the solid was crystallized from minimum amount of dry EtOH to yield colorless solid: mp 159-161° C.; 1H NMR (Me2SO-d6) δ3.40-3.52 (m, 2H, C5′H), 3.93 (m, 1H, C4′H), 4.19 (m, 1H, C3′H), 4.46 (m, 1H, C2′H) 4.74, 5.22, 5.62 (m, 3H, 3 OH, D2O exchangeable), 5.84 (d, 1H, J=3.90 Hz, C1′H), 7.95 (br s, 2H) and 9.02 (br s, 2H). Anal. Calc. for C8H13N5O5 (259.22): C, 37.07; H, 5.05; N, 27.02. Found: C, 37.36; H, 5.14; N, 27.01.