Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:24]([O:26]C(C)(C)C)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@@H:11]([CH3:13])[OH:12])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].C(O)(C(F)(F)F)=O.[NH:38]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[C@H:39](C(O)=O)[CH2:40][CH2:41][S:42]([CH3:44])=[O:43].C1C2C3C(=O)N(O)C(=O)C3C1C=C2.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[NH:38]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[C@H:39]([C:24]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15])[C@@H:11]([CH3:13])[OH:12])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5])=[O:26])[CH2:40][CH2:41][S:42]([CH3:44])=[O:43]
Reactant: CS(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C[C@@H](O)[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1C2C3C=CC(C3)C2C(=O)N1O
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](O)[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCS(C)=O)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 50.0 g of Boc-Asn-Thr-OBzl is added 170 ml of TFA and the mixture is shaken at room temperature for 30 minutes. The solution is concentrated and treated with 500 ml of diethyl ether. The resultant powder is collected by filtration and dried. It is dissolved in 400 ml of THF, and under ice-cooling 20 ml of TEA is added. To this solution is added Boc-Met(O)-ONB (prepared by dissolving 31.3 g of Boc-Met(O).OH and 23.3 g of HONB in 200 ml of THF, adding 26.8 g of DCC under ice-cooling and stirring the mixture for 4 hours). The mixture is stirred for 15 hours, after which time the solvent is distilled off under reduced pressure. To the residue are added ethyl acetate (200 ml) and ether (200 ml), and the resultant powders are collected by filtration and reprecipitated from acetonitrile. Yield 48.5 g (72.0%), m.p. 145°-147° C., [α]D23 -6.5° (c=1.1, DMF), Rf1 =0.19.
Reaction SMILES: [H-].[Na+].F[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12].[NH2:14][C:15]1[CH:28]=[CH:27][C:18]([O:19][CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=1>CS(C)=O.O>[F:10][C:7]1[CH:8]=[CH:9][C:4]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([O:19][CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:27][CH:28]=2)=[C:5]([N+:11]([O-:13])=[O:12])[CH:6]=1
Reactant: CCOC(=O)C(C)Oc1ccc(N)cc1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C(C)Oc1ccc(Nc2ccc(F)cc2[N+](=O)[O-])cc1
Reaction time: 24 h

Procedure:
2.5 g of sodium hydride paste (60% in mineral oil) was added in portions to a stirred solution of 9.9 g of 2,5-difluoronitrobenzene and 12.7 g of 1E in 200 ml of dimethyl sulfoxide. The resulting mixture was held at 160°-170° C. for 24 hours, then was cooled, diluted with 1000 ml of water and extracted with ether. The extract was chromatographed on silica gel to give ethyl 2-(4-(4-fluoro-2-nitrophenyl-amino)phenoxy)propionate (7A) as a viscous oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[F:9].C([Mg]Cl)(C)C.[Cl-].[Li+].[C:17]1(=[O:21])[CH2:20][CH2:19][CH2:18]1>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:17]2([OH:21])[CH2:20][CH2:19][CH2:18]2)=[CH:4][C:3]=1[F:9]
Reactant: O=C1CCC1
Reactant: Fc1cc(I)ccc1Br
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC1(c2ccc(Br)c(F)c2)CCC1
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 87.8 %

Procedure:
To 1-bromo-2-fluoro-4-iodobenzene (2390 mg, 7.90 mmol) in tetrahydrofuran (20 mL) at −40° C. was added isopropyl magnesium chloride.lithium chloride (1.3M in THF, 6.4 mL, 5.1 mmol) dropwise. The reaction mixture was stirred at −40° C. for 10 minutes, and treated with additional isopropyl magnesium chloride.lithium chloride (1.3M in THF, 1 mL, 1.3 mmol). The reaction mixture was stirred at −40° C. for an additional 20 minutes and then treated with cyclobutanone (624 mg, 8.72 mmol) dropwise at −40° C. The reaction mixture was warmed to room temperature, and stirred at room temperature for 16 hours. The reaction mixture was quenched with water and extracted with ethyl acetate (3×240 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound (1.7 g, 91%) as an oil.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:25]O>>[C:1]1([S:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)=[O:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCc2cc(OCCCCCSc3ccccc3)ccc2N1
Reactant: OO
Product: O=C1CCc2cc(OCCCCCS(=O)c3ccccc3)ccc2N1

Procedure:
Prepared analogous to Example 2 from 6-(5-phenylmercapto-pentoxy)-3,4-dihydro-carbostyril and hydrogen peroxide.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6]([OH:9])=[N:7][CH:8]=1.C([O-])(=O)C.[Na+].[Br:17]Br>C(O)(=O)C>[Br:17][C:5]1[C:6]([OH:9])=[N:7][CH:8]=[C:3]([C:2]([F:1])([F:10])[F:11])[CH:4]=1
Reactant: Oc1ccc(C(F)(F)F)cn1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Oc1ncc(C(F)(F)F)cc1Br
Temperature: 25 °C

Procedure:
To a solution of 5-trifluoromethyl-2-pyridinol (51 g, 310 mmol) and sodium acetate (26.2 g, 319 mmol) in glacial acetic acid (200 mL) was added bromine (16.7 mL, 325 mmol) and the resultant mixture was heated at 80° C. for 2.5 h. The reaction was allowed to cool to room temperature and then was evaporated under reduced pressure. The residue was neutralized with saturated aqueous sodium bicarbonate solution and extracted with 3 portions of ethyl acetate. The organic extracts were combined, dried over magnesium sulfate and concentrated under reduced pressure to afford the title compound. 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J=2.6 Hz, 1H), 7.89 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[C:5](Cl)=[O:6].[NH2:15][C:16]([CH3:32])([CH2:19][N:20]1[CH:28]=[C:27]2[C:22]([C:23]([Cl:31])=[C:24]([Cl:30])[CH:25]=[C:26]2[Cl:29])=[N:21]1)[C:17]#[N:18]>C1COCC1>[C:17]([C:16]([NH:15][C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([C:11]([F:14])([F:13])[F:12])=[C:2]([F:1])[CH:3]=1)([CH3:32])[CH2:19][N:20]1[CH:28]=[C:27]2[C:22]([C:23]([Cl:31])=[C:24]([Cl:30])[CH:25]=[C:26]2[Cl:29])=[N:21]1)#[N:18]
Reactant: CC(N)(C#N)Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)c(F)c1
Solvent: C1CCOC1
Product: CC(C#N)(Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1)NC(=O)c1ccc(C(F)(F)F)c(F)c1

Procedure:
Using a procedure similar to that described in Example 60, except using a solution of 3-fluoro-4-trifluoromethylbenzoyl chloride (0.16 mmole) in THF and a solution of 2-amino-2-methyl-3-(4,6,7-trichloro-2H-indazol-2-yl)propionitrile (0.075 mmole, described in Example 147) in THF mixed with TEA (3% v./v.), the title compound was isolated as solid residue (13.9 mg). It was dissolved in DMSO for further biological evaluation and analyzed by LCMS. MS (ES): M/Z [M+H]=493, RT=0.76 min.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:11]=[CH:10][N:9]([CH3:12])[N:8]=2)=[CH:4][CH:3]=1.[CH3:13][S:14]([C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:15].C([O-])([O-])=O.[K+].[K+]>>[CH3:13][S:14]([C:17]1[CH:22]=[C:21]([C:2]2[S:6][C:5]([C:7]3[CH:11]=[CH:10][N:9]([CH3:12])[N:8]=3)=[CH:4][CH:3]=2)[CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15]
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Cn1ccc(-c2ccc(Br)s2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cn1ccc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n1
Temperature: 85 °C
Reaction time: 6 h
Yield: 41.6 %

Procedure:
A stirred mixture of 3-(5-bromothiophen-2-yl)-1-methyl-1H-pyrazole (0.20 g, 0.83 mmol), 3-methanesulfonyl-phenylboronic acid (0.20 g, 1.0 mmol), K2CO3 (345 mg, 2.5 mmol), Cl2Pd(dppf).DCM (82 mg, 10 mol %) and H2O (0.6 mL) in dioxane (6 mL) was sparged with Argon for 5 min and then heated at 85° C. as a sealed flask. After 6 h the reaction mixture was allowed to cool to ambient temperature, filtered (Celite™) and the filter agent rinsed with EtOAc. The combined filtrates were concentrated under reduced pressure and purified by chromatography (silica, EtOAc/DCM, 2:98 to 5:95) to give the title compound (0.11 g, 42%) as a white solid. 1H-NMR (CD2Cl2): δ 8.15 (1H, m), 7.89 (1H, m), 7.80 (1H, m), 7.60 (1H, m), 7.40 (2H, m), 7.29 (1H, d), 6.50 (1H, d), 3.91 (3H, s), 3.07 (3H, s).
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([NH2:40])[CH:35]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([NH:40][C:2]3[N:20]=[C:5]4[C:6]([C:10]5[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=5)=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)[CH:35]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(N)c2)CC1
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(Cl)nc23)cc1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(Nc3nc4c(-c5ccc(S(C)(=O)=O)cc5)cccn4n3)c2)CC1

Procedure:
179 a) A suspension of 1-(3-nitro-phenyl)-piperazine hydrochloride (1.0 g, 4.1 mmol) and potassium carbonate (0.62 g, 4.5 mmol) in acetonitrile (10 mL) at room temperature was added di-tert-butyldicarbonate (1.0 g, 4.6 mmol) and was stirred at room temperature for 3 days. The mixture was poured into water (50 mL) and extracted with dichloromethane (3×50 mL). The combined organic layers were washed with water (50 mL) and saturated aqueous sodium chloride (50 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure. 4-(3-Nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester was isolated as a yellow solid (1.169 g, 93%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.72 (s, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.39 (t, J=8.2 Hz, 1H), 7.19 (dd, J=8.2, 1.7 Hz, 1H), 3.63-3.58 (m, 4H), 3.27-3.21 (m, 4H), 1.49 (s, 9H). MS=330 (M+Na)+. 179 b) (3-Amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester was prepared from 4-(3-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (1.17 g, 3.81 mmol) in a manner analogous to Example 111a. Product isolated as a yellow solid (0.993 g, 94%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.05 (t, J=7.7 Hz, 1H), 6.35 (d, J=8.8 Hz, 1H), 6.26-6.22 (m, 2H), 3.61 (br s, 2H), 3.57-3.53 (m, 4H), 3.12-3.07 (m, 4H), 1.48 (s, 9H). MS=278 (MH)+. 179 c) 4-{3-[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (500.0 mg, 1.625 mmol) and 4-(3-Amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (500.0 mg, 1.803 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (90.0 mg, 0.165 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a yellow foam (0.70 g, 79%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.51 (d, J=6.6 Hz, 1H), 8.24 (d, J=8.3 Hz, 2H), 8.08 (d, J=8.4 Hz, 2H), 7.66 (d, J=7.4 Hz, 1H), 7.32 (s, 1H), 7.24 (t, J=8.1 Hz, 1H), 7.05-6.99 (m, 2H), 6.89 (s, 1H), 6.59 (d, J=8.2 Hz, 1H), 3.63-3.58 (m, 4H), 3.22-3.17 (m, 4H), 3.10 (s, 3H), 1.50 (s, 9H). MS=549 (MH)+.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][CH:10]([OH:12])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1.O>C1COCC1>[C:13]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:11][CH:10]([O:12][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)[CH2:9]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 23 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
0.5 g (2 mmol) of 1-(diphenylmethyl)-3-hydroxyazetidine is added under an argon atmosphere to a suspension of 0.06 g (2.3 mmol) of Na in 20 ml of dry THF. After agitation for one hour at 23° C., a solution of 0.29 g (2.1 mmol) of 4-fluoronitrobenzene in 5 ml of dry THF is added dropwise to the reaction mixture. Agitation is maintained for another 2 hours at 23° C. and the whole is finally poured into 25 ml of water. The product is extracted twice with 25 ml of ethyl acetate, the organic phase is then washed twice with 25 ml of salt water, dried over magnesium sulphate, filtered and concentrated under vacuum. The product is purified on a silica column (eluant: 12% of ethyl acetate in heptane). The pure fractions are evaporated in order to produce a colourless oil with a yield of 40%.
Reaction SMILES: [CH:1]1([N:4]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.[CH2:20]([O:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1)[CH2:21][CH2:22][CH3:23].CCN(C(C)C)C(C)C>ClCCl>[CH2:20]([O:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([N:17]2[CH2:18][CH2:19][CH:14]([N:4]([CH:1]3[CH2:3][CH2:2]3)[S:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)(=[O:6])=[O:7])[CH2:15][CH2:16]2)(=[O:33])=[O:32])=[CH:27][CH:26]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCOc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=S(=O)(c1ccccc1)N(C1CCNCC1)C1CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCOc1ccc(S(=O)(=O)N2CCC(N(C3CC3)S(=O)(=O)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
143 mg (0.513 mmol) of N-cyclopropyl-N-piperidin-4-yl-benzenesulfonamide (available from Lancaster) and 128 mg (0.513 mmol) of 4-butoxyphenylsulfonyl chloride (available from Matrix Scientific) were each dissolved in 5 mL dichloromethane (DCM) and then combined. 1.5 eq. of diisoprolylethylamine (DIEA) (0.134 mL) was added to the mixture by syringe. The mixture was stirred overnight at room temperature and then concentrated under vacuum. The resultant product 27 was purified through a column of silica gel with a gradient of 0% to 20% EtOAc in hexanes and the pure material was concentrated (yield 24%, white solid). 1H NMR (CDCl3): δ 7.813-7.783 (m, 2H), 7.673-7.636 (m, 2H), 7.597-7.553 (m, 1H), 7.520-7.475 (m, 2H), 7.011-6.974 (m, 2H), 4.053-4.020 (t, 2H), 3.821-3.721 (m, 3H), 2.266-2.200 (t, 2H), 2.033-1.902 (m, 3H), 1.843-1.779 (m, 2H), 1.601-1.470 (m, 4H), 1.015-0.978 (t, 3H), 0.935-0.896 (m, 2H), 0.761-0.712 (m, 2H). LC: 100%. MS (e/z): 494 (M+H+).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].CC(C1C=CC(C2C=CC(OC)=CC=2)=CC=1)C(OCC)=O>>[C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(-c2ccc(OC(C)=O)cc2)cc1
Agent: CCOC(=O)C(C)c1ccc(-c2ccc(OC)cc2)cc1
Product: CC(=O)Oc1ccc(-c2ccc(O)cc2)cc1

Procedure:
The title compound is prepared using the method of part B of Example 16 subtituting 4-acetoxy-4'-methoxy-1,1'-biphenyl for α-methyl-4'-(methoxy)[1,1'biphenyl]-4-acetic acid, ethyl ester. Normal workup affords a white solid, m.p. 204°-207° C.; MS (EI m/z): 212 (M)+, 197 (b.p.,M-CH3)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].CS(C)=O.[Na+].[CH3:16][S:17]([O-:19])=[O:18]>O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[S:17]([CH3:16])(=[O:19])=[O:18])[CH:5]=[O:6]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(C=O)cc1F
Temperature: 90 °C

Procedure:
To a solution containing 0.5 g 3,4-difluorobenzaldehyde and 20 ml DMSO was added 0.71 g methanesulfinic acid sodium salt with stirring at 90° C. The solution was stirred 6 hours at 90° C. and then poured into water. Sodiumhydrogencarbonate was added and the product was extracted with ethyl acetate. The extract was evaporated to dryness in vacuo. The residue was triturated with 2-propanol, yield 0.93 g. 1H-NMR (DMSO-d6, 400 MHz): 3.52 (s, 3 H, CH3), 7.98-8.13 (m, 3 H, Ar), 10.22 (d, 1 H, CHO).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3[CH2:20][C@H:19]([NH:21][C:22](=[O:25])[CH2:23][OH:24])[C@@H:18]([OH:26])[C@H:17]3[OH:27])=[C:9]([NH:28][CH2:29][CH:30]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:8]=2)C=1.[N+:43](C1N=CNC=1)([O-])=O>>[NH2:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3[CH2:20][C@H:19]([NH:21][C:22](=[O:25])[CH2:23][OH:24])[C@@H:18]([OH:26])[C@H:17]3[OH:27])=[C:9]([NH:28][CH2:29][CH:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:8]=2)[N:43]=1
Reactant: Nc1cn(-c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)CO)[C@@H](O)[C@H]4O)c3n2)cn1
Reactant: O=[N+]([O-])c1c[nH]cn1
Product: Nc1ncn(-c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)CO)[C@@H](O)[C@H]4O)c3n2)n1

Procedure:
The title compound is prepared analogously to N-{(1S,2R,3S,4R)-4-[2-(4-amino-imidazol-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-hydroxy-acetamide (Intermediate ZU) from {(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentylcarbamoyl}-methyl ester (Intermediate Q1) by substituting 3-nitro-1H-[1,2,4]triazole for 4-nitro-1H-imidazole in step ZU1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[Cl:18][C:19]1[N:24]=[CH:23][C:22]([C:25](Cl)=[O:26])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[N:24]=[CH:23][C:22]([C:25]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:26])=[CH:21][CH:20]=1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(Cl)nc4)nc23)CC1

Procedure:
Beginning with 0.010 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.054 mMol 6-chloro-3-pyridinecarbonyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=2[Cl:15])[N:5]=[C:4]([CH:16]2[CH2:18][CH2:17]2)[C:3]=1[C:19]([NH2:21])=[O:20].[OH:22][C:23]1[CH:24]=[C:25]([CH2:31][C:32](OCC)=O)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30].[O-]CC.[Na+]>C(O)C>[Cl:13][C:12]1[CH:11]=[C:10]([Cl:14])[CH:9]=[C:8]([Cl:15])[C:7]=1[N:6]1[C:2]2=[N:1][C:32]([CH2:31][C:25]3[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:23]([OH:22])[CH:24]=3)=[N:21][C:19](=[O:20])[C:3]2=[C:4]([CH:16]2[CH2:17][CH2:18]2)[NH:5]1
Reactant: CCOC(=O)Cc1ccc(OC)c(O)c1
Reactant: NC(=O)c1c(C2CC2)nn(-c2c(Cl)cc(Cl)cc2Cl)c1N
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(Cc2nc3n(-c4c(Cl)cc(Cl)cc4Cl)[nH]c(C4CC4)c-3c(=O)n2)cc1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 22.3 %

Procedure:
To a stirred solution of 146 mg (0.42 mmol) of 5-amino-3-cyclopropyl-1-(2,4,6-trichlorophenyl)pyrazole-4-carboxamide in 6 mL of absolute ethanol was added 533 mg (2.53 mmol) of ethyl 3-hydroxy-4-methoxyphenylacetate followed by 1.91 mL (5.1 mmol) of 2.66 M sodium ethoxide in ethanol. The solution was stirred 18 h at reflux, and the heating mantle was then removed. The reaction was treated with 5 mL of 10% aq. HOAc, cooled to ambient temperature, and filtered. The filtrate was washed with 6 mL of 1:1 water-methanol then 6 mL of 1:1 ether-hexanes. The off-white solid was briefly air-dried to give 46 mg (22%) of 1-(2,4,6-trichlorophenyl)-3-cyclopropyl-6-(3-hydroxy-4-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one. Mass Spec.: 489 (M−H)−.
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[C:8]([CH3:11])[CH:7]=[C:6]([CH3:12])[C:3]=1[CH:4]=O>CO.[C].[Pd]>[CH3:4][C:3]1[C:6]([CH3:12])=[CH:7][C:8]([CH3:11])=[C:9]([CH3:10])[C:2]=1[OH:1]
Reactant: Cc1cc(C)c(C=O)c(O)c1C
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C)c(C)c(O)c1C
Temperature: 25 °C
Reaction time: 22 h
Yield: 12.1 %

Procedure:
2-Hydroxy-3,4,6-trimethylbenzaldehyde (6.58 g, 40.1 mmol) was dissolved in methanol (120 mL), 10% palladium-carbon (50% water-containing product, 1.0 g) was added under hydrogen atmosphere (balloon pressure), and the mixture was stirred at room temperature for 22 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The precipitated crystals were recrystallized from methanol to give the title compound (0.73 g, yield 12%) as colorless crystals. The mother solution was concentrated under reduced pressure to give second crop (5.10 g, yield 85%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:16][C:17]1[CH:29]=[CH:28][C:20]([CH2:21][N:22]2[CH:26]=[N:25][C:24]([NH2:27])=[N:23]2)=[CH:19][CH:18]=1>>[CH3:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][N:22]2[CH:26]=[N:25][C:24]([NH:27][C:2]3[CH:3]=[CH:4][C:5]([N:10]4[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]4)=[C:6]([CH:9]=3)[C:7]#[N:8])=[N:23]2)=[CH:28][CH:29]=1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Reactant: Cc1ccc(Cn2cnc(N)n2)cc1
Product: Cc1ccc(Cn2cnc(Nc3ccc(-n4cnc(C)c4)c(C#N)c3)n2)cc1

Procedure:
Prepared in analogy to example 1b) starting with 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile and 1-(4-methyl-benzyl)-1H-[1,2,4]triazol-3-ylamine. The title compound was obtained as a white solid (Yield=50%). MS ISP (m/e): 370.1 (100) [(M+H)+].
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[NH:11][C:12]2[C:17]([N+:18]([O-])=O)=[CH:16][CH:15]=[C:14]([NH:21][C:22]3[NH:23][N:24]=[C:25]([CH3:27])[CH:26]=3)[N:13]=2)=[CH:4][CH:3]=1.[In].[ClH:29]>CO>[ClH:29].[ClH:29].[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[NH:11][C:12]2[C:17]([NH2:18])=[CH:16][CH:15]=[C:14]([NH:21][C:22]3[NH:23][N:24]=[C:25]([CH3:27])[CH:26]=3)[N:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(Nc2ccc([N+](=O)[O-])c(NC3CCc4ccc(F)cc43)n2)[nH]n1
Agent: Cl
Agent: [In]
Solvent: CO
Product: Cc1cc(Nc2ccc(N)c(NC3CCc4ccc(F)cc43)n2)[nH]n1
Reaction time: 1 h

Procedure:
Dissolve N2-(6-fluoroindan-1-yl)-N6-(5-methyl-2H-pyrazol-3-yl)-3-nitropyridine-2,6-diamine (0.571 g, 1.55 mmol) in methanol (10 mL). Add indium (0.890 g, 7.75 mmol) and hydrochloric acid (12N, 0.65 mL, 7.75 mmol). Stir the mixture under nitrogen for one hour. Filter the reaction mixture through Celite® 521 and wash the solids with methanol. Concentrate the filtrate in vacuo to afford crude N2-(6-fluoroindan-1-yl)-N6-(5-methyl-2H-pyrazol-3-yl)-pyridine-2,3,6-triamine dihydrochloride.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][NH:10][C:11]([CH:13]1[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]1)=[O:12].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:27][C:2]([F:1])([F:26])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][NH:10][C:11]([CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:12]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NCc2ccccc2C(F)(F)F)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCc1ccccc1C(F)(F)F)C1CCNCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 1,1-dimethylethyl 4-[({[2-(trifluoromethyl)phenyl]methyl}amino)-carbonyl]-1-piperidinecarboxylate and CH2Cl2 (180 ml) at 0° C., a premixed solution of CH2Cl2 and TFA (180 ml) was added. The reaction mixture was stirred at 0° C. for 10 min and at room temperature for 2 h. The solvents were removed under reduced pressure to afford 11.9 g of the title compound. MS (ES+): m/e 287.9 [M+H]+.