Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][C:11]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl[C:30]1[CH:35]=[CH:34][N:33]=[C:32]([C:36]([NH:38][CH3:39])=[O:37])[CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[S:10][C:11]3[CH:17]=[CH:16][C:15]([O:18][C:30]4[CH:35]=[CH:34][N:33]=[C:32]([C:36]([NH:38][CH3:39])=[O:37])[CH:31]=4)=[CH:14][C:12]=3[N:13]=2)=[CH:6][CH:7]=1
Reactant: CNC(=O)c1cc(Cl)ccn1
Reactant: Oc1ccc2sc(Nc3ccc(Br)cc3)nc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(Oc2ccc3sc(Nc4ccc(Br)cc4)nc3c2)ccn1

Procedure:
The mixture containing 2-[(4-bromophenyl)amino]benzothiazol-5-ol (1 eq), Potassiumbis(trimethylsilyl)amide (4 eq), was stirred in dimethylformamide for 30 min at room temperature. To this mixture was added (4-chloro(2-pyridyl)-N-methylcarboxamide (1 eq) and Potassium carbonate (1.2 eq) and microwaved for 6 mins at 150° C. The reaction mixture was then concentrated and partitioned between ethyl acetate and water. The organic layer was separated and washed with brine, dried, filtered and concentrated. Purification on Prep LC yielded the desired product. MS: MH+=455
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15]>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:15][C:14]1[CH:16]=[CH:17][CH:18]=[C:12]([Cl:11])[CH:13]=1
Reactant: Nc1cccc(Cl)c1
Reactant: Clc1nc2ccccc2[nH]1
Product: Clc1cccc(Nc2nc3ccccc3[nH]2)c1

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 3-chloroaniline by Procedure A. The product was isolated by filtration to give the title compound as a hydrochloride salt (white solid, mp 252-257° C.). MS(ES+) m/z 244 ([M+1]+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:14][CH:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[F:23])[CH2:12]2)=[C:6]([CH:10]=1)[C:7](O)=[O:8].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[NH2:48][C:49]1([C:52]2[CH:61]=[CH:60][C:55]([C:56]([O:58][CH3:59])=[O:57])=[CH:54][CH:53]=2)[CH2:51][CH2:50]1.C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:12][CH:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[F:23])[CH2:14]2)=[C:6]([CH:10]=1)[C:7]([NH:48][C:49]1([C:52]2[CH:61]=[CH:60][C:55]([C:56]([O:58][CH3:59])=[O:57])=[CH:54][CH:53]=2)[CH2:51][CH2:50]1)=[O:8]
Reactant: O=C(O)c1cc(Cl)cnc1N1CC(Nc2ccc(F)cc2F)C1
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC(Nc4ccc(F)cc4F)C3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 173.5 %

Procedure:
A mixture of 5-chloro-2-(3-((2,4-difluorophenyl)amino)azetidin-1-yl)nicotinic acid (D118) (40 mg, 0.118 mmol), 1-Hydroxybenzotriazole hydrate (18 mg, 0.118 mmol) and 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (34 mg, 0.177 mmol) in dimethylformamide (5 ml) was stirred 10 min at room temperature. A solution of methyl 4-(1-aminocyclopropyl)benzoate hydrochloride (D7) (32.2 mg, 0.141 mmol) and triethylamine (0.02 ml, 0.141 mmol) in dry dimethylformamide (2 ml) was added and the mixture was stirred 24 h at room temperature. After solvent evaporation, water (10 ml) was added and the formed precipitate was filtered off and purified by Biotage SNAP-Si (10 g) cartridge eluting with a mixture dichloromethane/methanol from 100/0 to 80/20. Collected fractions, after solvent evaporation afforded the title compound (D169) (105 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:29]>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:10]([F:29])=[O:11])[CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H](c1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Fc1nc(F)nc(F)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(c1ccccc1)C(NC(=O)OC(C)(C)C)C(=O)F
Reaction time: 1.5 h

Procedure:
To a solution of (2S,3S)-2-tert-butoxycarbonylamino-3-phenyl-butyric acid (838 mg, 3.0 mmol) in dichloromethane (10 mL) at −35° C. was added dry pyridine (255 μL, 3.15 mmol) and cyanuric fluoride (375 μL, 4.5 mmol) under an atmosphere of dry argon. The mixture was stirred for 1.5 hours while maintaining the temperature between −35 and −25° C. A small amount of ice was added to the reaction mixture and the mixture stirred vigorously for 15 minutes. The organic layer was decanted away from the aqueous solution and the aqueous layer extracted with dichloromethane (2×10 mL). The combined organic layers were washed with ice cold water (15 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give (1-fluorocarbonyl-2-phenyl-propyl)-carbamic acid tert-butyl ester which was used in the subsequent step without further purification.
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[CH:23]=[CH:22][S:21][C:20]=1[C:24](Cl)=[O:25]>>[Cl:18][C:19]1[CH:23]=[CH:22][S:21][C:20]=1[C:24]([NH: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)=[O:25]
Reactant: O=C(Cl)c1sccc1Cl
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4sccc4Cl)nc23)CC1
Yield: 57.5 %

Procedure:
Beginning with 0.30 gm (1.3 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.29 gm (1.56 mMol) 3-chloro-2-thiophenecarbonyl chloride, 0.28 gm (57%) of the title compound were prepared as an orange foam essentially by the procedure described in Example 4.
Reaction SMILES: [C:1]([C:9]1[C:17]2[C:12](=[C:13]([N:18]3[CH2:23][CH2:22][N:21](C(=O)C(F)(F)F)[CH2:20][CH2:19]3)[CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].CCOC(C)=O.O>C(O)(C)C>[CH2:1]([C:9]1[C:17]2[C:12](=[C:13]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1c[nH]c2c(N3CCN(C(=O)C(F)(F)F)CC3)cccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Solvent: O
Product: c1ccc(Cc2c[nH]c3c(N4CCNCC4)cccc23)cc1
Temperature: 25 °C
Yield: 126.5 %

Procedure:
To a solution of 1-[4-(3-benzoyl-1H-indol-7-yl)-piperazin-1-yl]-2,2,2-trifluoro-ethanone (638 mg, 1.59 mmol) in isopropanol (30 ml) was added NaBH4 (0.12 g, 3.17 mmol). After heating at reflux for 3 days, the reaction mixture was allowed to cool to room temperature and poured into a mixture of EtOAc/H2O. The organic layer was separated and washed with water and brine. After drying over MgSO4, the organic fraction was concentrated in vacuo to give crude 3-benzyl-7-piperazin-1-yl-1H-indole as an oil (586 mg) which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]2[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:7]=1.C(N(CC)CC)C.[C:29](OC(=O)C)(=[O:31])[CH3:30].C(=O)(O)[O-].[Na+]>CN(C)C1C=CN=CC=1.O1CCOCC1.C(OCC)(=O)C>[C:29]([NH:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]2[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:7]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1cc(N)cc(Nc2ncccc2[N+](=O)[O-])c1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(NC(C)=O)cc(Nc2ncccc2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of 2-[3-amino-5-methoxycarbonylphenylamino]-3-nitropyridine (1.10 g), triethylamine (0.6 ml) and 4-dimethylaminopyridine (14 mg) in 1,4-dioxane (15 ml) was added acetic anhydride (0.40 ml). The mixture was stirred at room temperature for 20 hours, then poured into a mixture of ethyl acetate and aqueous sodium bicarbonate. The organic phase was separated, washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give 2-(3-acetylamino-5-methoxycarbonylphenylamino)-3-nitropyridine (1.21 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:13][C@@H:14]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:15]([O:17]C)=O)[C:5]([CH2:11]Cl)=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.[CH3:24][O:25][CH2:26][CH2:27][NH2:28].COC(=O)C[C@H]1C(=O)N(CC2CC2)CC2C3C=NNC=3C(Br)=CC=2C1>>[CH3:23][O:22][C:20](=[O:21])[CH2:19][C@H:14]1[C:15](=[O:17])[N:28]([CH2:27][CH2:26][O:25][CH3:24])[CH2:11][C:5]2[C:6]3[CH:7]=[N:8][NH:9][C:10]=3[C:2]([Br:1])=[CH:3][C:4]=2[CH2:13]1
Reactant: COC(=O)C[C@H](Cc1cc(Br)c2[nH]ncc2c1CCl)C(=O)OC
Reactant: COCCN
Agent: COC(=O)C[C@@H]1Cc2cc(Br)c3[nH]ncc3c2CN(CC2CC2)C1=O
Product: COCCN1Cc2c(cc(Br)c3[nH]ncc23)C[C@@H](CC(=O)OC)C1=O
Yield: 66 %

Procedure:
(S)-dimethyl 2-((7-bromo-4-(chloromethyl)-1H-indazol-5-yl)methyl)succinate (400 mg, 0.99 mmol) and 2-methoxyethylamine were reacted in a manner analogous to the preparation of ((S)-4-Bromo-9-cyclopropylmethyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohepta[e]inden-7-yl)-acetic acid methyl ester. Title compound was obtained as tan solid in 66% yield. MS m/e (M−H)−=408.1, 410.0.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1)=[O:5].C(N(CC)CC)C.[O:27]1[C:31]2[NH:32][CH2:33][C:34]3[N:35]([CH:37]=[CH:38][CH:39]=3)[CH2:36][C:30]=2[CH:29]=[CH:28]1>C(Cl)Cl>[O:27]1[C:31]2[N:32]([C:11]([C:10]3[CH:14]=[CH:15][C:7]([NH:6][C:4](=[O:5])[C:3]4[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=4[CH3:1])=[CH:8][CH:9]=3)=[O:12])[CH2:33][C:34]3[N:35]([CH:37]=[CH:38][CH:39]=3)[CH2:36][C:30]=2[CH:29]=[CH:28]1
Reactant: c1cc2n(c1)Cc1ccoc1NC2
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccoc32)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a mixture of 1.1 mmol of 4-[(2-methylbenzoyl)amino]benzoyl chloride in 10 ml of methylene chloride, cooled to 0° C. is added 1.5 mmol of triethylamine. To the mixture is added 1 mmol of 9,10-dihydro-4H-furo[2,3-e]pyrrolo[1,2-a][1,4]diazepine and the mixture stirred at room temperature for 2 hours. The reaction mixture is concentrated in vacuo and the residue is dissolved in 100 ml of ethyl acetate and washed with water, 2N citric acid, aqueous NaHCO3 and brine. The solution is dried with Na2SO4 and the volatiles concentrated in vacuo to give a solid which is purified by flash chromatography to give the desired product.
Reaction SMILES: O[C:2]1([C:17]([F:20])([F:19])[F:18])[CH2:15][C:14](=[O:16])[NH:13][C:12]2[C:3]1=[C:4]1[C:9](=[CH:10][CH:11]=2)[S:8][CH2:7][CH2:6][NH:5]1.C(=O)([O-])[O-].[Na+].[Na+]>S(=O)(=O)(O)O>[F:19][C:17]([F:18])([F:20])[C:2]1[C:3]2[C:12]([NH:13][C:14](=[O:16])[CH:15]=1)=[CH:11][CH:10]=[C:9]1[C:4]=2[NH:5][CH2:6][CH2:7][S:8]1
Reactant: O=C1CC(O)(C(F)(F)F)c2c(ccc3c2NCCS3)N1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=c1cc(C(F)(F)F)c2c3c(ccc2[nH]1)SCCN3
Temperature: 0 °C

Procedure:
The dehydration of 5-hydroxy-5-trifluoromethyl-3,4,5,8-tetrahydro-2H,6H-1-thia-4,8-diaza-phenanthren-7-one (69 mg, 0.23 mmol) was carried out in concentrated sulfuric acid at 150° C. The solution was cooled to about rrom temperature, added to ice water, made basic with 1M sodium carbonate, extract with ethyl acetate three times, the organic layers washed with brine, dried over sodium sulfate, filtered and the filtrate evaporated to yield 5-trifluoromethyl-3,4-dihydro-2H,8H-1-thia-4,8-diaza-phenanthren-7-one as a green solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[NH2:9][NH2:10].[F:11][C:12]([F:19])([F:18])[C:13](OCC)=O>C(O)C.CCOCC>[F:11][C:12]([F:19])([F:18])[C:13]1[NH:2][C:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)=[N:9][N:10]=1
Reactant: N#Cc1ccccn1
Reactant: CCOC(=O)C(F)(F)F
Reactant: NN
Solvent: CCO
Solvent: CCOCC
Product: FC(F)(F)c1nnc(-c2ccccn2)[nH]1
Reaction time: 12 h
Yield: 50 %

Procedure:
2-cyanopyridine (1.04 g, 10.0 mmol) is placed in a 25 ml round-bottomed flask and ethanol is added into 2-cyanopyridine. After completly dissolved, hydrazine (0.96 g, 30.0 mmol) is added. At the room temperature, the reaction is carried out for 12 hrs. White solids are obtained. Ether is used to rinse the solids in order to remove the unreacted hydrazine. The white solids are placed in a 25 ml round-bottomed flask and added with ethyl 2,2,2-trifluoroacetate (1.42 g, 10.0 mmol). 5.0 ml of ethanol is added and then hot reflux is performed for 12 hrs. After the reaction is finished, ether extraction is carried out and the organic layer is collected and then concentrated to obtain white solids. After purified by silicone chromatographic column, the product tfpytz is obtained. The yield is about 50%. 1H NMR (500 MHz, CDCl3): δ 8.78 (m, 1 H), 8.31 (d, 1 H, J=8.0 Hz), 7.97˜7.94 (m, 1 H), 7.53˜7.50 (m, 1 H). HRMS (EI) m/z:calculated value C8H5F3N4 214.0466; experimental value 214.0469.
Reaction SMILES: [NH:1]1C(=O)CC(=O)NC1=S.S([O-])(OCCCCCCCCCCCC)(=O)=O.[Na+].[OH-:28].[Na+].[CH3:30][N:31]1[C:37](=[O:38])[N:36]([CH3:39])[C:34](=[O:35])[C:33]2[NH:40][C:41]([C:43]3[CH:48]=[CH:47][C:46]([S:49]([OH:52])(=[O:51])=[O:50])=[CH:45][CH:44]=3)=[N:42][C:32]1=2.[CH:53]1[N:57]([C@@H:58]2[O:62][C@H:61]([CH2:63][OH:64])[C@@H:60]([OH:65])[CH2:59]2)[C:56]2[N:66]=[CH:67][NH:68]C[C@@H:70](O)[C:55]=2[N:54]=1>O.C(O)(=O)C>[C@@H:58]1([N:57]2[C:56]3[N:66]=[CH:67][N:68]=[C:70]([NH2:1])[C:55]=3[N:54]=[CH:53]2)[O:62][C@H:61]([CH2:63][OH:64])[C@@H:60]([OH:65])[C@H:59]1[OH:28].[CH3:30][N:31]1[C:37](=[O:38])[N:36]([CH3:39])[C:34](=[O:35])[C:33]2[NH:40][C:41]([C:43]3[CH:44]=[CH:45][C:46]([S:49]([OH:52])(=[O:50])=[O:51])=[CH:47][CH:48]=3)=[N:42][C:32]1=2
Reactant: OC[C@H]1O[C@@H](n2cnc3c2N=CNC[C@H]3O)C[C@@H]1O
Reactant: [OH-]
Reactant: O=C1CC(=O)NC(=S)N1
Agent: CCCCCCCCCCCCOS(=O)(=O)[O-]
Agent: Cn1c(=O)c2[nH]c(-c3ccc(S(=O)(=O)O)cc3)nc2n(C)c1=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 950 °C
Reaction time: 0.01 h

Procedure:
Concentrations of the products of lipid peroxidation [thiobarbituric acid reactive substances (TBARS)] were measured using the thiobarbituric acid reaction from representative samples of jejunum tissue of septic and control rats at 24 and 72 hours after sepsis induction. Tissue homogenate samples (0.2 ml; 10% w/v) were combined with 0.2 ml 8.1% sodium dodecyl sulfate, 1.5 ml of 20% acetic acid (the solution adjusted to pH 3.5 with NaOH), and 1.5 ml of 0.8% aqueous solution of thiobarbituric acid. Distilled water was added to bring the total volume up to 4 ml, then heated in an oil bath at 950° C. for 60 min. After cooling, 1 ml distilled water and 5 ml n-butanol/pyridine (15:1 v/v) was added. After shaking 30 sec, followed by centrifugation at 4000 rpm for 10 min, absorbance of the organic layer was measured at 532 nM. Data from tissue obtained from non-septic rats, and septic rats treated with saline (No Rx), 8-SPT, or pentostatin are expressed as nmols TBARS per mg protein in FIG. 6 Elevated TBARS were found as early as 24 hours after sepsis induction. Adenosine receptor blockade (8-SPT) resulted in exacerbation of the sepsis-induced elevation in TBARS. Inhibition of adenosine deaminase with pentostatin resulted in diminution of tissue TBARS during sepsis. These data confirm the presence of oxidative damage in this model of sepsis, and the ability to reduce oxidative damage by inhibiting adenosine deaminase. The data demonstrating exacerbation of oxidative damage with adenosine receptor blockade points to the primary role for endogenous adenosine in these responses.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([S:9][C@H:10]1[CH2:14][C@@H:13]([C:15]([NH:17][CH2:18][C:19]2[S:20][CH:21]=[CH:22][N:23]=2)=O)[N:12]([C:24]([O:26][CH2:27][CH:28]=[CH2:29])=[O:25])[CH2:11]1)(=[O:8])[CH3:7]>C1(C)C=CC=CC=1>[C:6]([S:9][C@H:10]1[CH2:14][CH:13]([C:15]2[N:23]3[C:19]([S:20][CH:21]=[CH:22]3)=[CH:18][N:17]=2)[N:12]([C:24]([O:26][CH2:27][CH:28]=[CH2:29])=[O:25])[CH2:11]1)(=[O:8])[CH3:7]
Reactant: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1C(=O)NCc1nccs1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: C=CCOC(=O)N1C[C@@H](SC(C)=O)CC1c1ncc2sccn12
Temperature: 100 °C
Reaction time: 1 h
Yield: 7.4 %

Procedure:
Phosphorus oxychloride (1.2 ml) is added to a solution of 1.00 g of (3S,5S)-3-acetylthio-1-allyloxycarbonyl-5-[(thiazol-2-yl)methylaminocarbonyl]pyrrolidine in 10 ml of toluene, and the mixture is stirred at 100° C. for one hr. The reaction mixture is concentrated under reduced pressure, dichloromethane is added to the residue, and the mixture is successively washed with an aqueous potassium carbonate solution and saturated saline and dried over magnesium sulfate. The solvent is removed by evaporation, and the residue is purified by column chromatography on silica gel to give 0.27 g of the title compound (stereoisomer A: a high polar component) and 0.07 g of the title compound (stereoisomer B: a low polar component).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#N.[CH2:11]([Mg]Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Mg].C(Cl)C1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:32]>CCOCC>[Br:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4](=[O:32])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N#Cc1ccc(F)cc1Br
Reactant: Cl[Mg]Cc1ccccc1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Mg]
Solvent: CCOCC
Solvent: ClCc1ccccc1
Product: O=C(Cc1ccccc1)c1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2-bromo-4-fluorobenzonitrile, 6.0 g. (0.03 mole) in 35 ml. of absolute ether is added dropwise to a stirred solution of benzylmagnesium chloride prepared from 2.9 g. (0.12 g. atom) of magnesium turnings and 15.2 g. (0.12 mole) of benzyl chloride in 65 ml. of absolute ether in a nitrogen atmosphere. The mixture is stirred at room temperature for about 18 hours. After cooling in an ice-bath, the adduct is hydrolyzed by the dropwise addition of 100 ml. of 0.5 M. citric acid. The organic phase is separated and the aqueous phase re-extracted with several portions of benzene. The combined organic layers are extracted with 45 ml. of ice-cold 6 N hydrochloric acid in several portions and the combined acid extracts are heated on the steam bath for 45 minutes. The product separates as an oil and is extracted into benzene. Evaporation of the washed and dried benzene extract leaves the yellow oily product that is purified by distillation; b.p. 112°-115° C./0.05 mm.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.[C:19]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:22]([CH:25]=O)=[CH:21][CH:20]=1.C(O)(=O)C.[BH3-]C#N.[Na+]>CN1C(=O)N(C)CC1.CO>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([NH:1][CH2:25][C:22]4[CH:23]=[CH:24][C:19]([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)=[CH:20][CH:21]=4)[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CN1CCN(C)C1=O
Solvent: CC(=O)O
Solvent: CO
Product: Clc1cccc(Nc2ncnc3[nH]nc(NCc4ccc(-c5ccccc5)cc4)c23)c1
Temperature: 50 °C

Procedure:
Under a nitrogen atmosphere, 261 mg (1.00 mmol) of 3-amino-4-(3-chlorophenylamino)-1 H-pyrazolo[3,4-d]pyrimidine (see Step 1.6), 273 mg (1.5 mmol) of biphenyl-4-carbaldehyde and 180 mg of acetic acid are stirred in 39 ml of DMEU/methanol (1:2) at RT for 1 hour. 440 mg (7 mmol) of NaCNBH3 are then added and the reaction mixture is heated to 50° C. After 15 hours a further 440 mg of NaCNBH3 are added and the reaction mixture is stirred at boiling temperature for 15 hours, then poured into 0.6 liter of a 1% aqueous K2B4O7.4H2O solution and stirred overnight to complete the reaction. The precipitated product is filtered off and washed with water. Heating in 20 ml of ethanol and filtration yield 4-(3-chloro-phenylamino)-3-(4-phenyl-benzylamino)-1H-pyrazolo[3,4-d]pyrimidine; m.p. 250-252° C.; HPLC: tRet(grad20-100/20=14.1; FAB-MS: (M+H)+=427.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[Br:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](Cl)=[O:28])=[CH:22][CH:21]=1>C1COCC1>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:27](=[O:28])[CH2:26][C:23]1[CH:24]=[CH:25][C:20]([Br:19])=[CH:21][CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)Cc1ccc(Br)cc1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(Cc1ccc(Br)cc1)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 80.5 %

Procedure:
To a round bottom flask contained (R)-4-benzyl-2-oxazolidinone (800 mg, 4.51 mmol) in THF (10 mL), n-BuLi (2.83 mL, 1.6M, 4.52 mmol) was added at −78° C., dropwise. The solution was stirred at −78° C. for 10 min. A solution of 2-(4-bromophenyl)acetyl chloride (1.0 g, 4.28 mmol) in 10 mL THF was added. The solution was stirred −78° C. for 30 min, and rt for 3 h, and then was quenched with sat. NH4Cl and extracted with EtOAc (3×20 mL). The organic layer washed with brine, dried (Na2SO4), and concentrated. Purification via flash chromatography (0-30% EtOAc in hexanes) gives 76A (1.29 g, 80%). MS (ESI) m/z 374.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:21][CH2:22][CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[C:5]([O:7][CH3:8])=[O:6].[O:31]1[C:35]2[CH:36]=[CH:37][C:38]([S:40](Cl)(=[O:42])=[O:41])=[CH:39][C:34]=2[O:33][CH2:32]1>N1C=CC=CC=1.C1(C)C=CC=CC=1>[O:31]1[C:35]2[CH:36]=[CH:37][C:38]([S:40]([NH:1][C:2]3[CH:3]=[C:4]([CH:9]=[C:10]([O:21][CH2:22][CH2:23][O:24][CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)[C:11]=3[O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[C:5]([O:7][CH3:8])=[O:6])(=[O:41])=[O:42])=[CH:39][C:34]=2[O:33][CH2:32]1
Reactant: COC(=O)c1cc(N)c(Oc2ccccc2OC)c(OCCOC2CCCCO2)c1
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OCO2
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COC(=O)c1cc(NS(=O)(=O)c2ccc3c(c2)OCO3)c(Oc2ccccc2OC)c(OCCOC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1.04 g of methyl 3-amino-4-(2-methoxy-phenoxy)-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate were dissolved in pyridine (30 ml), treated dropwise while cooling with ice with a solution of 1.1 g of benzo[1,3]-dioxol-5-sulphonyl chloride in toluene (10 ml) and subsequently stirred at RT for 20 hours. The reaction mixture was poured on to ice/3M HCl, the product was extracted with ethyl acetate and the organic phase was dried over magnesium sulphate. After removing the solvent there was obtained the desired methyl 3-(benzo[1,3]dioxol-5-sulphonylamino)-4-(2-methoxy-phenoxy)-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate as a resin.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[N:5][N:4]([CH2:7][C:8]2[S:9][CH:10]=[C:11]([C:13](=[O:15])[CH3:14])[N:12]=2)[N:3]=1.[I:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[O:27][C:26]([CH3:28])=[N:25][C:24]=2[C:29](O)=[O:30])=[CH:19][C:18]=1[CH3:32]>>[C:13]([C:11]1[N:12]=[C:8]([CH2:7][N:4]2[N:3]=[C:2]([NH:1][C:29]([C:24]3[N:25]=[C:26]([CH3:28])[O:27][C:23]=3[C:20]3[CH:21]=[CH:22][C:17]([I:16])=[C:18]([CH3:32])[CH:19]=3)=[O:30])[CH:6]=[N:5]2)[S:9][CH:10]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)c1csc(Cn2ncc(N)n2)n1
Reactant: Cc1nc(C(=O)O)c(-c2ccc(I)c(C)c2)o1
Product: CC(=O)c1csc(Cn2ncc(NC(=O)c3nc(C)oc3-c3ccc(I)c(C)c3)n2)n1

Procedure:
Following general procedure A, starting from 1-(2-((4-amino-2H-1,2,3-triazol-2-yl)methyl)thiazol-4-yl)ethanone and 5-(4-iodo-3-methylphenyl)-2-methyloxazole-4-carboxylic acid. LC-MS-conditions 02: tR=1.12 min; [M+H]+=549.20.