Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][CH3:15])[C@H:10]([CH2:16][N:17]([CH:34]([CH3:36])[CH3:35])[C:18](=[O:33])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32])[CH:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:37]1([CH2:43][S:44](Cl)(=[O:46])=[O:45])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH3:15])[S:44]([CH2:43][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)(=[O:46])=[O:45])[C@H:10]([CH2:16][N:17]([CH:34]([CH3:36])[CH3:35])[C:18](=[O:33])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32])[CH:20]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CNC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CN(C(=O)c1ccc(OC)c(OCCCOC)c1)C(C)C
Reactant: O=S(=O)(Cl)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN(C)S(=O)(=O)Cc2ccccc2)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3R*,4R*)-3-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-4-methylaminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (89 mg, 0.175 mmol) in CH2Cl2 (3 mL), alpha-toluenesulfonyl chloride (40 mg, 0.21 mmol) and triethylamine (30 μL, 0.21 mmol) are added under N2 atmosphere. The mixture is stirred overnight at RT, diluted with CH2Cl2 and poured into an aqueous saturated solution of NaHCO3. The organic layer is separated, and the aqueous one is extracted twice with CH2Cl2. The combined organic extracts are dried over Na2SO4, filtered and concentrated. The crude product is purified by preparative HPLC (C18-ODB-AQ, 5 μm, 20×50 mm, YMC, eluent: CH3CN /H2O+0.1% HCOOH flow: 20 mL/min). The HPLC fractions are collected, and the resulting solution is lyophilized to afford the title product. TLC, Rf (CH2Cl2/MeOH 95:5)=0.3. tR (HPLC, Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 ml/min): 5.81 min.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][O:20][C:21]4[CH:25]=[CH:24][O:23][N:22]=4)[O:16][C:15]3=[O:26])=[CH:10][C:9]=2[F:27])[CH2:4][CH2:3]1.[OH:28][CH2:29][CH2:30][NH:31][NH2:32]>CO.ClCCl>[OH:28][CH2:29][CH2:30][NH:31][N:32]=[C:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][O:20][C:21]4[CH:25]=[CH:24][O:23][N:22]=4)[O:16][C:15]3=[O:26])=[CH:10][C:9]=2[F:27])[CH2:6][CH2:7]1
Reactant: O=C1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)CC1
Reactant: NNCCO
Solvent: ClCCl
Solvent: CO
Product: O=C1O[C@@H](COc2ccon2)CN1c1ccc(N2CCC(=NNCCO)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.5 %

Procedure:
3-(4-(4-Oxopiperidin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one (125 mg, 0.33 mmol) was dissolved in MeOH (5 ml) and dichloromethane (5 ml), 2-hydroxyethylhydrazine (29 mg, 0.37 mmol) added, and the mixture stirred at ambient temperature under nitrogen for 18 hours. The mixture was evaporated, and the residue purified by chromatography on a 5 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 1.5% MeOH in dichloromethane. Relevant fractions were combined to give the desired product (98 mg). MS (ESP): 434 (MH+) for C20H24FN5O5.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([NH:11]C(OC(C)(C)C)=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:19]1([CH:25]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[OH:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[NH2:11][CH:4]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH2:3][CH2:2][N:30]1[CH2:29][CH2:28][CH:27]([CH:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[OH:26])[CH2:32][CH2:31]1
Reactant: CC(C)(C)OC(=O)NC(CCBr)c1ccccc1
Reactant: OC(c1ccccc1)C1CCNCC1
Product: NC(CCN1CCC(C(O)c2ccccc2)CC1)c1ccccc1

Procedure:
The procedure given in Example 2 except for the formation of salts was followed using 3-bromo-1-(tert-butoxycarbonyl)amino-1-phenyl propane and phenyl-piperidin-4-yl-methanol as reactants, instead of d-1-bromo-2-(tert-butoxycarbonyl)amino-3-phenyl propane and hexamethyleneimine to give [1-(3-Amino-3-phenyl-propyl)-piperidin-4-yl]-phenyl-methanol.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([CH3:9])=[C:6]([F:8])[CH:7]=1.[F:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:8][C:6]1[CH:7]=[C:2]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([F:13])[CH:19]=2)[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]=1[CH3:9]
Reactant: Cc1c(F)cc(Br)cc1[N+](=O)[O-]
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCO
Product: Cc1c(F)cc(-c2cccc(F)c2)cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 75.3 %

Procedure:
A mixture of 5-bromo-1-fluoro-2-methyl-3-nitro-benzene (5.0 g, 21.31 mmol, 1.0 eq), 3-fluorophenylboronic acid (3.29 g, 23.8 mmol, 1.1 eq), Pd(PPh3)4 (1.2 g, 1.07 mmol, 0.05 eq) and K2CO3 (11.8 g, 85.5 mmol, 4 eq) in a mixture of dioxane (150 mL) and EtOH (50 mL) was heated at 80° C. under N2 overnight. After cooling to room temperature the reaction was poured into water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo to give the title compound as an oil (4.0 g, 75%). This material was used without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[S:8][C:9]([C:11]([O:13]C)=[O:12])=[CH:10][C:5]2=[N:4][CH:3]=1.[OH-].[Na+].O.C1C[O:21][CH2:20][CH2:19]1>CO>[CH2:20]([O:21][C:2]1[N:7]=[C:6]2[S:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:5]2=[N:4][CH:3]=1)[CH3:19]
Reactant: C1CCOC1
Reactant: COC(=O)c1cc2ncc(Cl)nc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCOc1cnc2cc(C(=O)O)sc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of methyl 3-chlorothieno[2,3-b]pyrazine-6-carboxylate 92 (0.044 mmol, 10 mg) in methanol 250 uL and THF 250 uL was added sodium hydroxide 2N in water (0.219 mmol, 109 μA) and stirred overnight at rt. The reaction mixture was quenched in 2N HCl and extracted with CH2Cl2/methanol (9/1). The organic layer was dried and concentrated under reduced pressure to give 3-ethoxythieno[2,3-b]pyrazine-6-carboxylic acid 97 (9.3 mg, 100%).
Reaction SMILES: [Br:1]Br.[Cl:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]>ClCCl>[Br:1][CH:6]([CH2:5][CH2:4][Cl:3])[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: BrBr
Reactant: O=C(CCCCl)c1ccccc1
Solvent: ClCCl
Product: O=C(c1ccccc1)C(Br)CCCl
Reaction time: 0.25 h

Procedure:
Bromine (10 g.) was added dropwise to a stirred solution of 4-chlorobutyrophenone (9.7 g.) in dichloromethane (25 ml.), and the mixture was stirred for a further 15 minutes, then evaporated to dryness under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed twice with water then with brine, dried and evaporated to dryness to give α-bromo-4-chlorobutyrophenone as an oil.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=4)[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH:29]1[CH2:34][CH2:33][CH:32]([NH:35]C(=O)OC(C)(C)C)[CH2:31][CH2:30]1>>[CH3:22][N:20]1[CH:21]=[C:17]([C:14]2[CH:15]=[C:16]3[C:8]([C:6]4[N:7]=[C:2]([N:29]5[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]5)[CH:3]=[CH:4][CH:5]=4)=[N:9][NH:10][C:11]3=[CH:12][N:13]=2)[CH:18]=[N:19]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Cn1cc(-c2cc3c(-c4cccc(F)n4)nn(C4CCCCO4)c3cn2)cn1
Product: Cn1cc(-c2cc3c(-c4cccc(N5CCC(N)CC5)n4)n[nH]c3cn2)cn1
Yield: 36.8 %

Procedure:
Following the procedures as described in Example 189, 3-(6-fluoropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and tert-butyl piperidin-4-ylcarbamate were reacted and the product was deprotected to give 174 as a white solid (36.8% over two steps). 1H NMR (400 MHz, DMSO) δ 1H NMR (400 MHz, DMSO) δ 9.03 (d, J=1.2 Hz, 1H), 8.54 (d, J=1.3 Hz, 1H), 8.12 (s, 1H), 7.82 (s, 1H), 7.63 (dd, J=8.4, 7.5 Hz, 1H), 7.41 (d, J=7.3 Hz, 1H), 6.86 (d, J=8.5 Hz, 1H), 4.37 (d, J=13.1 Hz, 2H), 3.91 (s, 3H), 3.51-3.20 (m, 3H), 3.14-3.04 (m, 2H), 2.96-2.83 (m, 1H), 1.87 (d, J=9.9 Hz, 2H), 1.45-1.27 (m, 2H). LC/MS: m/z 375.1 [M+1]
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([C:27](O)=[O:28])[CH2:23][CH2:22]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:4][C:3]=1[Cl:30].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1>C(N(CC)CC)C>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][C@H:21]4[CH2:22][CH2:23][C@H:24]([C:27]([N:53]5[CH2:58][CH2:57][O:56][CH2:55][CH2:54]5)=[O:28])[CH2:25][CH2:26]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:4][C:3]=1[Cl:30]
Reactant: C1COCCN1
Reactant: Nc1c(Cl)cc(Nc2ncnc3cnc(N[C@H]4CC[C@H](C(=O)O)CC4)nc23)cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Product: Nc1c(Cl)cc(Nc2ncnc3cnc(N[C@H]4CC[C@H](C(=O)N5CCOCC5)CC4)nc23)cc1Cl

Procedure:
Prepared from 4-[(4-amino-3,5-dichlorophenyl)amino]-6-[(trans-4-carboxycyclohexyl)amino]pyrimido[5,4-d]pyrimidine by reaction with O-(benzotriazol-1-yl)-N,N,N',N',-tetramethyluronium tetrafluoroborate, triethylamine and morpholine. Melting point: 204°-207° C.; Rf : 0.53 (silica gel; petroleum ether/ethyl acetate/methanol=10:10:4)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:28]=[CH:29][CH:30]=1)[CH2:12][NH:13][CH2:14][CH2:15][NH:16][C@H:17]([CH:25]([CH3:27])[CH3:26])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[C:33](Cl)(Cl)=[O:34]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:28]=[CH:29][CH:30]=1)[CH2:12][N:13]1[CH2:14][CH2:15][N:16]([C@H:17]([CH:25]([CH3:26])[CH3:27])[C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[C:33]1=[O:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[C@@H](NCCNCc1cccc(OCc2ccccc2)c1)C(=O)OC(C)(C)C
Reactant: O=C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)[C@H](C(=O)OC(C)(C)C)N1CCN(Cc2cccc(OCc3ccccc3)c2)C1=O
Temperature: 0 °C
Reaction time: 6 h
Yield: 62.2 %

Procedure:
t-Butyl (R)-2-(2-(3-benzyloxybenzylamino)ethylamino)-3-methylbutyrate (155 mg; 0.37 mmol) was dissolved in toluene (5 ml) and cooled to 0° C. NaOH (1N; 5 ml; 5 mmol) was added, as was phosgene (20% in toluene; 0.37 ml; 0.75 mmol). The mixture was stirred at 0° C. for 6 h, the phases were separated, and the aqueous phase was extracted with CH2Cl2 (2×; 5 ml). The combined organic phases were dried over MgSO4, and the solvents were removed under reduced pressure. Purification of the residue by column chromatography (SiO2) resulted in t-butyl (R)-2-(3-(3-benzyloxybenzyl)-2-oxoimidazolidin-1-yl)-3-methylbutyrate (102 mg; 0.23 mmol). MS: 439.25 (M+H); Rt: 2.12 min (method: gradient 0 min 96% H2O (0.05% TFA) 2.0 min 95% acetonitrile, 95% acetonitrile to 2.4 min, 4% acetonitrile 2.45 min; flow rate 1 ml/min; column 0.4 μL (YMC J'sphere ODS H80 20X2 1.4μ); 30° C.)
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2.I[CH:14]([CH3:16])[CH3:15].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[C:3]([O:12][CH:14]([CH3:16])[CH3:15])=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2
Reactant: CC(C)I
Reactant: O=C1NCc2ccc(O)c(Cl)c21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc2c(c1Cl)C(=O)NC2
Temperature: 80 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
A mixture of 7-chloro-6-hydroxy-2,3-dihydro-isoindol-1-one (500 mg, 2.72 mmol), 2-iodopropane (556 mg, 3.27 mmol), and cesium carbonate (1.33 mg, 4.08 mmol) in DMF (20 mL) was stirred at 80° C. overnight. The solution was cooled to room temperature and the reaction mixture partitioned between ethyl acetate (50 mL) and water (50 mL). The organic phase was separated, washed with water (50 mL) and brine (50 mL), dried over sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography (silica gel, heptanes/EtOAc) to give 7-chloro-6-isopropoxy-2,3-dihydro-isoindol-1-one (133a, 300 mg, 65% yield) as a solid.
Reaction SMILES: [C:1]([CH:3]([OH:18])[CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)#[N:2].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[C:1]([CH:3]([O:18][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:4][CH:5]1[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH2:9][CH2:10]1)#[N:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CC(O)C#N)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CC(C#N)OS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
To a solution of tert-butyl 4-(2-cyano-2-hydroxyethyl)piperidine-1-carboxylate (67.0 g) and triethylamine (35.0 g) in dichloromethane (500 mL) was slowly added a solution of methanesulfonyl chloride (36.3 g) in dichloromethane (200 mL). The reaction system was stirred at room temperature for 2 hr, and added to ice water (300 mL). The organic layer was dried over anhydrous sodium sulfate, insoluble material was removed by filtration, and the filtrate was concentrated to give the title compound (80.0 g).
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:11]([OH:13])=O)[CH2:6][CH2:7][C:8](=[O:10])[NH2:9])(=[O:3])[CH3:2].C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[N:41]=[C:40]([OH:42])[C:39]([C:43]([OH:45])=[O:44])=[CH:38][N:37]=2)=[CH:32][CH:31]=1.CN1CCOCC1>CN(C)C=O>[C:1]([NH:4][CH:5]([C:11]([NH:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]2[N:41]=[C:40]([OH:42])[C:39]([C:43]([OH:45])=[O:44])=[CH:38][N:37]=2)=[CH:34][CH:35]=1)=[O:13])[CH2:6][CH2:7][C:8](=[O:10])[NH2:9])(=[O:3])[CH3:2]
Reactant: Nc1ccc(-c2ncc(C(=O)O)c(O)n2)cc1
Reactant: CC(=O)N[C@@H](CCC(N)=O)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(=O)NC(CCC(N)=O)C(=O)Nc1ccc(-c2ncc(C(=O)O)c(O)n2)cc1
Temperature: 5 °C
Reaction time: 3 h
Yield: 86.2 %

Procedure:
A solution of 14.1 g (75 mmol) of N-acetyl-L-glutamine and 9.75 ml (75 mmol) of triethylamine in 150 ml of dimethylformamide is stirred at -15° to -20° C. and 9.75 ml (75 mmol) of isobutylchloroformate is added. After stirring at -15° to -20° C. for 30 min a cold solution of 11.6 g (50 mmol) of 2-(4-aminophenyl)-4-hydroxy-5-pyrimidine carboxylic acid and 7.15 ml (50 mml) of N-methylmorpholine in 200 ml of dimethylformamide is added at -15° C. The reaction mixture is stirred at -15° for 20 min at 5° C. for 3 hrs, and at room temperature overnight. The reaction mixture is evaporated and the residue treated with water. The pH is lowered to 2.5 with hydrochloric acid and the solid is filtered, washed with water, and dried to afford 17.3 g of 2-[4-(N-acetyl-DL-glutaminylamino)phenyl]4-hydroxy-5-pyrimidine carboxylic acid; mp 247°-248° C. dec. [α]23D -2.8° (c0.7, DMSO)
Reaction SMILES: ClC1N=C(NC(C2C=CC3C(=CC=CC=3)C=2)C)N=C(N)N=1.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+].[NH2:31][CH:32]([CH2:36][N:37]1[CH:41]=[CH:40][C:39]([C:42]2[N:47]=[C:46]([NH2:48])[N:45]=[C:44]([NH:49][CH:50]([C:52]3[CH:61]=[CH:60][C:59]4[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=4)[CH:53]=3)[CH3:51])[N:43]=2)=[N:38]1)[C:33]([OH:35])=[O:34]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:31][C@@H:32]([CH2:36][N:37]1[CH:41]=[CH:40][C:39]([C:42]2[N:47]=[C:46]([NH2:48])[N:45]=[C:44]([NH:49][C@@H:50]([C:52]3[CH:61]=[CH:60][C:59]4[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=4)[CH:53]=3)[CH3:51])[N:43]=2)=[N:38]1)[C:33]([OH:35])=[O:34]
Reactant: CC(Nc1nc(N)nc(-c2ccn(CC(N)C(=O)O)n2)n1)c1ccc2ccccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(Nc1nc(N)nc(Cl)n1)c1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC#N
Product: C[C@@H](Nc1nc(N)nc(-c2ccn(C[C@H](N)C(=O)O)n2)n1)c1ccc2ccccc2c1
Temperature: 150 °C

Procedure:
6-Chloro-N-[1-naphthalen-2yl-ethyl]-[1,3,5]triazine-2,4-diamine (30 mg, 0.1 mmol), 2-boc-protected amino-3-{3-[4,4,5,5,-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propionic acid (50 mg, 0.15 mmol), 1 ml of acetonitrile, and 0.7 ml of water. Aqueous sodium carbonate (0.3 ml and 1N) was added to a microwave vial, followed by 5 mol percent of dichlorobis(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated to 150° C. for 5 minutes with microwave. After cooling, the reaction mixture was evaporated to dryness, the residue was dissolved in 2.5 ml of methanol, and then was purified with Prep-LC to give 6.8 mg of boc protected 2-amino-3-{3-[4-amino-6-(1-naphthalen-2-yl-ethylamino)[1,3,5]triazin-2-yl]-pyrazol-1-yl}proionic acid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.[CH:12]1[C:17]([NH2:18])=[CH:16][CH:15]=[C:14]([OH:19])[CH:13]=1>C(O)C>[OH:19][C:14]1[CH:15]=[CH:16][C:17]([NH:18][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[N:4][N:3]=2)=[CH:12][CH:13]=1
Reactant: Nc1ccc(O)cc1
Reactant: Clc1nncc2ccccc12
Solvent: CCO
Product: Oc1ccc(Nc2nncc3ccccc23)cc1

Procedure:
This example describes the synthesis of a compound having the formula ##STR62## A mixture of 2.00 g (12.1 mmol) of 1-chlorophthalazine and 2.64 g (24.2 mmol) of p-aminophenol in 40 ml of absolute ethanol was heated to reflux for 2 h. The precipitate was collected and successively washed with a saturated solution of NaHCO3 and water. The product was crystallized from methanol: mp 245°-247° C. The HCl salt had a mp>300° C.; the IR and NMR spectra were consistent with the assigned structure and the elemental analysis was consistent with the empirical formula (C14H11N3O.HCl).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.I[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:8]=[CH:7]2
Reactant: Cc1cccc2cc[nH]c12
Reactant: Ic1ccccc1
Product: Cc1cccc2ccn(-c3ccccc3)c12

Procedure:
Prepared by Procedure C and Scheme O using 7-methyl-1H-indole and iodobenzene: ESMS m/e: 208.1 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([Cl:11])[O:8][CH:7]=1)=[O:5])C.[OH-].[Na+]>C(O)C>[Cl:11][C:9]1[O:8][CH:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=1
Reactant: CCOC(=O)c1coc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1coc(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 69 %

Procedure:
5-Trimethylsilyl-3-furancarboxylic acid (4.1 g) (synthesized in accordance with the method described in Tetrahedron Lett., 25, 4451 (1984)) was dissolved in tetrahydrofuran (100 ml), and N,N-dimethylformamide (3 drops) was added. Oxalyl chloride (3.0 g) was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Ethanol (100 ml) and triethylamine (4.7 g) were added, and the resulting mixture was stirred at room temperature for 15 hours. The mixture as concentrated under reduced pressure, and water was added to the residue. The mixture was extracted with ethyl acetate, and the extract was washed with water and saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 5-trimethylsilyl-3-furancarboxylic acid ethyl ester (3.0 g) as oil. 5-Trimethylsilyl-3-furancarboxylic acid ethyl ester (3.0 g) was dissolved in acetonitrile (15 ml), and sulfuryl chloride (2.0 g) in acetonitrile (5 ml) was added dropwise. The mixture was stirred at room temperature for 30 minutes, poured into ice water and extracted with diethyl ether. The extract was washed with 10% aqueous sodium thiosulfate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 5-chloro-3-furancarboxylic acid ethyl ester (1.9 g) as oil. 5-Chloro-3-furancarboxylic acid ethyl ester (1.9 g) was dissolved in ethanol (15 ml), and 1N aqueous sodium hydroxide (12 ml) was added. The mixture was stirred at room temperature for 1.5 hour and concentrated under reduced pressure. The residue was dissolved in water and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous magensium sulfate and concentrated under reduced pressure. Precipaitated crystals were collected by filtration and washed with hexane to give 5-chloro-3-furancarboxylic acid (1.1 g) as crystals.
Reaction SMILES: [CH3:1][CH:2]([CH3:26])[CH2:3][C:4]1([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]1=[O:17].[Li+].CC([N-]C(C)C)C.[CH2:35]=[O:36]>C1COCC1>[OH:36][CH2:35][CH:18]([C:4]1([CH2:3][CH:2]([CH3:26])[CH3:1])[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:5]1=[O:17])[C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20]
Reactant: CC(C)CC1(CC(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Reactant: C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)CC1(C(CO)C(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Temperature: -78 °C
Yield: 116.4 %

Procedure:
A cold (-78° C.) solution of tert-butyl 3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate (EXAMPLE 1, step 3; 2.00 g, 5.56 mmol) in dry THF (20 mL) is treated with the dropwise addition of LDA (3.20 mL, 6.40 mmol, 2.0N). The solution is maintained at -78° C. for 30 min and then warmed to -30° C. Gaseous formaldehyde (generated by heating 834 mg of paraformaldehyde at 160° C. to provide approximately 28 mmol) is bubbled through the enolate solution. The solution is maintained at -30° C. for 1 hour and then quenched with saturated aqueous NH4Cl (5 mL) and diluted with H2O (20 mL). The product is extracted into EtOAc (3×50 mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to provide 2.52 g of a yellow solid which is purified by silica gel chromatography (100 g SG; 25% EtOAc/hexane) to give 1.43 g (83%) of the title compound as a golden oil. Another fraction containing 375 mg of a mix of both diastereomers is also recovered. Spectral data for the title compound: