Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[N:22]([C:24](Br)=[C:25]([CH3:27])[N:26]=4)[N:23]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH:36](B1OB(C=C)OB(C=C)O1)=[CH2:37].C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[N:22]([C:24]([CH:36]=[CH2:37])=[C:25]([CH3:27])[N:26]=4)[N:23]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CB1OB(C=C)OB(C=C)O1
Reactant: Cc1nc2cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nn2c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: C=Cc1c(C)nc2cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nn12
Reaction time: 0.5 h

Procedure:
200 mg (0.375 mmol) {1-[4-(3-Bromo-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamic acid tert.-butyl ester, intermediate example Int-2-3, 90.3 mg (0.375 mmol) 2,4,6-trivinyl-cyclotriboroxane, 43 mg (0.038 mmol) tetrakis triphenylphosphine palladium(0) and 51.8 mg (0.375 mmol) potassium carbonate in 2.9 mL dimethoxyethane and 1 mL water were heated in a microwave vial at 110° C. for 16 hours. The reaction mixture was poured on water/saturated ammonium chloride/dichloromethane and vigorously stirred for 30 minutes. The organic phase was separated and the aqueous phase extracted once more with dichloromethane. The combined organic extracts were washed twice with brine, dried, and the solvent was removed. The crude product (244 mg) was used in the next step without further purification.
Reaction SMILES: Cl.[N:2]1([C:8]2[N:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[N:18]=[C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:20][C:21]=3[C:22]([F:25])([F:24])[F:23])=[O:16])=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[C:39](Cl)(=[O:41])[CH3:40]>C(Cl)Cl>[C:39]([N:5]1[CH2:6][CH2:7][N:2]([C:8]2[N:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[N:18]=[C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:20][C:21]=3[C:22]([F:24])([F:25])[F:23])=[O:16])=[CH:10][CH:9]=2)[CH2:3][CH2:4]1)(=[O:41])[CH3:40]
Reactant: O=C(Nc1ccc(N2CCNCC2)nc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cn2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-piperazin-1-yl-pyridin-3-yl)-amide hydrochloride salt (65 mg, 0.13 mmol) in methylene chloride (5 mL) was added triethylamine (0.15 mL). The mixture was cooled in an ice bath and acetyl chloride (12 μL) was added. The mixture was stirred at room temperature for 30 minutes and partitioned between methylene chloride and brine. The organic layer was dried over sodium sulfate and the solvents were evaporated. The residue was first dried in vacuum and then triturated with methanol (3 mL) to give 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-yl)-pyridin-3-yl]-amide (21 mg) as a solid. LC-MS calcd for C22H20F3N5O3 (m/e) 459.2, obsd 460.0 (M+H). The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].[CH3:14]N(C=O)C.S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:14][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:2]([F:1])[CH:3]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 70 °C
Reaction time: 16 h
Yield: 97 %

Procedure:
To a 500 ml flask under nitrogen atmosphere was charged 3-fluoro-4-nitro benzoic acid (10 g, 0.054 mol, 1 eq) and 250 ml of Toluene followed by DMF (210 ul, 3.7 mmol, 0.05 eq) and was heated to 70° C. At 40° C. thionyl chloride (8.0 ml, 0.11 mol, 2.0 eq) was added and the reaction was allowed to stir at 70° C. for 16 hours. The reaction was removed from the heat and placed in an ambient temperature bath. 100 ml of anhydrous methanol was added and then concentrated on rotary evaporator under reduced pressure, and bath temp of 45° C. The final volume was reduced to ˜70 ml and slowly add hexane 100 ml with stiring to yield a light yellow solid, yield 97%. 1H NMR (Solvent CDCl3), Singlet, 3 H, 3.99 ppm, Doublet of Doublets, 2H, 7.95 ppm, Triplet, 1H, 8.15 ppm. Thin Layer Chromatography elution 5% methanol/dichloromethane, Rf=0.9.
Reaction SMILES: C[O-].[Na+].C(O)(=O)C.[CH:8]([NH2:10])=[NH:9].C[O:12][C:13](=O)[CH:14]([CH2:18][CH2:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:15](=O)[CH3:16].C(O)(=O)C>CO>[CH2:21]([O:20][CH2:19][CH2:18][C:14]1[C:13]([OH:12])=[N:9][CH:8]=[N:10][C:15]=1[CH3:16])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)C(CCOCc1ccccc1)C(C)=O
Reactant: N=CN
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ncnc(O)c1CCOCc1ccccc1
Reaction time: 0.25 h

Procedure:
NaOMe (2.75 g, 50 mmol) is added to a stirred solution of formamidine acetate (25 mmol) in MeOH (75 ml) at room temperature. The mixture is stirred for 15 minutes. 2-(2-Benzyloxy-ethyl)-3-oxo-butyric acid methyl ester (20 mmol) is added and the mixture is stirred at room temperature overnight. Acetic acid (1.5 g, 20 mmol) is added and the solvent is removed in vacuo. Water (30 ml) is added to the residue and the mixture is extracted with 2-butanone (3×30 ml). The combined extracts are washed with brine (40 ml), dried (Na2SO4) and evaporated, to provide a yellow solid (160).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.[C:20]([CH2:22][C:23](Cl)=[O:24])#[N:21]>O1CCCC1>[C:20]([CH2:22][C:23]([NH:4][C:3]1[CH:5]=[C:6]([N+:10]([O-:12])=[O:11])[C:7]([CH3:9])=[CH:8][C:2]=1[CH3:1])=[O:24])#[N:21]
Reactant: N#CCC(=O)Cl
Reactant: Cc1cc(C)c([N+](=O)[O-])cc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C)c([N+](=O)[O-])cc1NC(=O)CC#N
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of 76.6 g (0.455 mol) of 2,4-dimethyl-5-nitroaniline and 64 ml (0.46 mol) triethylamine in 500 ml abs. tetrahydrofurane is added dropwise within 1 h 47.2 g (0.455 mol) cyanoacetyl chloride in 100 ml tetrahydrofurane. After stirring for 2 h at 25° C. and 3 h at 80° C. and cooling to 25° C. the reaction mixture is filtered and poured into water. The precipitate is separated, washed with water and toluene/petrolether and dried. Yield: 84 g (78%) N-cyanoacetyl-2,4-dimethyl-5-nitroaniline, mp. 229°-230° C.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.[CH2:11]([O:13][C:14]1[CH:28]=[CH:27][C:17]([O:18][C:19]2[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=2)=[CH:16][CH:15]=1)[CH3:12]>C(Cl)(Cl)Cl>[CH2:11]([O:13][C:14]1[CH:28]=[CH:27][C:17]([O:18][C:19]2[CH:26]=[CH:25][C:22]([CH2:23][NH:24][C:8]([C:4]3[S:3][C:2]([CH3:1])=[N:6][C:5]=3[CH3:7])=[O:10])=[CH:21][CH:20]=2)=[CH:16][CH:15]=1)[CH3:12]
Reactant: CCOc1ccc(Oc2ccc(CN)cc2)cc1
Reactant: Cc1nc(C)c(C(=O)O)s1
Solvent: ClC(Cl)Cl
Product: CCOc1ccc(Oc2ccc(CNC(=O)c3sc(C)nc3C)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
To a stirred mixture of 2,4-dimethyl-1,3-thiazole-5-carboxylic acid (156 mg, 0.993 mM) and chloroform (20 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimde (190 mg, 0.393 mM) at 0°-10° C., and the mixture was stirred for 30 min at the same temperature. To this was added a solution (10 ml) of 4-(4-ethoxyphenoxy)benzylamine (242 mg, 0.993 mM) in chloroform at 0°-10° C., and the mixture was stirred for 12 h at the room temperature. The mixture was poured into ice water, and the mixture was extracted with chloroform. The extract was washed with saturated ammonium chloride solution and brine, dried with magnesium sulfate, and concentrated in vacuo. The residue was chromatographed over silica gel to give N-[4-(4-ethoxyphenoxy)benzyl]-2,4-dimethyl-1,3-thiazole-5-carboxamide (171 mg, 45%) as colorless crystals, m.p. 99°-101° C.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:9]=1)=[O:7]>O1CCCC1.O>[C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:9]=1)([OH:7])=[O:5]
Reactant: COC(=O)c1cn(-c2ccnc3ccccc23)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cn(-c2ccnc3ccccc23)c2ccccc12
Yield: 117.6 %

Procedure:
0.37 g (8.84 mmol) of lithium hydroxide monohydrate and 45 cm3 of water are added at 25° C. to 0.89 g (2.95 mmol) of 3-methoxycarbonyl-1-(quinol-4-yl)-1H-indole dissolved in 45 cm3 of tetrahydrofuran. After stirring at reflux for 17 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in 30 cm3 of water and then triturated with 8.8 cm3 of N hydrochloric acid. After filtering off and drying the solid residue under reduced pressure (2.7 kPa) at 40° C., 1 g of 3-carboxy-1-(quinol-4-yl)-1H-indole is obtained in the form of a yellow solid. Mass spectrum (EI): m/e 288 (M+·), m/e 243.
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[O:5][CH2:4][C:2]1=[O:3].[OH:8][C@H:9]1[C@H:14](OC2CCC(=O)C=2)[C:13]2[CH:22]=[C:23]([C:26]#[N:27])[CH:24]=[CH:25][C:12]=2[O:11][C:10]1([CH3:29])[CH3:28].[H-].[Na+]>O1CCCC1>[OH:8][C@H:9]1[C@H:14]([O:3][C:2]2[CH2:4][O:5][C:6](=[O:7])[CH:1]=2)[C:13]2[CH:22]=[C:23]([C:26]#[N:27])[CH:24]=[CH:25][C:12]=2[O:11][C:10]1([CH3:29])[CH3:28]
Reactant: O=C1COC(=O)C1
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](OC2=CC(=O)CC2)[C@@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](OC2=CC(=O)OC2)[C@@H]1O

Procedure:
601 mg of tetronic acid and 1.01 g of the epoxide of example 1 are reacted analogously to example 6 with 180 mg of sodium hydride (80%) and 747 mg of borontrifluoride-diethyletherate in tetrahydrofurane. Usual work up yields white crystalls of the title compound. m.p. 111°-114° C. (dichloromethane/ether)
Reaction SMILES: C(OC([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:19]=2)=[CH:14][C:13]=1[CH2:31][CH3:32])=O)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:22][CH2:23]2)=[CH:14][C:13]=1[CH2:31][CH3:32]
Reactant: CCc1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)ccc1NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Reaction time: 18 h
Yield: 61 %

Procedure:
tert-Butyl 4-(4-(((benzyloxy)carbonyl)amino)-3-ethylphenyl)-5,6-dihydropyridine-1(2H)-carboxylate (I39) (0.500 g, 1.14 mmol) was dissolved in ethanol (20 mL), and a slurry of 10% Pd/C (0.25 g) in ethanol (2 mL) was added. The mixture was stirred under hydrogen for 18 hours, then filtered through celite, washing the celite with ethanol (30 mL). The combined filtrates were evaporated, and chromatography (12 g silica cartridge, 0-80% ethyl acetate/petroleum benzine 40-60° C.) gave the title compound (I40) (0.212 g, 61% yield) as a pink syrup; 1H NMR (400 MHz, CDCl3) δ 6.90 (d, J=2.0 Hz, 1H), 6.87 (dd, J=8.0, 2.1 Hz, 1H), 6.63 (d, J=8.0 Hz, 1H), 4.21 (s, 2H), 3.55 (s, 2H), 2.78 (t, J=12.2 Hz, 2H), 2.59-2.46 (m, 3H), 1.78 (d, J=13.2 Hz, 2H), 1.66-1.53 (m, overlaps with water), 1.48 (s, 9H), 1.25 (t, J=7.5 Hz, 3H). LCMS Method C: rt 5.33 min; m/z 249.2 [M-tBu+2H]+, 205.2 [M-Boc+2H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)=[O:7].[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28]([CH:30]3[CH2:32][CH2:31]3)=[O:29])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1>>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:22]=[C:23]([NH:27][C:28]([CH:30]4[CH2:31][CH2:32]4)=[O:29])[CH:24]=[CH:25][CH:26]=3)[CH2:17][CH2:16]2)=[CH:9][CH:10]=1
Reactant: O=C(CCCCCl)c1ccc(Cl)cc1
Reactant: O=C(Nc1cccc(C2CCNCC2)c1)C1CC1
Product: O=C(CCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1)c1ccc(Cl)cc1

Procedure:
Prepared by Procedure K and Scheme B1 using 5-chloro-1-(4-chlorophenyl)-1-pentanone and N-[3-(4-piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e: 439.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.[N:11]([O-])=[O:12].[Na+]>Cl.O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([N:11]=[O:12])[CH2:6][CH2:5]2
Reactant: O=N[O-]
Reactant: Cc1ccc2c(c1)CCN2
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1ccc2c(c1)CCN2N=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 98.7 %

Procedure:
5-Methylindoline (1.0 g, 7.5 mmol) was stirred in 3N HCl (20 mL) at 0° C. Sodium nitrite (0.621 g, 9.0 mmol) in water (2 mL) was added dropwise and the mixture was stirred at 0° C. for 5 min. followed by RT for 20 min. The reaction mixture was extracted with DCM (500 mL), and the organic layer was dried over sodium sulfate and concentrated under vacuum to obtain 1.2 g of 5-methyl-1-nitrosoindoline.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[C:21]([CH2:22][C@@H:23]5[CH2:27][CH2:26][NH:25][CH2:24]5)=[N:20][NH:19][C:18]4=[O:28])=[CH:13][CH:12]=3)=[CH:10][C:5]=2[CH:4]=[CH:3]1.C(N(CC)C(C)C)(C)C.[C:38](Cl)(=[O:41])[CH2:39][CH3:40]>ClCCl>[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[C:21]([CH2:22][C@@H:23]5[CH2:27][CH2:26][N:25]([C:38](=[O:41])[CH2:39][CH3:40])[CH2:24]5)=[N:20][NH:19][C:18]4=[O:28])=[CH:13][CH:12]=3)=[CH:10][C:5]=2[CH:4]=[CH:3]1
Reactant: O=c1[nH]nc(C[C@@H]2CCNC2)n1-c1ccc(-c2ccc3occc3c2)cc1
Reactant: CCC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(=O)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4occc4c3)cc2)C1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 60.9 %

Procedure:
Under nitrogen, a mixture of 4-[4-(1-benzofuran-5-yl)phenyl]-5-[(3S)-3-pyrrolidinylmethyl]-2,4-dihydro-3H-1,2,4-triazol-3-one hydrochloride (116 mg, 0.292 mmol) and N,N-diisopropylethylamine (0.15 mL, 0.88 mmol) in dichloromethane (1.3 mL) was stirred at room temperature for 2 min. The mixture was cooled to 0° C. and treated with propionyl chloride (0.026 mL, 0.292 mmol) dropwise by syringe. The mixture became a dark brown solution and the reaction was stirred at 0° C. for 90 min. The reaction was quenched with water (2 mL) and diluted with ethyl acetate (20 mL). The mixture was transferred to a separatory funnel, water (10 mL) was added and the layers were separated. The pH of the aqueous layer was tested by pH paper and found to be pH˜5-6. The aqueous layer was extracted with ethyl acetate (10 mL). The organic layers were combined, dried over magnesium sulfate and concentrated in vacuo to give a tan foamy solid. Purification of the residue by silica gel chromatography (Analogix IF280, SF10-4 g, 0-10% MeOH/EtOAc, 30 min) provided the title product as an ivory solid (74 mg, 61%). MS(ES)+ m/e 417.2 [M+H]+.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[C:9]([C:11](=[O:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[S:14]([CH3:17])(=[O:16])=[O:15])(=[O:3])[CH3:2].[CH3:18][N:19]([CH:21](OC)OC)[CH3:20]>CN(C=O)C>[C:1]([O:4][C:5]1[CH:10]=[C:9]([C:11](=[O:13])/[CH:12]=[CH:18]/[N:19]([CH3:21])[CH3:20])[CH:8]=[CH:7][C:6]=1[S:14]([CH3:17])(=[O:16])=[O:15])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(C(C)=O)ccc1S(C)(=O)=O
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CC(=O)Oc1cc(C(=O)/C=C/N(C)C)ccc1S(C)(=O)=O
Yield: 27.7 %

Procedure:
A solution of 5-acetyl-2-(methylsulfonyl)phenyl acetate (1.5 g, 5.8 mmol) and DMF-DMA (1.2 g, 10 mmol) in DMF (20 mL) was stirred at 100° C. overnight. The reaction mixture was cooled, concentrated, and purified by flash column chromatography (PE/EtOAc=4:1˜2:1) to give the title compound (0.5 g, 30%). [M+H] Calc'd for C13H17NO4S, 284; Found, 284.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:9][CH2:10][CH2:11][C:5]2=[N:4][C:3]=1[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1.B(O)(O)[C:30]1[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[N:26]1[CH:27]=[CH:28][C:23]([C:3]2[N:4]=[C:5]3[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:6]3=[N:7][C:2]=2[C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)=[CH:24][CH:25]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CCOC(=O)CCCCCCN1CCCc2nc(-c3ccncc3)c(Cl)nc21
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
Product: CCOC(=O)CCCCCCN1CCCc2nc(-c3ccncc3)c(-c3ccc(C)cc3)nc21
Temperature: 150 °C

Procedure:
A mixture of ethyl 7-(3-chloro-2-(pyridin-4-yl)-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoate (step 3) (58 mg, 0.144 mmol), p-tolylboronic acid (39.1 mg, 0.288 mmol) and potassium carbonate (59.7 mg, 0.432 mmol) in dioxane (2 ml) was degassed by bubbling nitrogen through (×3). Pd(Ph3P)4 (33.3 mg, 0.029 mmol) was added and the mixture was degassed by bubbling nitrogen through (×3). The mixture was heated at 150° C. for 2 hours using microwave irradiation. The mixture was diluted with water and extracted with EtOAc (×2). The combined extracts were washed with brine, dried (MgSO4) and evaporated under vacuum. The crude product was purified by chromatography on silica eluting with 50-100% EtOAc in iso-hexane followed by 5-10% THF in DCM. The fractions were evaporated under vacuum and the residue was purified by ion exchange using a Isolute SCX-2 cartridge, loading and washing with methanol and eluting with 2M NH3 in MeOH to afford the title compound;
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[N:6][CH:7]=1.[NH2:11][CH2:12][C:13]([CH3:16])([OH:15])[CH3:14].C(N(C(C)C)C(C)C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C1COCC1>[OH:15][C:13]([CH3:16])([CH3:14])[CH2:12][NH:11][C:8]([C:3]1[C:2]([NH2:1])=[CH:7][N:6]=[CH:5][N:4]=1)=[O:10]
Reactant: Nc1cncnc1C(=O)O
Reactant: CC(C)(O)CN
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)CNC(=O)c1ncncc1N
Temperature: 25 °C
Reaction time: 21 h
Yield: 71.3 %

Procedure:
To a stirred mixture of 5-aminopyrimidine-4-carboxylic acid (200 mg, 1.44 mmol) and 1-amino-2-methylpropan-2-ol (128 mg, 1.44 mmol) at rt in THF (5 ml) under an argon atmosphere were added N-ethyldiisoproplyamine (743 mg, 978 μl, 5.75 mmol) and 1-propanephosphonic acid cyclic anhydride (2.29 g, 2.16 ml, 3.59 mmol). The mixture was stirred at rt for 21 hrs, then concentrated. The crude product was purified by column chromatography with EtOAc/MeOH as eluent providing the title compound (216 mg, 72%) as off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[S:11](Cl)(=[O:13])=[O:12].[Cl:15][C:16]1[CH:28]=[N:27][C:19]2[NH:20][C:21]3[CH2:26][CH2:25][NH:24][CH2:23][C:22]=3[C:18]=2[CH:17]=1.O>N1C=CC=CC=1>[Cl:15][C:16]1[CH:28]=[N:27][C:19]2[NH:20][C:21]3[CH2:26][CH2:25][N:24]([S:11]([C:4]4[CH:5]=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:3]=4[O:2][CH3:1])(=[O:13])=[O:12])[CH2:23][C:22]=3[C:18]=2[CH:17]=1
Reactant: COc1ccc(OC)c(S(=O)(=O)Cl)c1
Reactant: Clc1cnc2[nH]c3c(c2c1)CNCC3
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(OC)c(S(=O)(=O)N2CCc3[nH]c4ncc(Cl)cc4c3C2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
2,5-Dimethoxybenzenesulfonyl chloride (63 mg, 0.26 mmol) was added to a solution of 3-chloro-6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrole (50 mg, 0.24 mmol) in pyridine (2 mL), and the reaction was stirred overnight at room temperature. The reaction mixture was added to water (20 mL), and the resulting precipitate was filtered and dried under vacuum to provide 36 (94 mg, 96% yield) as a yellow solid. LC-MS (M+H=408, obsd.=408).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]#[C:10][C:11]([F:14])([F:13])[F:12].[C:15]([CH2:17][CH2:18][N:19]([CH:24]=O)[CH2:20]C(O)=O)#[N:16]>C(OC(=O)C)(=O)C>[C:15]([CH2:17][CH2:18][N:19]1[CH:24]=[C:10]([C:11]([F:14])([F:12])[F:13])[C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])=[CH:20]1)#[N:16]
Reactant: FC(F)(F)C#Cc1cccc(Cl)c1Cl
Reactant: N#CCCN(C=O)CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: N#CCCn1cc(-c2cccc(Cl)c2Cl)c(C(F)(F)F)c1

Procedure:
23.9 g of 2,3-dichloro-(3,3,3-trifluoropropyn-1-yl)-benzene and 15.6 g of N-(2-cyanoethyl)-N-formylglycine are dissolved in 100 ml of acetic anhydride, and the solution is refluxed for 24 h. The mixture is concentrated by evaporation under reduced pressure; the residue is then taken up in toluene, and purified by chromatography through silica gel. The solvent is evaporated off, and from the eluate is obtained 1-(2-cyanoethyl)-3-(2,3-dichlorophenyl)-4-trifluoromethylpyrrole, m.p. 83°-85° C. from ether/hexane (compound No. 3.28).
Reaction SMILES: [OH:1][C:2]1[C:12]([C:13](=[O:16])[CH2:14][CH3:15])=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7]C)=[O:5].[CH:17]1([C:20](Cl)=[O:21])[CH2:19][CH2:18]1>>[CH:17]1([C:20]([O:1][C:2]2[C:12]([C:13](=[O:16])[CH2:14][CH3:15])=[CH:11][CH:10]=[CH:9][C:3]=2[C:4]([O:6][CH3:7])=[O:5])=[O:21])[CH2:19][CH2:18]1
Reactant: CCOC(=O)c1cccc(C(=O)CC)c1O
Reactant: O=C(Cl)C1CC1
Product: CCC(=O)c1cccc(C(=O)OC)c1OC(=O)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
This compound was prepared in 2 steps. The first step was carried out according to the procedure of Intermediate CXXVII starting from ethyl 2-hydroxy-3-propionylbenzoate instead of methyl 2-hydroxy-3-propionylbenzoate and from cyclopropylcarbonyl chloride (prepared as described by G. B. Payne et al., J. Org. Chem. 22, 1680 (1957)) instead of 2-phenylbenzoyl chloride. The reaction was carried for 2 hours at 80° C. After cooling, to room temperature, the mixture was concentrated (in vacuo) to a small volume and added to water. The crude methyl 2-cyclopropylcarbonyloxy-3-propionylbenzoate so obtained was used for the second step without further purification.
Reaction SMILES: [NH2:1][C@H:2]([C:17]([OH:19])=[O:18])[CH2:3][CH2:4][C:5]([NH:7][C@H:8]([C:14]([OH:16])=[O:15])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:6].CC(C)=O.[C:24](Cl)(=[O:36])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].Cl>O.[OH-].[Na+]>[C:24]([NH:1][C@H:2]([C:17]([OH:19])=[O:18])[CH2:3][CH2:4][C:5]([NH:7][C@H:8]([C:14]([OH:16])=[O:15])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:6])(=[O:36])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: N[C@@H](CCC(=O)N[C@@H](CCC(=O)O)C(=O)O)C(=O)O
Reactant: CCCCCCCCCCCC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CCCCCCCCCCCC(=O)N[C@@H](CCC(=O)N[C@@H](CCC(=O)O)C(=O)O)C(=O)O
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
A suspension of 16 g (0.058 mols) of γ-glutamylglutamic acid in 55 ml of water was dissolved in a 27-% sodium hydroxide aqueous solution until the pH reached 11, and 27 ml of acetone were added thereto. To the solution were added dropwise 12.6 g (0.058 mole) of lauroyl chloride over a period of 1 hour. When adding lauroyl chloride, the temperature was maintained at 10° C., and 27-% sodium hydroxide was added dropwise simultaneously to keep the pH at 11. After the completion of the addition of lauroyl chloride, the reaction solution was warmed at 30° C., and allowed to stand for 30 minutes. Subsequently, the pH was adjusted to 1 with the addition of conc. hydrochloric acid. The solid precipitate was separated by filtration, and dried to obtain 23.6 g of N-(N'-lauroyl-γ-glutamyl)glutamic acid in a yield of 89%. This solid was analyzed by infrared spectrophotometry. A peak diagnostic of an amide group was observed at 1,640 cm-1 and a peak diagnostic of a carboxyl group was observed at 1,730 cm-1, respectively. FAB mass spectrum: 459 (MH+).