Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[NH2:27].[Br:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41](O)=[O:42]>>[Br:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([NH:27][C:26]1[CH:28]=[C:29]([O:33][CH3:34])[C:30]([O:31][CH3:32])=[C:24]([O:23][CH3:22])[CH:25]=1)=[O:42]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: O=C(O)CCCCCBr
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Product: COc1cc(NC(=O)CCCCCBr)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 39.4 %

Procedure:
WSC (2.11 g, 11 mmols) and HOBt (1.68 q, 11 mmols) were added to a (15 ml) solution of 3,4,5-trimethoxyaniline (2.75 g, 15 mmols) and 6-bromohexanoic acid (1.95 g, 10 mmols), and stirred at room temperature for 12 hours. The reaction mixture was extracted with ether, The organic layer was washed with water, 1 N HCl, an aqueous saturated solution of sodium hydrogencarbonate and saturated saline in that order, and dried with anhydrous magnesium sulfate, and the solvent was evaporated. Then, the residue was purified through silica, gal column chromatography (developer:hexane/acetone=5/1), and the resulting crystals were recrystallized from ether-hexane to obtain 1.42 g (yield: 40%) of 6-bromo-N-(3,4,5-trimethoxyphenyl) hexanamide colorless needle-like crystals.
Reaction SMILES: C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26]O[CH2:24][CH2:23]1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36](=[O:57])[NH:37][C:38]2[CH:56]=[CH:55][C:41]([O:42][C:43]3[C:44]4[CH:51]=[C:50]([C:52](O)=[O:53])[NH:49][C:45]=4[N:46]=[CH:47][N:48]=3)=[CH:40][CH:39]=2)=[CH:31][CH:30]=1.[Cl-].[NH4+]>C(N(CC)CC)C.CN(C)C=O>[CH2:27]([N:22]([CH2:23][CH3:24])[CH2:21][CH2:20][CH2:19][NH:18][C:52]([C:50]1[NH:49][C:45]2[N:46]=[CH:47][N:48]=[C:43]([O:42][C:41]3[CH:55]=[CH:56][C:38]([NH:37][C:36]([NH:35][C:32]4[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=4)=[O:57])=[CH:39][CH:40]=3)[C:44]=2[CH:51]=1)=[O:53])[CH3:26]
Reactant: O=C(Nc1ccc(F)cc1)Nc1ccc(Oc2ncnc3[nH]c(C(=O)O)cc23)cc1
Reactant: NCCCN1CCOCC1
Agent: [Cl-]
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)CCCNC(=O)c1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ncnc2[nH]1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
After adding 0.8 ml of dimethylformamide, 21 μl of triethylamine, 9.5 μl of diphenylphosphoryl azide (DPPA) and 6.5 μl of 4-(3-aminopropyl)morpholine to 12 mg of the 4-{4-[3-(4-fluorophenyl)ureido]phenoxy)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid synthesized in Production Example 164, the mixture was stirred at room temperature for 2 days. Saturated ammonium chloride was added, liquid separation and extraction were performed with an ethyl acetate-tetrahydrofuran mixed solvent, and the organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered with plug cotton and concentrated to dryness to obtain 9 mg of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][N:11]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=2)[C:12](=[O:25])[C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([Cl:23])[C:14]=2[F:24])[CH:5]=[CH:6][C:7]=1[F:8].[CH2:37](B(O)O)[CH2:38][CH3:39]>>[C:33]([C:30]1[CH:31]=[CH:32][C:27]([CH2:26][N:11]([CH2:10][CH2:9][C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([CH2:37][CH2:38][CH3:39])[CH:3]=2)[C:12](=[O:25])[C:13]2[CH:18]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:16]=[C:15]([Cl:23])[C:14]=2[F:24])=[CH:28][CH:29]=1)([CH3:34])([CH3:36])[CH3:35]
Reactant: CC(C)(C)c1ccc(CN(CCc2ccc(F)c(Br)c2)C(=O)c2cc(C(F)(F)F)cc(Cl)c2F)cc1
Reactant: CCCB(O)O
Product: CCCc1cc(CCN(Cc2ccc(C(C)(C)C)cc2)C(=O)c2cc(C(F)(F)F)cc(Cl)c2F)ccc1F

Procedure:
The title compound was prepared in analogy to example 3, using N-[2-(3-bromo-4-fluoro-phenyl)-ethyl]-N-(4-tert-butyl-benzyl)-3-chloro-2-fluoro-5-trifluoromethyl-benzamide (Example B178) and n-propylboronic acid. 552.2 [ISP (M+H)+]
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:6]2[C:7]([O:12][C:13]3[N:18]=[CH:17][C:16]([NH2:19])=[CH:15][N:14]=3)=[CH:8][CH:9]=[C:10]([CH3:11])[C:5]=2[O:4][CH2:3]1.[CH3:21][C:22]([O:25][C:26]([NH:28][C@H:29]([CH2:33][CH3:34])[C:30](O)=[O:31])=[O:27])([CH3:24])[CH3:23].CCN(CC)CC.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C(OCC)(=O)C>[CH3:1][C:2]1([CH3:20])[C:6]2[C:7]([O:12][C:13]3[N:14]=[CH:15][C:16]([NH:19][C:30]([C@H:29]([NH:28][C:26](=[O:27])[O:25][C:22]([CH3:24])([CH3:23])[CH3:21])[CH2:33][CH3:34])=[O:31])=[CH:17][N:18]=3)=[CH:8][CH:9]=[C:10]([CH3:11])[C:5]=2[O:4][CH2:3]1
Reactant: Cc1ccc(Oc2ncc(N)cn2)c2c1OCC2(C)C
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1cnc(Oc2ccc(C)c3c2C(C)(C)CO3)nc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 57.6 %

Procedure:
2-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-5-pyrimidinamine (Intermediate 33, 220 mg, 0.81 mmol) was dissolved in ethyl acetate (10 mL) and of (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)butanoic acid (181.1 mg, 0.89 mmol) was added followed by the addition of Et3N (0.35 mL, 2.02 mmol). The resulting solution was cooled down to 5° C. and a solution of T3P 50% w/w in ethyl acetate (0.53 mL, 0.89 mmol) was added drop wise in 15 min. The reaction mixture was stirred for 30 min at 5° C. The reaction was quenched with water (50 mL) and ethyl acetate (50 mL), two phases were separated and the organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography on silica gel using cyclohexane/ethyl acetate 60:40 as eluent affording the title compound (213 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][C@H:18]3[CH3:24])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.BrC1C=C(NC2C=CC(N3CCNC[C@@H]3C)=CN=2)C(=O)N(C)C=1>>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][C@@H:18]3[CH3:24])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: C[C@@H]1CN(C)CCN1c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Agent: C[C@H]1CNCCN1c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Product: C[C@H]1CN(C)CCN1c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Yield: 75 %

Procedure:
Following the procedures as described for compound 109e, (S)-5-bromo-1-methyl-3-(5-(2-methylpiperazin-1-yl)pyridin-2-ylamino)pyridin-2(1H)-one (377 mg, 1 mmol) was methylated by reductive formylation to give 110a as a white solid (294 mg, 75%). LCMS: [M+H]+ 393. See FIG. 10.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:14])[NH:10][CH2:11][CH2:12]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[C:19]#[N:20].C(=O)([O-])[O-].[Ca+2].[I-].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH2:1]([O:8][C:9]([NH:10][CH2:11][CH2:12][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[C:19]#[N:20])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cccc(O)c1
Reactant: O=C(NCCBr)OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CN(C)C=O
Product: N#Cc1cccc(OCCNC(=O)OCc2ccccc2)c1

Procedure:
8 g of benzyl-N-(2-bromoethyl)carbamate, 3.7 g of 3-hydroxybenzonitrile, 4.3 g of calcium carbonate, 5.1 g of potassium iodide and 1.1 g of tetrabutylammonium iodide were stirred in dimethylformamide at 60° C. After the treatment with ethyl acetate as the extractant in an ordinary manner, the product was purified by the silica gel column chromatography to obtain 3-[2-(benzyloxycarbonylamino)ethoxy]benzonitrile. Acetic acid containing 20% of hydrogen bromide was added to the product under cooling with ice, and the resultant mixture was stirred at room temperature for 2 hours. The solvent was evaporated, and the residue was washed with ethyl acetate to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([NH:12][C:13](=[O:15])[CH3:14])=[S:11].[C:16](=O)([O-])[O-].[Na+].[Na+].CI>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10](=[N:12][C:13](=[O:15])[CH3:14])[S:11][CH3:16]
Reactant: CC(=O)NC(=S)Nc1c(Cl)cccc1Cl
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CI
Solvent: CC(C)=O
Product: CSC(=NC(C)=O)Nc1c(Cl)cccc1Cl
Reaction time: 10 h

Procedure:
5.2 g (0.02 M) of N-(2,6-dichlorophenyl)-N'-acetylthiourea, 1.3 g (0.012 M) of sodium carbonate, 1.5 ml (0.024 M) of methyliodide and 200 ml of acetone are boiled under energetic shaking for 10 hours. The acetone is distilled off and the residue is washed and then filtered. After drying 4.9 g (88.5% from the theoretical yield of N-(2,6-dichlorophenyl)-N'-acetyl-S-methylisothiourea are obtained with a melting point 135-139° C. After recrystallization from ethanol, the melting point of the product is 139°-141° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].[CH3:12][C:13]([CH:15]=O)=O>O>[CH3:15][C:13]1[CH:12]=[N:11][C:6]2[C:7](=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:10]=1
Reactant: CC(=O)C=O
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Solvent: O
Product: Cc1cnc2cc([N+](=O)[O-])ccc2n1
Temperature: 80 °C
Reaction time: 4 h
Yield: 59.7 %

Procedure:
To a suspension of 4-nitro-1,2-phenylenediamine (10.0 g) in water (150 mL) was added dropwise a 40% aqueous solution of pyruvic aldehyde (11.76 g) at room temperature. The reaction solution was stirred at 80° C. for 4 hours, and cooled to room temperature. Water (200 mL) was added to the mixture, and the mixture was extracted with chloroform (150 mL×3). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residual solid was recrystallized from ethanol, collected by filtration, and dried to give 2-methyl-6-nitroquinoxaline (7.38 g, 60%) as red solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH2:11][C:12](=O)[CH3:13])[N:4]=1.Cl.[CH3:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23]N.C(OCC)(=O)C.O>C1(C)C=CC=CC=1.[Cl-].[Zn+2].[Cl-].C(OCC)(=O)C.CCCCCC>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([C:11]2[C:19]3[C:18](=[C:17]([CH3:16])[CH:22]=[CH:21][CH:20]=3)[NH:23][C:12]=2[CH3:13])[N:4]=1
Reactant: COc1cc(OC)nc(CC(C)=O)n1
Reactant: Cc1ccccc1NN
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(OC)nc(-c2c(C)[nH]c3c(C)cccc23)n1
Yield: 34.2 %

Procedure:
In 20 ml of toluene were dissolved 0.77 g (3.9 m moles) of 1-(4,6-dimethoxypyrimidine-2-yl)-2-propanone and 0.69 g (4.3 m moles) of 2-methylphenylhydrazine hydrochloride. Thereto was added 0.64 g (4.7 m moles) of zinc chloride, followed by refluxing for 2 hours. The reaction mixture was allowed to cool, and then ethyl acetate and water were added to dissolve the whole reaction mixture. The oily layer was washed with water, separated and dried over Glauber's salt. The resulting oily layer was concentrated under reduced pressure using a rotary evaporator, to obtain an orange solid. The solid was treated with ethyl acetate/n-hexane to obtain 0.38 g (1.34 m moles) of 3-(4,6-dimethoxypyrimidine-2-yl)-2,7-dimethylindole. Yield: 34% Melting point: 145 to 147° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2/[CH:20]=[CH:21]/[C:22]([O:24][CH2:25][CH3:26])=[O:23])[C@H:12]([CH3:27])[N:11]1[C:28](=[O:38])[CH2:29][C:30]1[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=1[Cl:37])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CO.[B-](F)(F)(F)F.CC(C)P([C]1[CH][CH][CH][CH]1)C(C)C.CC(C)P([C]1[CH][CH][CH][CH]1)C(C)C.C1CC=CCCC=C1.[Fe].[Rh]>[Si:1]([O:8][CH2:9][C@H:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C@H:12]([CH3:27])[N:11]1[C:28](=[O:38])[CH2:29][C:30]1[C:31]([Cl:37])=[CH:32][CH:33]=[CH:34][C:35]=1[Cl:36])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CCOC(=O)/C=C/c1cccc2c1C[C@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)Cc1c(Cl)cccc1Cl)[C@H]2C
Agent: [Fe]
Agent: [Rh]
Agent: C1=C\CC/C=C\CC/1
Solvent: CO
Solvent: C1=CCCC=CCC1
Product: CCOC(=O)CCc1cccc2c1C[C@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)Cc1c(Cl)cccc1Cl)[C@H]2C
Yield: 91.3 %

Procedure:
In the dry box to a 85 ml Parr autoclave with stir bar and glass liner, add 1,1′-bis(di-i-propylphosphino)ferrocene(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate (7 mg, 0.010 mmol). Add ethyl (2E)-3-{(1S,3R)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-[(2,6-dichlorophenyl)acetyl]-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl}prop-2-enoate (133 mg, 0.23 mmol) as a solution in anhydrous methanol (5 mL). Seal the autoclave and remove from the dry box. Purge the vessel with hydrogen and pressurize to 690 kPa of hydrogen. Stir at room temperature overnight. Vent and open the vessel. Concentrate the reaction mixture under reduced pressure. Purify the residue by silica gel chromatography, eluting with 25% methyl t-butyl ether:hexanes to give the title compound as a clear colorless oil (121 mg, 0.21 mmol). MS (m/z): 578 (M+1).
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].N12CCN(CC1)CC2>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C:19]2[NH:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:18]=2[CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: Nc1ccccc1I
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Pd+2]
Agent: C1CN2CCN1CC2
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2[nH]c3ccccc3c2C1
Temperature: 110 °C
Yield: 17.3 %

Procedure:
General Method: A mixture of 2-iodoaniline (0.315 g, 1.44 mmol), 4-oxo-1-piperidinecarboxylic acid tert-butyl ester (0.860 g, 4.31 mmol), 1,4-diazabicyclo[2.2.2]octane (Dabco™) (0.483 mL, 4.31 mmol) and palladium acetate (0.016 g, 0.072 mmol) in dry DMF (7 mL) was degassed via vacuum/argon purging, and then it was heated to 110° C. for 3.5 h. The reaction mixture was subsequently cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was separated, dried (MgSO4), filtered and evaporated to dryness. The residue was chromatographed (SiO2/hexanes:ethyl acetate, 1:1) to give the title compound (0.068 g, 17%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.88 (s, 1H), 7.45 (d, J=7.6 Hz, 1H), 7.31 (d, J=7.6 Hz, 1H), 7.12 (m, 2H), 4.64 (s, 2H), 3.82 (s, 2H), 2.82 (s, 2H), 1.50 (s, 9H); LCMS: m/e 273 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:3]=1[O:4]C(C)C([O-])=O.ClC1C=C([N+]([O-])=O)C=CC=1O.C1(O)C=CC=CC=1.C1N(CCCS(O)(=O)=O)CCOC1.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].O=C(CCC([O-])=O)C([O-])=O>CS(C)=O>[N+:14]([C:12]1[CH:13]=[CH:2][C:3]([OH:4])=[CH:10][CH:11]=1)([O-:16])=[O:15]
Reactant: CC(Oc1ccc([N+](=O)[O-])cc1Cl)C(=O)[O-]
Agent: O=C([O-])CCC(=O)C(=O)[O-]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)(O)CCCN1CCOCC1
Solvent: CS(C)=O
Solvent: Oc1ccccc1
Product: O=[N+]([O-])c1ccc(O)cc1
Reaction time: 0.17 h

Procedure:
A convenient assay of AAD-13 was devised using 2-(2-chloro,4-nitrophenoxy)propionate (CNPP) as substrate. Cleavage of CNPP by AAD-13 will release 2-chloro,4-nitrophenol. This phenol has a bright yellow absorbance at 410 nm at pH 7 enabling the reaction to be followed continuously or by endpoint analysis. The presence of AAD-13 activity can be monitored visually without the need for addition of further reagents. Microplate-based spectrophotometric assays were performed in a total volume of 0.2 ml 20 mM MOPS pH 6.75 containing 200 μM NH4FeSO4, 200 μM sodium ascorbate, 1 mM α-ketoglutarate, the appropriate amount of CNPP (added from a 10 mM stock made up in DMSO), and enzyme. Assays are initiated by addition of CNPP, enzyme, or α-ketoglutarate at time zero and the increase in absorbance followed for 10 min at 410 nm in a microplate reader. The first 2 min of the reaction will be used to determine initial rates. A calibration curve performed under standard assay conditions (200 μl final assay volume) indicated that an absorbance at 410 nm of 0.1 was obtained from 25.1 μM 2-chloro, 4-nitrophenol. Using this assay, the kinetic constants for CNPP as a substrate were determined to be Km=31±5.5 μM and kcat=16.2±0.79 min−1.
Reaction SMILES: [C:1]1([CH:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>O>[C:1]1([CH:7]2[CH2:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]2=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C(Cc1ccccc1)c1ccccc1
Solvent: O
Product: O=C1c2ccccc2CC1c1ccccc1
Reaction time: 0.75 h

Procedure:
Polyphosphoric acid (50 g) was heated in an oil bath at 140-145° C. and 2,3-diphenyl-propanoic acid (2.5 g) was added. Heating was continued for 45 min. Water was added. The mixture was cooled and extracted with ethyl acetate. The organic extracts were washed with 1 M NaOH solution and water. After drying the solvent was evaporated under reduced pressure. The product thus obtained was further purified by trituration in heptane.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]([CH2:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)#[N:25]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:30]4[CH:31]=[CH:32][C:27]([CH2:26][C:24]#[N:25])=[CH:28][CH:29]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#CCc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4ccc(CC#N)cc4)ncc3O2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 4-(cyanomethyl)phenylboronic acid following a procedure analogous to that described in Example 28. LC (method 7): tR=1.22 min; Mass spectrum (ESI+): m/z=420 [M+H]+.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[CH2:19][CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CN1C(=O)N(C)CCC1.[CH3:42][O:43][C:44]1[CH:45]=[C:46]([CH:49]=[CH:50][CH:51]=1)[CH2:47]I>C1COCC1>[C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:47][C:46]2[CH:49]=[CH:50][CH:51]=[C:44]([O:43][CH3:42])[CH:45]=2)[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: COc1cccc(CI)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CCC(=O)O1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: COc1cccc(C[C@@H]2C[C@@H]([C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)OC2=O)c1

Procedure:
In analogy with Example 44c), 1.5 g of 5(S)-[l(S)-(Boc-amino)-2-phenylethyl]-dihydrofuran-2-(3H)-one [Example 2b)] in 3 ml of abs. THF are deprotonated (-75° C.) with 9.62 ml of a 1M solution of lithium bis(trimethylsilyl)amide in THF, and with the addition of 0.998 ml of DMPU and alkylated with 1.22 g of 3-methoxybenzyl iodide. Chromatography on silica gel (eluent E) affords the pure title compound. TLC Rf (hexane/ethyl acetate, 2.5:1)=0.32. FAB-MS (M+H)+ =426.
Reaction SMILES: ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([OH:19])=O.C(N(CC)CC)C.C1(OC2C=CC=CC=2)C=CC=CC=1.[NH2:43][C:44]1[N:49]=[CH:48][C:47]([N+:50]([O-:52])=[O:51])=[CH:46][N:45]=1>C(OCC)(=O)C.C(OCC)C>[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([NH:43][C:44]1[N:49]=[CH:48][C:47]([N+:50]([O-:52])=[O:51])=[CH:46][N:45]=1)=[O:19]
Reactant: Nc1ncc([N+](=O)[O-])cn1
Reactant: O=C(O)c1cccc(Cl)c1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCOCC
Product: O=C(Nc1ncc([N+](=O)[O-])cn1)c1cccc(Cl)c1
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 99.6 %

Procedure:
Triphosgene (5.63 g, 19 mmol) was added to an ice cold solution of 3-chlorobenzoic acid (17.76 g, 114 mmol) and triethylamine (16 ml, 114 mmol) in ethyl acetate (250 ml). The reaction was stirred for 15 min then 1 hour at ambient temperature. The mixture was filtered to remove triethylamine hydrochloride then concentrated in vacuo. Diphenyl ether (16 g) and 2-amino-5-nitropyrimidine (4 g, 28.6 mmol) were added, mixed and heated 20 hours at 150° C. The mixture was cooled and diluted with diethylether (100 ml). Collected of the solid by suction filtration yielded, 2-(N-3-chlorobenzoyl)amino-5-nitropyrimidine (7.94 g, 100% yield) as a beige solid:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[CH2:13][CH2:14][N:15]([CH3:17])[CH2:16][C:11]3=[C:10]([C:18]([OH:20])=O)[N:9]=2)=[C:4]([F:21])[CH:3]=1.CCN(C(C)C)C(C)C.[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([S:38]([NH2:41])(=[O:40])=[O:39])=[CH:34][CH:33]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[CH2:13][CH2:14][N:15]([CH3:17])[CH2:16][C:11]3=[C:10]([C:18]([NH:31][C:32]3[CH:37]=[CH:36][C:35]([S:38](=[O:40])(=[O:39])[NH2:41])=[CH:34][CH:33]=3)=[O:20])[N:9]=2)=[C:4]([F:21])[CH:3]=1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: CN1CCn2c(-c3ccc(Cl)cc3F)nc(C(=O)O)c2C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCn2c(-c3ccc(Cl)cc3F)nc(C(=O)Nc3ccc(S(N)(=O)=O)cc3)c2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The carboxylic acid intermediate 18D (400 mg) and DIEA (600 μL) were dissolved in DMF (10 mL). An aliquot of this stock solution (400 μL) was dispensed into a vial charged with 4-aminobenzene-sulfonamide (0.10 mmol). TBTU was added (0.50 mmol) to the vial and the mixture was stirred at room temperature for 2 hours. The crude mixture was purified by prep LC-MS using a gradient elution of 5% to 95% MeCN/water in 15 min. The product was taken up with DCM and diluted with hexanes. Evaporation under nitrogen flow gave the desired product, Compound 208 as a solid. LCMS (+ESI) m/z 464 [M+H]+
Reaction SMILES: [Li]CCCC.[CH2:6]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:15]=2)[C:10]1=[O:22])[CH2:7][CH3:8].[CH3:23][C:24]([O:27][C:28](/[N:30]=[N:31]/[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:29])([CH3:26])[CH3:25].O>O1CCCC1>[CH3:26][C:24]([O:27][C:28]([NH:30][N:31]([C:9]1([CH2:6][CH2:7][CH3:8])[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:15]=2)[C:10]1=[O:22])[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:29])([CH3:23])[CH3:25]
Reactant: CCCC1Cc2cc(C(F)(F)F)ccc2C1=O
Reactant: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCC1(N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)Cc2cc(C(F)(F)F)ccc2C1=O
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
To a solution of diisopropropylamine (1.3 mL, 9.1 mmol) in 30 mL tetrahydrofuran cooled to −78° C. was added 6.0 mL n-BuLi (1.6M, 9.5 mmol). The mixture was allowed to warm to −20° C. over 20 min, then re-cooled to −78° C. A solution of the product from Step C (2.0 g, 8.3 mmol) in 15 mL tetrahydrofuran was added dropwise. After 30 min, a solution of di-tert-butylazodicarboxylate (2.1 g, 9.1 mmol) in 20 mL tetrahydrofuran was added dropwise. The reaction was allowed to slowly warm to RT and stirred overnight. Water was added and the mixture was extracted with ethyl acetate, dried (MgSO4), filtered and concentrated. The residue was purified by chromatography on silica gel eluting with 10% ethyl acetate/hexane to afford 2.92 g of a white solid, m.p. 135-137° C.