Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:5]=[C:4]([C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20])[CH:3]=1.[Br:25]N1C(=O)CCC1=O>ClCCl>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:5]=[C:4]([C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20])[C:3]=1[Br:25]
Reactant: COc1c(Cl)ccc(-c2nc(C(=O)OC(C)C)cc(N)c2F)c1F
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COc1c(Cl)ccc(-c2nc(C(=O)OC(C)C)c(Br)c(N)c2F)c1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 82.5 %

Procedure:
Propan-2-yl 4-amino-5-fluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl)picolinate (500 mg, 1.402 mmol) was dissolved in dichloromethane (3.2 mL). N-Bromo-succinimide (299 mg, 1.682 mmol) was added, and the solution was stirred at ambient temperature for 20 h. The reaction mixture was then concentrated to dryness. The residue was purified by chromatography (40 g silica gel column; 0-70% EtOAc-hexanes) to give a tan solid (504 mg, 83%): 1H NMR (400 MHz, DMSO-d6) δ 7.47 (dd, J=8.5, 1.6 Hz, 1H), 7.29 (dd, J=8.5, 7.1 Hz, 1H), 7.01 (s, 2H), 5.22-5.10 (m, 1H), 3.93 (d, J=0.9 Hz, 3H), 1.32 (d, J=6.3 Hz, 6H); EIMS m/z 350.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[N:11]=[C:10]2[C:18]2[C:19]([NH2:23])=[N:20][O:21][N:22]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br>ClCCl>[NH2:23][C:19]1[C:18]([C:10]2[N:9]([C:6]3[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=3)[C:17]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[N:11]=2)=[N:22][O:21][N:20]=1
Reactant: COc1ccc(-n2c(-c3nonc3N)nc3cnccc32)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Nc1nonc1-c1nc2cnccc2n1-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.7 %

Procedure:
To a solution of the product of Example 30 (100 mg, 0.32 mmol) in anhydrous dichloromethane (1.0 ml) stirred at 0° C., was added dropwise a 10M solution of boron tribromide (2.91 ml, 2.92 mmol) in dichloromethane and the mixture stirred at room temperature for 16 hours. The reaction was then quenched with water (20 ml), and the pH adjusted to 14 with 50% sodium hydroxide solution. The aqueous phase was washed with dichloromethane (×3), neutralised with 5N hydrochloric acid, and the resulting precipitate collected, washed with water (×3), diethyl ether and dried in vacuo to yield the title compound (59 mg, 62%); MS (ES+) m/e 295 [M+H]+.
Reaction SMILES: [OH-].[Na+].O1CCCC1.C([O:10][C:11]([C:13]1[C:22]2[C:17](=[CH:18]C=C(O)[CH:21]=2)[N:16]=[C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:14]=1)=[O:12])C.[C:30]([O:33][C:34](=[O:36])[CH3:35])(=O)[CH3:31]>ClCCl>[C:34]([O:33][C:30]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:31]=1)[N:16]=[C:15]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:14]=[C:13]2[C:11]([OH:12])=[O:10])(=[O:36])[CH3:35]
Reactant: CCOC(=O)c1cc(-c2ccccc2)nc2ccc(O)cc12
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)Oc1ccc2nc(-c3ccccc3)cc(C(=O)O)c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
An aqueous sodium hydroxide solution (0.3184 g/30.0 mL) was added to a tetrahydrofuran (30.0 mL) solution of 6-hydroxy-2-phenyl-4-quinolinecarboxylic acid ethyl ester (1.1120 g, 3.79 mmol) obtained above, and the mixture was stirred at room temperature for 3 hours. To the reaction solution, dichloromethane (30.0 mL) and acetic anhydride (2.0 mL) were added. The mixture was washed with water and saturated saline and dried over anhydrous sodium sulfate, and then, the solvent was distilled off. The obtained residue was purified by silica gel column chromatography to obtain the title compound (1.0903 mg, 3.55 mmol) as a pale yellow powder.
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]=[C:10]([N:12]3[CH2:17][CH2:16][CH:15]([C:18]([O:20]CC)=[O:19])[CH2:14][CH2:13]3)[O:11][C:7]=2[C:6]([N:23]2[CH2:27][CH2:26][C@H:25]([N:28]([CH3:30])[CH3:29])[CH2:24]2)=[C:5]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:4]=1[CH3:37])#[N:2].[OH-].[Na+].Cl>O1CCCC1>[C:1]([C:3]1[C:8]2[N:9]=[C:10]([N:12]3[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=[O:19])[CH2:14][CH2:13]3)[O:11][C:7]=2[C:6]([N:23]2[CH2:27][CH2:26][C@H:25]([N:28]([CH3:30])[CH3:29])[CH2:24]2)=[C:5]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:4]=1[CH3:37])#[N:2]
Reactant: CCOC(=O)C1CCN(c2nc3c(C#N)c(C)c(-c4ccccc4)c(N4CC[C@H](N(C)C)C4)c3o2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(N3CCC(C(=O)O)CC3)nc2c1C#N
Temperature: 25 °C
Reaction time: 19 h
Yield: 73.1 %

Procedure:
Ethyl 1-{4-cyano-7-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-5-methyl-6-phenyl-1,3-benzoxazol-2-yl}piperidine-4-carboxylate (I-162) (0.26 g, 0.52 mmol) was dissolved in tetrahydrofuran (10 ml), then 1 N sodium hydroxide (0.60 ml, 0.60 mmol) was added. After stirring at room temperature for 19 hours, 1 N sodium hydroxide (0.40 ml, 0.40 mmol) was further added, followed by stirring at room temperature for 24 hours. 1 N Hydrochloric acid (1.00 ml, 1.00 mmol) was added, then the solvent was evaporated away under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol:water=8:3:0.5), then ethanol and a small amount of ether were added, and the insoluble matter was collected by filtration to obtain a colorless solid (0.18 g, 71%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([NH2:7])=[CH:5][CH:6]=1.[N+:8]([C:11]1[CH:16]=[CH:15][C:14](Cl)=[CH:13][CH:12]=1)([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+]>[Cu].CN(C)C=O>[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([C:6]2[CH:5]=[C:4]([NH2:7])[SH:3]([C:14]3[CH:15]=[CH:16][C:11]([N+:8]([O-:10])=[O:9])=[CH:12][CH:13]=3)([C:14]3[CH:15]=[CH:16][C:11]([N+:8]([O-:10])=[O:9])=[CH:12][CH:13]=3)([C:14]3[CH:15]=[CH:16][C:11]([N+:8]([O-:10])=[O:9])=[CH:12][CH:13]=3)[C:2]=2[NH2:1])=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: Nc1ccc(N)s1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC1=CC(c2ccc([N+](=O)[O-])cc2)=C(N)[SH]1(c1ccc([N+](=O)[O-])cc1)(c1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Reaction time: 96 h

Procedure:
In 600 parts of dimethylformamide, 0.5 mol (60 parts) of 2,5-diaminothiophene, 2.3 mol (360 parts) of p-nitrochlorobenzene, 1.2 mol (170 parts) of anhydrous potassium carbonate and 10 parts of copper powder were refluxed with stirring for 4 days. After the reaction was completed, the reaction mixture was filtered, and the residue was thoroughly washed with dimethylformamide, water and acetone, and then dried. Thus, 105 parts of reddish brown tetrakis(p-nitrophenyl)-2,5-diaminothiophene was obtained.
Reaction SMILES: CS(C)=O.[C:5](Cl)(=[O:9])[C:6](Cl)=O.[O:11]1[C:17]2[CH:18]=[CH:19][CH:20]=C[C:16]=2[CH2:15][CH:14](CO)[CH2:13][CH2:12]1.C(N(CC)CC)C>C(Cl)Cl>[O:11]1[C:17]2=[CH:18][CH:19]=[CH:20][C:6]([CH:5]=[O:9])=[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: OCC1CCOc2ccccc2C1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=Cc1cccc2c1CCCCO2
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
DMSO (1.85 ml, 26 mmol) was added slowly to a -78° C. solution of oxalyl chloride in methylene chloride (10 ml of 2M, 20 mmol). To this solution was added slowly a solution of 2,3,4,5-tetrahydrobenzoxepin-4-methanol (2.3 g, 13 mmol) in methylene chloride, and the mixture was stirred 30 min at -78° C. Triethyl amine (7.53 ml, 52 mmol) was added slowly to the reaction mixture, which was then allowed to warm to room temperature. The mixture was diluted with methylene chloride (50 ml) and washed with water and then brine. The organic layer was concentrated in vacuo to an oil (2.28 g, 100%).
Reaction SMILES: [CH3:1]COCC.C[Si](C=[N+]=[N-])(C)C.[Cl:13][C:14]1[N:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17].CC(O)=O>C1COCC1.CO>[Cl:13][C:14]1[N:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:15]=1[C:16]([O:18][CH3:1])=[O:17]
Reactant: CCOCC
Reactant: Cc1ccc(C(=O)O)c(Cl)n1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)c1ccc(C)nc1Cl
Reaction time: 0.5 h
Yield: 93 %

Procedure:
A 2 M ether solution of (trimethylsilyl)diazomethane (30 mL, 60.0 mmol) was added to a solution of 2-chloro-6-methylnicotinic acid (8 g, 45.2 mmol) in THF (100 mL) and MeOH (25 mL) in a room temperature water bath. After 30 min, HOAc (2 mL) was added. The mixture was concentrated and purified by silica gel chromatography, eluting with 0-20% EtOAc in hexanes, to give methyl 2-chloro-6-methylnicotinate as colorless oil (7.77 g, 93% yield). MS (ES+) m/z: 186 (M+H); LC retention time: 2.64 min (analytical HPLC Method A).
Reaction SMILES: C([O:5][C:6]([C:8]1[N:16]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[C:15]2[C:10](=[N:11][C:12]([N:26](C(OC(C)(C)C)=O)[NH:27][C:28](OC(C)(C)C)=O)=[CH:13][CH:14]=2)[CH:9]=1)=[O:7])(C)(C)C.[CH3:42]C(O)=O>>[CH3:42][C:28]1[N:11]2[C:10]3[CH:9]=[C:8]([C:6]([OH:5])=[O:7])[N:16]([S:17]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)(=[O:19])=[O:18])[C:15]=3[CH:14]=[CH:13][C:12]2=[N:26][N:27]=1
Reactant: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc2c(cc(C(=O)OC(C)(C)C)n2S(=O)(=O)c2ccccc2)n1
Reactant: CC(=O)O
Product: Cc1nnc2ccc3c(cc(C(=O)O)n3S(=O)(=O)c3ccccc3)n12

Procedure:
A solution of di-tert-butyl 1-[2-(tert-butoxycarbonyl)-1-(phenylsulfonyl)-1H-pyrrolo[3,2-b]pyridin-5-yl]hydrazine-1,2-dicarboxylate (0.430 g, 0.730 mmol, from Step 2) in AcOH (7 mL) was heated in the microwave to a temperature of 180° C. for 3 minutes. The solid product was isolated by filtration and air dried, and used without further purification. Yield: (0.106 g, 41%). LCMS (M+H)+: 357.1.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:18][CH2:19][C:20]([OH:22])=[O:21]>O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:6][CH:5]=1
Reactant: Sc1ccc(Br)cc1
Reactant: O=C(O)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: O=C(O)CCSc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1.44 g (35.7 mmol) of NaOH in 20.0 ml degassed H2O (sparged with argon) was added 6.79 g (35.7 mmol) of 4-bromothiophenol. The resulting mixture was stirred at room temperature for 30 minutes. A second flask was charged with 2.26 g (16.3 mmol) of K2CO3 and 15 ml of degassed H2O. To this solution was added (in portions) 5.00 g (32.7 mmol) of 3-bromopropionic acid. The resulting potassium carboxylate solution was added to the sodium thiolate solution, and the resulting mixture stirred at room temperature for 48 hours. The mixture was filtered and the filtrate extracted with benzene, and the combined organic layers were discarded. The aqueous layer was acidified with 10% HCl and extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaCl, dried over MgSO4 and concentrated under reduced pressure. The resulting solid was recrystallized from Et2O-hexanes to give the title compound as off-white crystals. 1H NMR (CDCl3): δ 7.43 (2H, d, J=8.4 Hz), 7.25 (2H, d, J=8.4 Hz), 3.15 (2H, t, J=7.3 Hz), 2.68 (2H, t, J=7.3 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1([NH:24][C:25](=[O:34])[CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22](=[O:23])[N:5]2[C:6]([C:11]([O:13][CH2:14][O:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[O:12])=[C:7]([CH3:10])[C:8](=[O:9])[C@H:4]12.C(O)(=O)C>O1CCCC1.C1(C)C=CC=CC=1.[Zn]>[CH3:1][O:2][C:3]1([NH:24][C:25](=[O:34])[CH2:26][O:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:22](=[O:23])[N:5]2[CH:6]([C:11]([O:13][CH2:14][O:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[O:12])[CH:7]([CH3:10])[C:8](=[O:9])[C@H:4]12
Reactant: COC1(NC(=O)COc2ccccc2)C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(C)C(=O)[C@@H]21
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC1(NC(=O)COc2ccccc2)C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)C(C)C(=O)[C@@H]21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The freshly prepared pivaloyloxymethyl 6-methoxy-2-methyl-1-oxo-6-(2-phenoxyacetamido)carbapen-2-em-3-carboxylate of Method B, Example 25, was dissolved in the minimum necessary tetrahydrofuran and added to a slurry of specially activated zinc powder (Example 2; 500 mg.) in a mixture of 1 ml. acetic acid and 0.5 ml. of tetrahydrofuran maintained at 0° C. After stirring for 1 hour at 0° C., the reaction mixture was diluted with toluene, evaporated to dryness in vacuo and chased several times with toluene. The residue was redissolved in methylene chloride, zinc removed by filtration, and the filtrate reconcentrated to dryness in vacuo. The residue was taken up in ether, insoluble impurities removed by filtration and the filtrate again evaporated to dryness in vacuo to yield pivaloyloxymethyl 6-methoxy-2-methyl-1-oxo-6-(2-phenoxyacetamido)carbapenam-3-carboxylate [20 mg.; Rf 0.70 (4:1 chloroform:ethyl acetate)].
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[C:16]=2[CH2:22][CH3:23])(O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CC(O)=O>[CH2:1]([N:8]1[CH2:9][CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[C:16]=2[CH2:22][CH3:23])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1c(Br)cccc1C1(O)CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: CC(=O)O
Product: CCc1c(Br)cccc1C1=CCN(Cc2ccccc2)CC1
Yield: 84 %

Procedure:
To a solution of 1-benzyl-4-(3-bromo-2-ethyl-phenyl)-piperidin-4-ol (D116) (30 g, 80.15 mmol) in HOAc (300 mL) was added hydrochloric acid (45 mL, 37%). The reaction mixture was refluxed for 12 hr and concentrated in vacuo. The residue was purified by column chromatography to afford 1-benzyl-4-(3-bromo-2-ethyl-phenyl)-1,2,3,6-tetrahydro-pyridine (D117) (24 g). MS (ES): C20H22BrN requires 355. found 356 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][C:5]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:11][C:4]=2[NH:3]1.[H-].[Na+].Br[CH:39]([CH3:42])[C:40]#[N:41]>CN(C=O)C>[C:31]([O:30][C:29](=[O:35])[NH:28][C:24]1([C:21]2[CH:22]=[CH:23][C:18]([C:9]3[C:10]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[CH:11][C:4]4[N:3]([CH:39]([C:40]#[N:41])[CH3:42])[C:2](=[O:1])[CH2:7][O:6][C:5]=4[N:8]=3)=[CH:19][CH:20]=2)[CH2:25][CH2:26][CH2:27]1)([CH3:32])([CH3:34])[CH3:33]
Reactant: CC(Br)C#N
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CO4)cc2)CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C#N)N1C(=O)COc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc21
Reaction time: 1 h
Yield: 34.2 %

Procedure:
In a 50 ml round bottom flask was added tert-butyl 1-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (50 mg, 0.106 mmol) in DMF (Volume: 4 ml) to give a brown solution. sodium hydride (10.18 mg, 0.254 mmol) and 2-bromopropanenitrile (17.05 mg, 0.127 mmol) were added. The reaction mixture was stirred at 50 degree for 1 h then room temperature overnight. The reaction mixture was partitioned between DCM (20 ml) and water (20 ml). The organic phase was separated and concentrated. The residue was purified by column (biotage, 25 g) eluted with ethyl acetate/cyclohexane (0-50%) to give product (19 mg). LCMS (Method A): RT=7.14 min, M+H+=525.0.
Reaction SMILES: [S:1]1(=[O:10])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[C:11](O)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:11]([C:7]1[CH:8]=[CH:9][C:4]2[N:3]=[CH:2][S:1](=[O:10])[C:5]=2[CH:6]=1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)c1ccccc1
Reactant: O=S1C=Nc2ccccc21
Product: O=C(c1ccccc1)c1ccc2c(c1)S(=O)C=N2
Temperature: 140 °C

Procedure:
Grind benzothiazolinone (10 g) and benzoic acid (9.7 g) in a mortar. Introduce the preparation into a flask and add polyphosphoric acid (100 g). Heat at 140° C. for 4 hours with mechanical stirring. Hydrolyse the reaction mixture in ice. Remove the resulting precipitate by filtration, wash it with ether and recrystallise from a 4/6 cyclohexane/toluene mixture.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([NH:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Br[CH:17]([CH3:25])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>>[Cl:1][C:2]1[CH:9]=[C:8]([N:10]([CH2:11][C:12]([F:13])([F:14])[F:15])[C@H:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH3:25])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(NCC(F)(F)F)cc1Cl
Reactant: CC(Br)C(=O)OC(C)(C)C
Product: C[C@@H](C(=O)OC(C)(C)C)N(CC(F)(F)F)c1ccc(C#N)c(Cl)c1

Procedure:
Synthesized in a manner similar to example 1B using 2-chloro-4-[(2,2,2-trifluoroethyl)amino]benzonitrile and 1,1-dimethylethyl 2-bromopropanoate: MS (ES) m/z 363 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)=[O:9])[CH2:3][CH2:2]1.[F:22][C:23]([F:30])([F:29])[C:24](OCC)=[O:25]>C1COCC1>[F:22][C:23]([F:30])([F:29])[C:24]([N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:19])([F:20])[F:21])=[CH:13][CH:12]=2)=[O:9])[CH2:3][CH2:2]1)=[O:25]
Reactant: CCOC(=O)C(F)(F)F
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)NC1CCNCC1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)NC1CCN(C(=O)C(F)(F)F)CC1
Temperature: 25 °C
Yield: 37.2 %

Procedure:
Intermediate 42 (100 mg, 0.33 mmol) was dissolved in dry THF (1 mL), ethyl trifluoroacetate (30 μl 0.39 mmol) was added and the reaction was refluxed for 18 hours. The reaction was cooled to RT, evaporated and the residue chromatographed from EtOAc to give compound 53 (49 mg, 37%) as a white solid: Mp 150-154° C. 1H NMR (500 MHz, DMSO-d6) δ 8.59 (s, 1H), 7.47 (d, J=9.0 Hz, 2H), 7.22 (d, J=8.6 Hz, 2H), 6.27 (d, J=7.6 Hz, 1H), 4.15 (d, J=13.1 Hz, 1H), 3.80 (d, J=11.1 Hz, 2H), 3.38 (t, J=11.9 Hz, 1H), 3.11 (t, J=12.1 Hz, 1H), 1.94 (t, J=15.2 Hz, 2H), 1.46-1.34 (m, 2H). Purity 100%. HRMS calculated for C15H15F6N3O3+H+ 400.1096. found (ESI(+), [M+H]) 400.1078.
Reaction SMILES: Br[C:2]1[C:3]([N:22]([CH2:24][CH2:25][OH:26])[CH3:23])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].CC1(C)C(C)(C)OB([C:35]2[N:39](COCC[Si](C)(C)C)[N:38]=[CH:37][CH:36]=2)O1.C([O-])([O-])=O.[Na+].[Na+].C(N)CN.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>CCOC(C)=O.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.CCO.O.COCCOC>[OH:26][CH2:25][CH2:24][N:22]([CH3:23])[C:3]1[C:2]([C:35]2[NH:39][N:38]=[CH:37][CH:36]=2)=[CH:21][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])=[CH:5][N:4]=1
Reactant: CN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1Br
Reactant: CC1(C)OB(c2ccnn2COCC[Si](C)(C)C)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: NCCN
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1-c1ccn[nH]1
Temperature: 75 °C
Reaction time: 24 h

Procedure:
5-Bromo-6-((2-hydroxyethyl)(methyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 19.1, 87 mg, 0.2 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (130 mg, 0.401 mmol), Pd(PPh3)2Cl2 (14.06 mg, 0.020 mmol), Na2CO3 (85 mg, 0.801 mmol), DME (850 μL), water (243 μL) and EtOH (121 μL) were added to a MW vial, which was sealed, evacuated/purged with argon and subjected to MW irradiation at 125° C. for 20 h. The RM was diluted with DME (3 mL), treated with Si-Thiol (Silicycle, 1.44 mmol/g, 83 mg, 0.120 mmol, centrifuged, the supernatant was filtered and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative SFC (Column NH2, from 8% to 13% in 10 min). The resulting intermediate was treated with ethylene diamine (33.7 μL, 0.499 mmol) and 1 M TBAF in THF (1.496 mL, 1.496 mmol) and stirred at 75° C. for 24 h. The solvent was evaporated off under reduced pressure to give a, diluted with EtOAc (30 mL), washed 3 times with sat. aq. NaHCO3, brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a. The crude product was purified by preparative SFC (Column DEAP, isocratic 23% in 9 min) to yield the title product as yellow wax. UPLC-MS (Condition 3) tR=0.92 min, m/z=422.2 [M+H]+, m/z=420.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.77 (s, 3H) 3.44 (t, J=5.87 Hz, 2H) 3.55 (q, J=5.46 Hz, 2H) 4.63 (br. s, 1H) 6.48 (d, J=2.20 Hz, 1H) 7.35 (d, J=8.56 Hz, 2H) 7.70-7.84 (m, 1H) 7.84-7.91 (m, 2H) 8.15 (d, J=1.96 Hz, 1H) 8.71 (d, J=2.20 Hz, 1H) 10.26 (s, 1H).
Reaction SMILES: O1CCOCC1.Cl[CH2:8][C:9]([NH:11][C:12]1[C:13]([N+:30]([O-:32])=[O:31])=[CH:14][C:15]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:16]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:17]=1)=[O:10].[CH2:33]([NH2:37])[CH2:34][CH2:35][CH3:36]>O>[CH2:33]([NH:37][CH2:8][C:9]([NH:11][C:12]1[C:13]([N+:30]([O-:32])=[O:31])=[CH:14][C:15]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:16]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:17]=1)=[O:10])[CH2:34][CH2:35][CH3:36]
Reactant: CCCCN
Reactant: CS(=O)(=O)Nc1cc(NC(=O)CCl)c([N+](=O)[O-])cc1Oc1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CCCCNCC(=O)Nc1cc(NS(C)(=O)=O)c(Oc2ccccc2)cc1[N+](=O)[O-]
Yield: 72 %

Procedure:
To 7 ml of a dioxane solution containing 1.4 g of N-(5-chloroacetylamino-4-nitro-2-phenoxyphenyl)methanesulfonamide was added 0.77 g of n-butylamine at room temperature, followed by stirring for an hour. Water was added to the reaction solution, the precipitate was collected by filtration and recrystallized from ethanol to give 1.1 g of N-[5-(n-butylaminoacetylamino)4-nitro-2-phenoxyphenyl]methanesulfonamide as yellow needles.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=[O:14])[C:7](=[O:18])[C:6]3([CH3:23])[CH2:19][O:20][CH2:21][CH2:22][N:5]3[C:4]=2[N:3]=1.[CH3:24][NH:25][C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=1)=[O:27].C([O-])(O)=O.[Na+].O[Li].O.Cl>O.CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl.O1CCOCC1>[CH3:16][C:12]([N:8]1[C:7](=[O:18])[C:6]2([CH3:23])[CH2:19][O:20][CH2:21][CH2:22][N:5]2[C:4]2[N:3]=[C:2]([C:32]3[CH:31]=[CH:30][C:29]([NH:28][C:26]([NH:25][CH3:24])=[O:27])=[CH:34][CH:33]=3)[N:11]=[CH:10][C:9]1=2)([CH3:17])[C:13]([OH:15])=[O:14]
Reactant: CC(C)(C(=O)O)N1C(=O)C2(C)COCCN2c2nc(Cl)ncc21
Reactant: CNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: CNC(=O)Nc1ccc(-c2ncc3c(n2)N2CCOCC2(C)C(=O)N3C(C)(C)C(=O)O)cc1
Temperature: 100 °C

Procedure:
To crude 2-(2-chloro-6a-methyl-6-oxo-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-2-methylpropanoic acid (79 mg, about 0.233 mmol, as a mixture with its methylester) was added 1-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (0.077 g, 0.28 mmol), Pd(dppf)Cl2-dichloromethane, 1,4-dioxane (3 mL) and NaHCO3 (sat., 1.5 mL). It was heated under an air-filled balloon (1 atm) at 100° C. (bath temperature) for 1.5 hours and then LiOH.H2O (100 mg) was added and heated continued at 80° C. (bath temperature) for 1 hour and 40 minutes The mixture was diluted with water and MeOH, passed through a microfilter. The filtrate was acidified with concentrated HCl (0.1 mL) to pH<7 and then purified on the HPLC (20-20% of AcCN [containing 0.035% TFA] in water [containing 0.05% TFA], Phenomenex Gemini 5 μm C18, 75×30 mm column) to give 2-methyl-2-(6a-methyl-2-(4-(3-methylureido)phenyl)-6-oxo-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)propanoic acid as a clear semisolid (10.2 mg). 1H NMR (400 MHz, METHANOL-d6) δ ppm 1.55 (s, 3 H) 1.68 (s, 3 H) 1.81 (s, 3 H) 2.80 (s, 3 H) 3.49 (m, 1 H) 3.69 (dd, J=12, 4 Hz, 1 H) 3.74 (d, J=12 Hz, 1 H) 4.05 (d, J=12 Hz, 1 H) 4.15 (dd, J=12, 4 Hz, 1 H) 4.48 (d, J=12 Hz, 1 H) 7.62 (d, J=8 Hz, 2 H) 8.10 (s, 1 H) 8.14 (d, J=8 Hz, 2 H). MS [M+H] found 455.4.