Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N-:1]=[N+]=[N-].Cl.[O:5]=[C:6]1[C:11](C(NN)=O)=[CH:10][C:9]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[N:8][NH:7]1.N([O-])=O.[Na+].Cl.O=C1C(C(N=[N+]=[N-])=O)=CC(C2C=CN=CC=2)=NN1>O>[NH2:1][C:11]1[C:6](=[O:5])[NH:7][N:8]=[C:9]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH:10]=1
Reactant: NNC(=O)c1cc(-c2ccncc2)n[nH]c1=O
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [N-]=[N+]=NC(=O)c1cc(-c2ccncc2)n[nH]c1=O
Solvent: O
Product: Nc1cc(-c2ccncc2)n[nH]c1=O
Temperature: 25 °C

Procedure:
The above procedure of Example G-1 first procedes through the acid azide as seen by the following isolation of the acid azide as its monohydrochloride: To a solution chilled in an ice bath and containing 3.0 g. of 2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acid hydrazide and 60 ml. of 6 N hydrochloric acid was added dropwise with stirring a solution containing 3.0 g. of sodium nitrite in 10 ml. of water over a 30 minute period. The reaction mixture was then stirred for an additional 1 hour, allowing the reaction mixture to warm up to room temperature. The separated solid was collected, washed with water and dried in a vacuum oven over P2O5 at 25° C. for 48 hours to yield 3.0 g. of 2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acid azide monohydrochloride, m.p. >300° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][NH:5][C:6]([C:8]1[C:17]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][C:20]=2[Cl:26])=[C:16]([F:27])[C:11]2[N:12]=[CH:13][N:14]([CH3:15])[C:10]=2[CH:9]=1)=[O:7].[C:28]([NH:35][C@H:36]([C:40](O)=[O:41])[CH:37]([CH3:39])[CH3:38])([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.Cl>O.CC(N(C)C)=O>[Br:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:17]2[C:8]([C:6]([NH:5][O:4][CH2:3][CH2:2][O:1][C:40](=[O:41])[CH:36]([NH:35][C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH:37]([CH3:39])[CH3:38])=[O:7])=[CH:9][C:10]3[N:14]([CH3:15])[CH:13]=[N:12][C:11]=3[C:16]=2[F:27])=[C:20]([Cl:26])[CH:21]=1
Reactant: Cn1cnc2c(F)c(Nc3ccc(Br)cc3Cl)c(C(=O)NOCCO)cc21
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)C(NC(=O)OC(C)(C)C)C(=O)OCCONC(=O)c1cc2c(ncn2C)c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 46.4 %

Procedure:
Dimethylacetamide (30 mL) was added to a mixture of 6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethoxy)-amide (3 g, 6.555 mmol), BOC-L-valine (1.710 g, 7.866 mmol), HOBT·H2O (1.004 g, 6.555 mmol) and, TEA (0.929 g, 9.177 mmol) in a 500 mL RBF with a magnetic stirrer and nitrogen line. After 5 minutes, EDCl (1.759 g, 9.177 mmol) was added to the brown solution in the 500 mL RBF. The mixture was stirred overnight at room temperature. The reaction mixture was added slowly to 210 mL of deionozied water with mechanical stirring. The white slurry was stirred for 1 hour, filtered through a medium fritted funnel. The cake was washed with about 100 mL of water and pulled air through the cake for 10-15 minutes. Tert-butyl methyl ether (70 mL) was added to the cake and stirred with a spatula. The vacuum filtration was continued. The solids were dried under vacuum at 50° C. to give 2 g of the product containing about 80% of the undesired isomer. The t-butyl methyl ether layer was concentrated to a foam (2.18 g) enriched in the desired product comprising a mixture of isomers.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13][CH2:12]1>>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:12][CH2:13][CH:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:15][CH2:16]2)=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(N)cn2)CC1

Procedure:
Intermediate B-33 was prepared by the general procedure for intermediate B-2, by using 2-chloro-5-nitropyridine and tert-butyl piperidin-4-ylcarbamate as the starting material. LCMS [M+1]+ 293.2.
Reaction SMILES: Cl[C:2]1[C:3]([C:14]([O:16]CC)=[O:15])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([CH3:12])=[C:7]([CH3:13])[CH:6]=2.C(=O)([O-])[O-].[Ba+2].O.[H][H]>C(O)C.[Pd](Cl)Cl>[CH3:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[CH3:13])[N:4]=[C:3]([C:14]([OH:16])=[O:15])[CH:2]=[N:11]2
Reactant: CCOC(=O)c1nc2cc(C)c(C)cc2nc1Cl
Reactant: [H][H]
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Ba+2]
Solvent: CCO
Solvent: O
Product: Cc1cc2ncc(C(=O)O)nc2cc1C
Reaction time: 18 h

Procedure:
3-Chloro-6,7-dimethyl-2-quinoxalinecarboxylic acid, ethyl ester (Example 14a) (6.0 g), palladium chloride (0.4 g) and barium carbonate (17.4 g) in ethanol (500 ml) containing water (6 ml) were stirred in an atmosphere of hydrogen at room temperature and atmospheric pressure for 18 hours. The mixture was filtered and the filtrate was evaporated. The residue was crystallised from a mixture of ethyl acetate and light petroleum (b.p. 60°-80°). The solid was dissolved in aqueous sodium hydroxide (20 ml., 2N) and ethanol (20 ml) and the solution was heated under reflux for 10 minutes and cooled. Hydrochloric acid was added and the solid was collected and crystallised from aqueous ethanol. It had m.p. 214.5°-216° (20%).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[C:9]12[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH:14][C:13](=O)O[C:10]2=[O:11].CS(C)=O>O>[CH3:13][N:14]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=2[C:10](=[O:11])[N:1]2[CH2:8][CH2:7][CH2:6][CH:2]2[C:3]1=[O:5]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: CS(C)=O
Solvent: O
Product: CN1C(=O)C2CCCN2C(=O)c2ccccc21

Procedure:
A mixture of 12.3 g. of L-proline, 17.7 g. of N-mthyl isatoic anhydride and 100 ml. of dimethyl sulfoxide is heated on a steam bath for 40 minutes. The mixture is cooled and diluted with 250 ml. of cold water. The precipitate is recovered by filtration, washed with water and then ether, air dried and then recrystallized from ethanol yielding the intermediate L-1-(N-methylanthrailoyl)proline, melting point 140°-142°C., [α]D25 -165°C. (1.1%, methanol).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:38])[NH:27][C:28]4[CH:37]=[CH:36][C:31]([C:32]([O:34]C)=[O:33])=[CH:30][CH:29]=4)=[CH:21][CH:20]=3)[N:8]=2)[CH2:3][CH2:2]1.C1COCC1.CO.O[Li].O>O>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:38])[NH:27][C:28]4[CH:37]=[CH:36][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=4)=[CH:21][CH:20]=3)[N:8]=2)[CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc(NC(=O)Nc2ccc(-c3nc(N4CCOCC4)nc(N4CCOCC4)n3)cc2)cc1
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc(C(=O)O)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Yield: 95.6 %

Procedure:
To a stirred mixture of methyl 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzoate (1.4 g, 2.69 mmol), THF (10 mL), MeOH (5 mL) and H2O (2.5 mL) was added LiOH.H2O (339 mg, 8.07 mmol) then heated under reflux for 8 hrs. Concentrated and added H2O (5 mL) then acidified with 2N HCl. The solid was filtered washed with H2O and dried to give the product as a tan solid (1.3 g, 96% yield); MS (ESI) m/z=506.3
Reaction SMILES: [CH:1]1([C@H:4]2[O:16][C@H:5]2[C:6]([O:8]CC2C=CC=CC=2)=[O:7])[CH2:3][CH2:2]1>O1CCCC1.[C].[Pd]>[CH:1]1([C@H:4]2[O:16][C@H:5]2[C:6]([OH:8])=[O:7])[CH2:3][CH2:2]1
Reactant: O=C(OCc1ccccc1)[C@@H]1O[C@@H]1C1CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1O[C@@H]1C1CC1
Reaction time: 2 h

Procedure:
A 2.04 g of benzyl (2R,3R)-3-cyclopropyl-2,3-epoxypropionate is dissolved in 40 ml of tetrahydrofuran and subjected to catalytic hydrogenation at room temperature under atmospheric pressure using 1 g of 10 % palladium-carbon. After 2 hours, the catalyst is removed by filtration. After 40 ml of toluene is added to the filtrate, the resulting mixture is concentrated under reduced pressure to remove tetrahydrofuran to give a solution of (2R,3R)-3-cyclopropyl-2,3-epoxypropionic acid in toluene. Then, 2.74 g of 4α-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β,13α-dihydroxy-7β,10β-bis(2,2,2-trichloroethoxycarbonyloxy)tax-11-en-9-one, 1.89 g of 1,3-dicyclohexylcarbodiimide and 187 mg of 4-dimethylaminopyridine are added to the resulting solution of (2R,3R)-3-cyclopropyl-2,3-epoxypropionic acid in toluene. The mixture is stirred at 80° C. for one hour. The reaction mixture is cooled to room temperature and treated in the same manner as described in Example 4(1-1). The residue is purified by silica gel frash column chromatography (solvent; ethyl acetate:hexane=1:2) to give 3.02 g of 4α-acetoxy-2α-benzoyloxy-13α-[(2R,3R)-3-cyclopropyl-2,3-epoxypropionyloxy]-5β,20-epoxy-1β-hydroxy-7β,10β-bis(2,2,2-trichloroethoxycarbonyloxy)tax-11-en-9-one. The physical properties of the product are the same as those of the compound of Example 4(1-1).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([CH:19]=[CH:20][CH:21]=3)[C:14]([O:16]CC)=[O:15])[CH:9]=2)[NH:4][N:3]=1.[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([CH:19]=[CH:20][CH:21]=3)[C:14]([OH:16])=[O:15])[CH:9]=2)[NH:4][N:3]=1
Reactant: CCOC(=O)c1cccc(-c2cnc3[nH]nc(C)c3c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1n[nH]c2ncc(-c3cccc(C(=O)O)c3)cc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of ethyl 3-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)benzoate (119) (10 mg, 0.142, 1 eq) in ethanol (5 mL) was added 4N sodium hydroxide solution (4 mL) and the reaction mixture was stirred at room temperature for 4 hrs. After completion of the reaction the solvents were distilled off and diluted with water and the pH adjusted to 4 and extracted into chloroform. The organic layer was dried over sodium sulphate and the solvents were removed to get the compound 3-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)benzoic acid 120 and this was further titrated with hexane and diethyl ether to get 15 mg of 120.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)=[CH:43][CH:42]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH:55]=[O:56])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:57]=[O:58].N12CCCN=C1CCCCC2>CN(C)C=O>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:42]=[CH:43][C:44]([O:47][CH2:48][C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)=[CH:45][CH:46]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@:10]1([CH2:57][OH:58])[CH:55]=[O:56])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCc4ccccc4)cc3)c2)O[C@H](C=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: C=O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCc4ccccc4)cc3)c2)O[C@](C=O)(CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.1 %

Procedure:
To a solution of (2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[3-[(4-benzyloxyphenyl)methyl]-4-chloro-phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 25i (1.0 g, 1.3 mmol) in N,N-dimethyl formamide (20 mL) was added formaldehyde (2.6 mL, 32.5 mmol, 37 wt % solution) at room temperature, and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.3 mL, 0.78 mmol) was added to adjust the pH to 9. The mixture was stirred at room temperature for 16 hours and extracted with ethyl acetate (50 mL×2). The combined organic layers were washed with water (30 mL×2) and saturated aqueous sodium chloride (30 mL×2) in turn, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound 25j as yellow oil (1.04 g, 100%). This material was not further purified.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6](O)=[O:7].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[CH2:6][OH:7]
Reactant: COc1cc(C(=O)O)ccc1C
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(CO)ccc1C
Yield: 83 %

Procedure:
Into a solution of 10.0 g of 3-methoxy-4-methylbenzoic acid in 100 ml of dried tetrahydrofuran, while being cooled in ice and stirred under a nitrogen stream, was added dropwise over a period of 15 minutes 80 ml of a 1M solution of borane-tetrahydrofuran complex in tetrahydrofuran. The mixture was then stirred at room temperature for 3 hours. After addition of 10 ml of water, the reaction mixture was stripped of the solvent by distillation. The residue was dissolved in ether, washed with saturated aquecus sodium bicarbonate solution, then with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and stripped of the solvent by distillation to yield 7.6 g of 3-methoxy-4-methylbenzyl alcohol in the form of yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14](=[O:21])[CH2:13][CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(O[CH:29](N(C)C)[N:30]([CH3:32])[CH3:31])(C)(C)C>C(OCC)(=O)C>[CH3:29][N:30]([CH:32]=[C:13]1[C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:10]([C:8](=[O:9])[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:23][CH:22]=2)[CH2:11][CH2:12]1)[CH3:31]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: O=C1CCCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccccc21
Solvent: CCOC(C)=O
Product: CN(C)C=C1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccccc2C1=O
Reaction time: 1.5 h

Procedure:
A mixture of 0.780 g of 1,2,3,4-tetrahydro-1-(4-nitrobenzoyl)-5H-1-benzazepin-5-one and 10 ml of tert-butoxy bis(dimethylamino)methane (Bredereck's Reagents is heated on a steam bath while stirring for 1.5 hours (solid dissolved). Cooling gives a solid and the mixture is diluted with ethyl acetate and filtered. The solid is dissolved in dichloromethane-ethyl acetate (7:3) and the solution filtered through a thin pad of hydrous magnesium silicate. The filter pad is washed with dichloromethane-ethyl acetate (7:3) and the combined filtrate evaporated to give 0.43 g of yellow crystals, Mass Spec (CI) MH+ =366, m.p. 180°-183° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12].O1CCOCC1.CCN(C(C)C)C(C)C.[CH2:31]([SH:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:38][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)/C=C/c1cc(Br)ccc1N
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1N
Temperature: 80 °C
Yield: 122.4 %

Procedure:
A screw cap vial was charged with (E)-ethyl 3-(2-amino-5-bromophenyl)acrylate (0.820 g, 2.086 mmol), xantphos (0.092 g, 0.159 mmol), tris(dibenzylideneacetone)dipalladium (0.073 g, 0.080 mmol), 1,4-Dioxane (3.18 ml), and DIPEA (1.108 ml, 6.37 mmol). The vial was purged with Argon, sealed and heated to 80° C. for 10 minutes. The reaction was cooled to RT and benzyl mercaptan (0.395 ml, 3.34 mmol) was added and the reaction was continued heating at 80° C. for an additional 30 minutes. The reaction was cooled to RT, diluted with water and extracted with DCM (3×). The combined organics were washed with water and brine, dried over magnesium sulfate, filtered and concentrated. The resulting material was concentrated, dissolved in minimal DCM and purified via column chromatography (silica gel 40 g, gradient elution 0 to 50% EtOAc:Heptane) to afford 0.80 g of (E)-ethyl 3-(2-amino-5-(benzylthio)phenyl)acrylate. m/z (ESI) 314.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:7]2[CH:8]=[C:9](/[CH:11]=[CH:12]/[C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.S(NN)(C1C=CC(C)=CC=1)(=O)=O.CC([O-])=O.[Na+]>COCCOC.O>[Br:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH2:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1
Reactant: Brc1cnc(N2CCOCC2)c2nc(/C=C/c3ccc4ccccc4n3)cn12
Agent: CC(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)NN)cc1
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Brc1cnc(N2CCOCC2)c2nc(CCc3ccc4ccccc4n3)cn12
Temperature: 80 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
To a solution of compound 2b (5.00 g, 10.9 mmol, as prepared in Example 2, Step B) in DME/H2O (10:1 v/v, 150 mL) was added TosNHNH2 (6.41 g, 34.5 mmol) and NaOAc (4.70 g, 57.3 mmol). The reaction mixture was stirred at 80° C. overnight. After cooling to rt, the reaction was quenched with H2O (200 mL). The solids were collected by filtration and washed with Et2O to obtain compound 3a as a white solid (3.50 g, 67% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C21H20BrN5O: 438.1 (M+H). found: 438.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH:8]1[C:17]2[C:12](=[CH:13][C:14]([CH:18]=[O:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][Mg+].[Br-]>C1COCC1>[C:1]([O:5][C:6](=[O:20])[NH:7][CH:8]1[C:17]2[C:12](=[CH:13][C:14]([CH:18]([OH:19])[CH3:21])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCCc2cc(C=O)ccc21
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(O)c1ccc2c(c1)CCCC2NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of (6-formyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-carbamic acid tert-butyl ester (Step c, 2.80 g, 10.2 mmol, 1.0 eq) in THF (100 mL) at −78° C. was added a solution of MeMgBr (Aldrich, 1.4 M in toluene/THF (3:1), 29 mL, 40.7 mmol, 4.0 eq) slowly. The reaction was stirred at −78° C. for 20 min, warmed to RT and stirred at RT for 2 h. The reaction was quenched with saturated NaHCO3 (120 mL), and the crude was extracted with EtOAc (100 mL×3). The extract phase was washed with saturated NaCl, dried over Na2SO4, filtered and concentrated. The title compound was obtained as a white solid. MS (ESI, pos. ion) m/z: 292 (M+1).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6](=[O:17])[NH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[F:18][C:19]([F:41])([F:40])[C:20]([C:26]1[CH:39]=[CH:38][C:29]([CH2:30][N:31]2[CH2:36][CH2:35][NH:34][CH2:33][C:32]2=[O:37])=[CH:28][CH:27]=1)([OH:25])[C:21]([F:24])([F:23])[F:22].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl>[CH:1]1([CH2:4][NH:5][C:6]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([N:34]3[CH2:35][CH2:36][N:31]([CH2:30][C:29]4[CH:38]=[CH:39][C:26]([C:20]([OH:25])([C:19]([F:18])([F:40])[F:41])[C:21]([F:24])([F:22])[F:23])=[CH:27][CH:28]=4)[C:32](=[O:37])[CH2:33]3)=[O:14])=[CH:15][CH:16]=2)=[O:17])[CH2:2][CH2:3]1
Reactant: O=C1CNCCN1Cc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reactant: O=C(NCC1CC1)Nc1ccc(C(=O)O)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCC1CC1)Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)C(=O)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.4 %

Procedure:
To a stirring solution of 4-(3-(cyclopropylmethyl)ureido)benzoic acid (0.337 mmol, 79 mg), 1-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazin-2-one (0.281 mmol, 100 mg) and triethylamine (0.842 mmol, 85 mg) in dichloromethane (10 ml) was added 1-propanephosphonic acid cyclic anhydride (0.421 mmol, 268 mg; 50% solution in ethyl acetate). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane (20 mL) and washed with saturated aqueous sodium hydrogen carbonate solution (30 mL). The organic phase was concentrated and the resulting residue was purified by column chromatography on silica gel (eluting with 5% methanol/95% dichloromethane) to afford the title compound (36 mg). MS (ESI) m/z 573.0 [M+H]+
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[C:7]2[CH2:8][N:9]([CH:12]3[CH2:15][O:14][CH2:13]3)[CH2:10][CH2:11][N:6]2[N:5]=1)([O-])=O>C(O)C.[Pd]>[O:14]1[CH2:15][CH:12]([N:9]2[CH2:10][CH2:11][N:6]3[N:5]=[C:4]([NH2:1])[CH:16]=[C:7]3[CH2:8]2)[CH2:13]1
Reactant: O=[N+]([O-])c1cc2n(n1)CCN(C1COC1)C2
Agent: [Pd]
Solvent: CCO
Product: Nc1cc2n(n1)CCN(C1COC1)C2
Reaction time: 8 h
Yield: 98.9 %

Procedure:
To a solution of 2-nitro-5-oxetan-3-yl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine (255 mg, 1.13 mmol) in ethanol (20 mL) was treated with palladium on carbon (10%, 60 mg) and flushed with argon. The resulting mixture was stirred under a hydrogen (1 atm) overnight. The reaction mixture was filtered through a celite pad, and the pad washed with ethanol. The filtrate was concentrated in vacuo to give 5-oxetan-3-yl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylamine (217 mg, 99%) as a off-white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:16])[CH:13]=2)[NH:8][C:7]1=[O:17])[CH3:2].[O-]CC.[Na+].C(O)C.[C:26]([O:30][C:31](=[O:37])[NH:32][CH2:33][CH2:34][CH2:35]Br)([CH3:29])([CH3:28])[CH3:27]>CN(C)C=O.C(Cl)(Cl)Cl.CO.O>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:16][CH2:35][CH2:34][CH2:33][NH:32][C:31]([O:30][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:37])[CH:13]=2)[NH:8][C:7]1=[O:17])[CH3:2]
Reactant: CCOC(=O)CC1Cc2cc(O)ccc2NC1=O
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: CC[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCO
Product: CCOC(=O)CC1Cc2cc(OCCCNC(=O)OC(C)(C)C)ccc2NC1=O
Temperature: 0 °C
Reaction time: 96 h
Yield: 80 %

Procedure:
A solution of (6-hydroxy-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl)-acetic acid ethyl ester (2.0 g, 8.0 mmol) in N,N-dimethylformamide (16 mL) was treated with a solution of sodium ethoxide (21 wt %) in ethanol (3.0 mL, 8.0 mmol) at rt and after 15 min, (3-bromopropyl)-carbamic acid tert-butyl ester (1.9 g, 8.0 mmol) was added. After 4 days, the solution was treated with water (75 mL) and the resulting gum was briefly heated, then cooled to 0° C. The precipitated solid was triturated for 6 h, to give the crude product (2.7 g). Flash chromatography (90 g silica; CHCl3, then 1% MeOH (saturated with NH3) —CHCl3) gave the title compound (2.6 g, 79% yield) as a white solid.