Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][NH:18][CH3:19]>CCOCC>[CH3:17][N:18]([CH3:19])/[CH:1]=[CH:2]/[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=CC=Cc1ccccc1
Reactant: CNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: CN(C)/C=C/Cc1ccccc1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
A mixture of 19.6 mL (20.0 grams, 149 mmol) of cinnamaldehyde, 40.6 grams (298 mmol) of potassium carbonate, and 150 mL of ether was cooled to −60° C. and treated with a prechilled (−78° C.) solution of 17.8 mL (13.5 grams, 300 mmol) of liquid dimethylamine, condensed from the gas at −78° C., in 20 mL of ether. After stirring for 0.5 hours at −60° C., the mixture was allowed to slowly warm to room temperature and then stirred for an additional 3 hours. The mixture was filtered, concentrated, and distilled to give 10.2 grams (42% yield) of the title compound as a yellow liquid, bp 95-100° C./2.8-3.0 Torr. The liquid slowly polymerized on standing and was used directly. 1H NMR (CDCl3) d 2.57 (6H, s), 3.30 (2H, d, J=7 Hz), 4.35 (1H, dt, J=7, 14 Hz), 5.99 (1H, dt, J=1, 14 Hz), 7.15-732 (5H, m).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([CH2:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)[C:6]=1[Cl:7].[I:19][CH3:20]>C(#N)C>[I-:19].[Cl:7][C:6]1[N:5]([CH2:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)[CH2:4][NH+:3]([CH3:20])[C:2]=1[Cl:1]
Reactant: Clc1ncn(Cc2ccc3ccccc3c2)c1Cl
Reactant: CI
Solvent: CC#N
Product: C[NH+]1CN(Cc2ccc3ccccc3c2)C(Cl)=C1Cl
Product: [I-]

Procedure:
4,5-dichloroimidazole (40.0 mmol, 5.479 g) and KOH (44.0 mmol, 2.469 g) were placed in a round bottom flask with 100 mL acetonitrile. The mixture was brought to reflux (85° C.) and stirred 1 h until KOH was consumed. 2-Bromomethylnapthalene (40.00 mmol, 8.844 g) was added and the solution was stirred at reflux for 17 hours. KBr was removed by vacuum filtration and the filtrate was collected. The volatiles were removed by rotary evaporation to give 4,5-dichloro-1-(naphthalen-2-ylmethyl)-1H-imidazole as a light brown solid. 4,5-dichloro-1-(naphthalen-2-ylmethyl)-1H-imidazole (18 mmol) was dissolved in acetonitrile (40 mL) in a round bottom flask. The solution was brought to reflux and iodomethane (5 mL) was added. The reaction was stirred at reflux for 20 h after which time it was cooled. The resulting white precipitate was collected by filtration and analyzed. Yield: 89.6% 1H NMR (300 MHz, d6-DMSO): δ 3.86 (s), 5.68 (s), 7.53-7.59 (m), 7.93-8.03 (m), 9.51 (s) ppm.
Reaction SMILES: [CH2:1]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[CH2:17]([Li])CCC.IC>C(OCC)C.CCCCCC>[CH2:1]([N:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1
Reactant: [Li]CCCC
Reactant: COc1cccc(CNc2ccccc2)c1
Solvent: CI
Solvent: CCCCCC
Solvent: CCOCC
Product: COc1cccc(CN(C)c2ccccc2)c1

Procedure:
5.15 g of N-(3-Anisyl)-N-phenyl-amine were dissolved in 25.0 ml of anhydrous diethylether. 11.0 g of a 2.50 M solution of n-butyl lithium in n-hexane was added with stirring. After completion of the addition the reaction mixture was heated to reflux for 30 min 3.90 g of iodomethane are added and the reaction mixture was heated to reflux for additional 4 hours. After extraction with 2.00 N sodium hydroxide solution (three times) the organic layer was dried with anhydrous sodium sulfate. After filtration the solvent was removed in vacuo and the crude product purified by fractionated distillation in vacuo. At a temperature of 70-90° C./0.01 mbar 2.40 g (45.0%) of APMA was collected as yellow liquid.
Reaction SMILES: [F:1][CH:2]([F:9])[CH:3]1[NH:8][CH2:7][CH2:6][NH:5][CH2:4]1.[CH2:10]([N:12]1[C:21]2[C:16](=[CH:17][C:18]([F:24])=[C:19](F)[C:20]=2[F:22])[C:15](=[O:25])[C:14]([C:26]([OH:28])=[O:27])=[CH:13]1)[CH3:11]>N1C=CC=CC=1>[F:1][CH:2]([F:9])[CH:3]1[NH:8][CH2:7][CH2:6][N:5]([C:19]2[C:20]([F:22])=[C:21]3[C:16]([C:15](=[O:25])[C:14]([C:26]([OH:28])=[O:27])=[CH:13][N:12]3[CH2:10][CH3:11])=[CH:17][C:18]=2[F:24])[CH2:4]1
Reactant: FC(F)C1CNCCN1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(C(F)F)C3)c(F)c21

Procedure:
The above 100 mg of 3-difluoromethylpiperazine and 200 mg of 1-ethyl-1,4-dihydro-6,7,8-trifluoro-4-oxo-3-quinolinecarboxylic acid in 5 ml of pyridine was stirred at 75° C. overnight, then cooled and the solvent removed in vacuo. The residue was triturated in a hot methanol/chloroform mixture and then purified by chromatography on silica gel, eluting with methanol:dichloromethane (5:95), giving 90 mg of the desired product, mp 212°-227° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[S:20][C:21](Br)=[CH:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[CH:25]([C:28]1[CH:29]=[C:30]([OH:34])[CH:31]=[CH:32][CH:33]=1)([CH3:27])[CH3:26].C([O-])([O-])=O.[Cs+].[Cs+].CN1C(=O)CCC1>CCOC(C)=O.[Cu]I.C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[S:20][C:21]([O:34][C:30]3[CH:31]=[CH:32][CH:33]=[C:28]([CH:25]([CH3:27])[CH3:26])[CH:29]=3)=[CH:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(C)c1cccc(O)c1
Reactant: CC(NC(=O)c1ccc(Br)s1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(C)c1cccc(Oc2ccc(C(=O)NC(C)c3cc(F)c(NS(C)(=O)=O)c(F)c3)s2)c1
Yield: 3.6 %

Procedure:
In a 5 ml glass tube were placed 5-bromo-thiophene-2-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.14 mmol), 3-isopropylphenol (62 mg, 0.27 mmol), CuI (5 mg, weight of 10%), Cs2CO3 (88 mg, 0.27 mmol), NMP (1 mL), ethanol (1 mL), and a magnetic stir bar. The vial was sealed with septum and placed into the Microwave cavity. The vial was irradiated in a Microwave synthesizer at 195° C. for 120 min. The mixture was diluted with EtOAc and washed with 1N HCl and water. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The crude residue was purified by column chromatography (gradient 12% to 100% EtOAc in n-hexane) to give title compound (2.5 mg, 4.5%).
Reaction SMILES: Cl.C([O:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]2[N:11]([C:13]([CH2:16][C:17]3[C:18]([F:28])=[C:19]4[C:24](=[CH:25][C:26]=3[F:27])[N:23]=[CH:22][CH:21]=[CH:20]4)=[N:14][N:15]=2)[N:12]=1)=[CH2:6])C>CC(O)=O>[F:28][C:18]1[C:17]([CH2:16][C:13]2[N:11]3[N:12]=[C:7]([C:5](=[O:4])[CH3:6])[CH:8]=[CH:9][C:10]3=[N:15][N:14]=2)=[C:26]([F:27])[CH:25]=[C:24]2[C:19]=1[CH:20]=[CH:21][CH:22]=[N:23]2
Reactant: C=C(OCC)c1ccc2nnc(Cc3c(F)cc4ncccc4c3F)n2n1
Agent: Cl
Solvent: CC(=O)O
Product: CC(=O)c1ccc2nnc(Cc3c(F)cc4ncccc4c3F)n2n1
Temperature: 40 °C
Reaction time: 6 h
Yield: 49.7 %

Procedure:
Aqueous 3N HCl (0.2 mL, 0.6 mmol) was added to a solution of 6-[6-(1-ethoxy-vinyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl]-5,7-difluoro-quinoline (87 mg, 0.237 mmol) in HOAc (2 mL). The reaction mixture was stirred at 40° C. for 6 h. LC/MS showed reaction was complete. The solvent was removed in vacuo, and the residue dissolved in EtOAc was neutralized, and extracted with EtOAc. The organic layer was dried, concentrated and purified by flash chromatography to afford 40 mg of the title compound as pale yellow solid. 1H-NMR (400 MHz, MeOH-d4) δ ppm 8.95 (dd, 1H), 8.56 (d, 1H), 8.29 (d, 1H), 7.85 (d, 1H), 7.60-7.67 (m, 2H), 4.94 (s, 2H), 2.67 (s, 3H). LCMS (method A): [MH]+=339, tR=4.88 min.
Reaction SMILES: [C:1]([NH:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([CH2:26][CH2:27][CH3:28])=[CH:24][C:23](C(O)=O)=[N:22]2)=[CH:16][CH:15]=1)(=[O:7])=[O:6])(=[O:3])[CH3:2].CN([C:35]([O:39]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CN(C=O)C.[NH2:70][C@H:71]([CH2:77][C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1)[C@@H:72]([OH:76])[C:73]([OH:75])=[O:74]>>[C:1]([NH:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([CH2:26][CH2:27][CH3:28])=[CH:24][C:23]([C:35]([NH:70][C@H:71]([CH2:77][C:78]3[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=3)[C@@H:72]([OH:76])[C:73]([OH:75])=[O:74])=[O:39])=[N:22]2)=[CH:16][CH:15]=1)(=[O:6])=[O:7])(=[O:3])[CH3:2]
Reactant: N[C@H](Cc1ccccc1)[C@@H](O)C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCCc1cc(C(=O)O)nn1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)=O)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(C(=O)N[C@H](Cc2ccccc2)[C@@H](O)C(=O)O)nn1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)=O)cc1
Temperature: 45 °C
Reaction time: 0.25 h
Yield: 56.3 %

Procedure:
A solution of 1-(2′-acetylsulfamoylbiphenyl-4-ylmethyl)-5-propyl-1H-pyrazole-3-carboxylic acid (250 mg, 570 μmol), HATU (215 mg, 566 μmol) and DIPEA (592 μL, 3.4 mmol) in DMF (18 mL, 230 mmol) was stirred to pre-activate the acid. After 15 minutes, (2R,3R)-3-amino-2-hydroxy-4-phenylbutyric acid (110 mg, 566 μmol) was added The resulting solution was stirred at 45° C. overnight. The mixture was concentrated, re-dissolved in water/MeCN/TFA and purified using reverse phase liquid chromatography to yield the title compound (197 mg, 97% purity). MS m/z: [M+H]+ calcd for C32H34N4O7S, 619.22; found 619.6.
Reaction SMILES: [CH2:1]([CH:3]([CH2:8][CH3:9])[C:4]([O:6][CH3:7])=[O:5])[CH3:2].[CH2:10]([Li])CCC.C(NC(C)C)(C)C.CI>>[CH2:1]([C:3]([CH3:10])([CH2:8][CH3:9])[C:4]([O:6][CH3:7])=[O:5])[CH3:2]
Reactant: [Li]CCCC
Reactant: CCC(CC)C(=O)OC
Solvent: CI
Solvent: CC(C)NC(C)C
Product: CCC(C)(CC)C(=O)OC

Procedure:
A 16.5 Kg portion of methyl 2-ethylbutyrate was reacted with 60 Kg of n-butyl lithium, diisopropylamine, and 19.1 Kg of methyl iodide to provide 17.4 Kg of methyl 2-ethyl-2-methylbutyrate. A 7.5 Kg portion of the ester thus formed was reacted with 3.25 Kg of acetonitrile and 5.03 g of sodium hydride in 33 liters of tetrahydrofuran to provide 1-ethyl-1-methylpropyl cyanomethyl ketone. The ketone thus formed was reacted with 4.35 Kg of hydroxylamine hydrochloride and 2.54 Kg of sodium hydroxide in 44 liters of water to provide 5.65 Kg of 5-amino-3-(1-ethyl-1-methylpropyl)isoxazole.
Reaction SMILES: [C:1]([C:3]1[C:8]([F:9])=[CH:7][C:6]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[C:5]([F:23])[CH:4]=1)#N.[OH-:24].[Na+].Cl.[OH2:27]>C(O)C>[C:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][N:10]([C:6]2[C:5]([F:23])=[CH:4][C:3]([C:1]([OH:27])=[O:24])=[C:8]([F:9])[CH:7]=2)[CH2:11][CH2:12]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(F)c(C#N)cc2F)CC1
Reactant: [OH-]
Reactant: O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2cc(F)c(C(=O)O)cc2F)CC1
Temperature: 90 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
Tert-butyl 4-(4-cyano-2,5-difluorophenyl)piperazine-1-carboxylate (20 mg, 0.062 mmol) was dissolved in ethanol (1 mL) and treated with water (0.2 mL) and 50% NaOH (0.2 mL, 2.500 mmol). The reaction mixture was stirred at 90° C. for 1 h, diluted with water (2 mL) and acidified with 1N HCl to pH<4. The solid was filtered, washed with water and dried in vacuum to afford 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2,5-difluorobenzoic acid (21.0 mg, 0.061 mmol, 99% yield) as a white solid. ESI-MS: m/z 343 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[N:16]=[C:15]([C:25]([N:27]3[CH2:31][CH2:30][S:29][CH2:28]3)=[O:26])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.ClC1C=C(C2N(C3C=NC=CC=3)N=C(C(N3CCS(=O)C3)=[O:52])C=2)C=C(F)C=1.ClC1C=CC=C(C(OO)=O)C=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[N:16]=[C:15]([C:25]([N:27]3[CH2:31][CH2:30][S:29](=[O:52])[CH2:28]3)=[O:26])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:10])([F:11])[F:12])[CH:7]=1
Reactant: O=C(c1cc(-c2cc(F)cc(Cl)c2)n(-c2cccnc2)n1)N1CCS(=O)C1
Reactant: O=C(c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2ccc(Cl)nc2)n1)N1CCSC1
Agent: O=C(OO)c1cccc(Cl)c1
Product: O=C(c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2ccc(Cl)nc2)n1)N1CCS(=O)C1

Procedure:
38 mg (0.07 mmol) of the compound of Example 36 is reacted analogously to the synthesis of the compound of Example 6 with 18 mg (0.07 mmol, 70%) of meta-chloroperbenzoic acid for 72 hours at room temperature. After the crude product is purified by means of preparative HPLC (mobile solvent: acetonitrile/water gradient), 31 mg (79% of theory) of the title compound is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]([CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)=[O:13].N1C=CC=CC=1.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=1[S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]([CH:14]1[CH2:19][CH2:18][N:17]([S:39]([C:33]2[CH:34]=[C:35]([Cl:38])[CH:36]=[CH:37][C:32]=2[Cl:31])(=[O:41])=[O:40])[CH2:16][CH2:15]1)=[O:13]
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Reactant: O=C(Nc1ccccc1Oc1ccc(Cl)cc1Cl)C1CCNCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccccc1Oc1ccc(Cl)cc1Cl)C1CCN(S(=O)(=O)c2cc(Cl)ccc2Cl)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 44 %

Procedure:
To an ice cooled solution of piperidine-4-carboxylic acid [2-(2,4-dichlorophenoxy)-phenyl]amide (AMR01038, 80 mg, 0.219 mmol) in dry DCM (6 mL) were added pyridine (0.035 mL, 0.438 mmol) and 2,5-dichlorobenzenesulphonyl chloride (59.2 mg, 0.241 mmol). The reaction mixture was stirred at room temperature for 24 h, and then at reflux for 3 h. After quenching with saturated NaHCO3, the resulting solution was extracted with DCM (3×20 mL), and the combined organic layers were washed with water, 1M HCl (3×20 mL) and brine, dried (MgSO4), filtered and evaporated. Flash column chromatography on silica gel using hexane/EtOAc 8:2 as eluent gave 1-(2,5-dichlorobenzenesulfonyl)piperidine-4-carboxylic acid [2-(2,4-dichlorophenoxy)-phenyl]amide (56 mg, 44%) as a white solid, mp 194-196° C. Rf: 0.81 (DCM/MeOH 9:1). 1H NMR (300 MHz, CDCl3) δ 1.74-1.96 (4H, m, 2CH2), 2.34 (1H, m, CH), 3.80 (2H, td, J=13.1, 3.4 Hz, CH2), 6.65 (1H, dd, J=8.1, 1.4 Hz, ArH), 6.87 (1H, d, J=8.8 Hz, ArH), 6.94 (1H, td, J=7.7, 1.7 Hz, ArH), 7.05 (1H, td, J=8.0, 1.4 Hz, ArH), 7.15 (1H, dd, J=8.8, 2.5 Hz, ArH), 7.37 (2H, d, J=1.4 Hz, ArH), 7.41 (1H, d, J=2.5 Hz, ArH), 7.68 (1H, br s, NH), 7.97 (1H, t, J=1.4 Hz, ArH) and 8.29 (1H, dd, J=8.0, 1.0 Hz, ArH). LC/MS (APCI) tr=5.62 min, m/z 577.21 (59), 575.26 (100), 573.24 (M++H, 90) HPLC tr=3.363 min (97.70%)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.O>CC(C)=O>[F:8][C:4]1[CH:3]=[C:2]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Fc1cccc(Br)c1
Reactant: COc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(-c2cccc(F)c2)cc1
Temperature: 40 °C
Yield: 86.6 %

Procedure:
1-Bromo-3-fluorobenzene (28.8 g, 0.165 mol), potassium carbonate (50 g, 0.362 mol), 4-methoxybenzene boronic acid (27.6 g, 0.182 mol), water (100 ml) and acetone (300 ml) were placed in 1 L round-bottom three necked flask equipped with condenser, thermometer, mechanical stirrer and nitrogen inlet and outlet. The reaction flask was flushed with nitrogen and minor flow was held during whole reaction time. The mixture was heated up to the boiling point to 40° C. to degas the reaction system and then cooled down and the catalyst palladium acetate (0.1 g) was added. The temperature has increased of few degrees and the solution turned brown. The mixture was refluxed for 6 hours, then was cooled down, poured on cold water and the precipitated gray solid was filtered off. The raw product was recrystallized from ethanol (500 ml). The product (28.9 g) in a form of white crystals was obtained, 88% of theor. yield. The melting point 63-64° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[CH2:7][CH2:8][C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:14][C@H:15]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=1)[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(Cl)Cl>[Br:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][C@@H:15]([NH:14][C:9](=[O:11])[CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:12])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:28][CH:27]=1
Reactant: CCOC(=O)C[C@H](N)Cc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@@H](Cc1ccc(Br)cc1)NC(=O)CCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
To a solution of 4-tert-butoxy-4-oxobutanoic acid (2.38 g, 13.64 mmol) in DMF (30 mL) and DCM (30 mL) is added (R)-ethyl 3-amino-4-(4-bromophenyl)butanoate hydrochloride (4 g, 12.4 mmol), HATU (5.19 g, 13.64 mmol), and TEA (6.91 mL, 49.6 mmol). After stirring at room temperature for 2 hours, the reaction is quenched with H2O, and the crude is diluted with EtOAc, the organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give (R)-tert-butyl 4-(1-(4-bromophenyl)-4-ethoxy-4-oxobutan-2-ylamino)-4-oxobutanoate (4.0 g). HPLC retention time=1.70 minutes (condition A); MS (m+1)=444.1.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:1]1([S:7]([O:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Oc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: O=S(=O)(Oc1ccccc1)c1ccccc1
Yield: 80.9 %

Procedure:
All apparatus is rigorously dried and flushed with nitrogen before use. The reaction is performed in a 25 ml flask equipped with a magnetic stirring bar and a calcium chloride drying tube. The flask is charged with benzenesulfonyl chloride (11.60 g, 65.7 mmol), phenol (5.60 g, 59.6 mmol), and 4-dimethylaminopyridine (0.36 g, 2.98 mmol), and anhydrous pyridine (20 ml). The reaction mixture is stirred and heated at reflux, and the progress of the reaction is monitored by high performance liquid chromatography. At the conclusion of the reaction, the mixture is cooled and quenched with water (25 ml), extracted with ether (50 ml), and washed successively with 50 ml portions of water, 5% sodium hydroxide (2×), water, and brine. The organic phase is then dried over magnesium sulphate, filtered, and concentrated to yield 13.1 g (94%) of the crude product as a yellow oil. This product is further purified by distillation on a Kugelrohr apparatus under vacuum to give 11.3 g (81%) of the product as a colorless oil. The oxidative stability of the product is determined by pressure differential scanning calorimetry (PDSC). The results are reported below in Table 1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@@H:4]1[CH2:8][C:7](=[CH2:9])[CH2:6][N:5]1C(OCC1C=CC=CC=1)=O.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:20])[C@@H:4]1[CH2:8][CH:7]([CH3:9])[CH2:6][NH:5]1
Reactant: C=C1C[C@@H](C(=O)OC)N(C(=O)OCc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@@H]1CC(C)CN1
Yield: 99.9 %

Procedure:
(S)-1-Benzyloxycarbonyl-4-methylideneproline methyl ester (1.80 g (6.5 mmol), prepared as described in 1)) was dissolved in methanol (50 ml). The resulting solution was stirred at room temperature in an atmosphere of hydrogen in the presence of 10% palladium on charcoal (180 mg) for 2 hours. At the end of this time, the reaction mixture was filtered to remove the catalyst and the filtrate was concentrated by evaporation under reduced pressure, to give the title compound (0.93 g) as a pale yellow oil (yield quantitative).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:26]([NH:38][C:39]2[CH:40]=[C:41]3[C:46](=[CH:47][CH:48]=2)[C:45]([N:49]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])=[N:44][CH:43]=[CH:42]3)[C:27]2[CH:32]=[C:31]([CH2:33][CH3:34])[CH:30]=[C:29](OC)[C:28]=2[F:37])[N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.BrC1N=C(C(C2C=C(CC)C=C([Cl:99])C=2F)O)N(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1.BrC1N=C(C(Cl)C2C=C(CC)C=C(OC)C=2F)N(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1.NC1C=C2C(=CC=1)C(N(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=NC=C2>>[Br:1][C:2]1[N:3]=[C:4]([CH:26]([NH:38][C:39]2[CH:40]=[C:41]3[C:46](=[CH:47][CH:48]=2)[C:45]([N:49]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])=[N:44][CH:43]=[CH:42]3)[C:27]2[CH:32]=[C:31]([CH2:33][CH3:34])[CH:30]=[C:29]([Cl:99])[C:28]=2[F:37])[N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1
Reactant: CCc1cc(OC)c(F)c(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: CCc1cc(Cl)c(F)c(C(O)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(N)ccc12
Agent: CCc1cc(OC)c(F)c(C(Cl)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Product: CCc1cc(Cl)c(F)c(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1

Procedure:
According to the procedure for the preparation of Intermediate 206.4, Intermediate 221.2 (309 mg, 0.537 mmol) was converted to the chloro intermediate, then displaced with di-tert-butyl (6-aminoisoquinolin-1-yl)imidodicarbonate (rt for 15 h, 40° C. for 9 h, 50° C. for 6 h) to afford after flash chromatography (O to 50% EtOAc/hexanes gradient) 400 mg of Iintermediate 221.3 as a pale yellow solid. LCMS (50 to 100% B, 4 min gradient, A=95% H2O/5% CH3CN/0.1% TFA, B=5% H2O/95% CH3CN/0.1% TFA) RT=5.43 min, 918.76 (M+H)+.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[C:35](=[O:36])[C:14]2=[CH:15][N:16]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([N:30]4[CH:34]=[CH:33][CH:32]=[N:31]4)=[CH:26][CH:25]=3)[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[C:13]2=[N:12]1)=[N+]=[N-].CP(C)C.[OH-].[Na+].O>O1CCCC1>[NH2:1][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[C:35](=[O:36])[C:14]2=[CH:15][N:16]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([N:30]4[CH:34]=[CH:33][CH:32]=[N:31]4)=[CH:26][CH:25]=3)[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[C:13]2=[N:12]1
Reactant: [N-]=[N+]=NCc1ccccc1-n1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Agent: CP(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NCc1ccccc1-n1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2-[2-(Azidomethyl)phenyl]-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one (Example 661, 92 mg, 0.19 mmol) was dissolved in tetrahydrofuran (6 mL) and cooled to 0° C. Trimethylphosphine (0.97 mL, 1 M tetrahydrofuran solution, 0.97 mmol, 5 equiv) was added, the ice bath removed and the mixture was warmed to ambient temperature and stirred for 2 hours. The mixture was treated with sodium hydroxide (1.9 mL, 1 M aqueous, 10 equiv) and stirred for an additional 1 hour. The mixture was poured into water and extracted with chloroform (4×150 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 85:15; dichloromethane:methanol containing 10% ammonium hydroxide), providing the titled compound: 1H-NMR (400 MHz, d6-DMSO, hydrochloride salt) δ 9.27 (1H, s), 8.47 (1H, d, J=2.6 Hz), 8.33 (1H, dd, J=7.9, 1.4 Hz), 8.36-8.27 (3H, br s), 7.86-7.82 (3H, m), 7.73 (1H, d, J=1.5 Hz), 7.70-7.64 (3H, m), 7.60-7.55 (2H, m), 7.52-7.47 (3H, m), 6.54 (1H, m), 5.83 (2H, s), 4.04 (2H, q, J=5.6 Hz) ppm; high resolution mass spectrometry (ES+) m/z 447.1911 [(M+H)+; calculated for C27H23N6O: 447.1928].