Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:37])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29](=[O:36])(=[O:35])[NH:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14].[Li+].[OH-].CO>C1COCC1.O>[Cl:14][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([Cl:13])[C:7]=1[C:6]([NH:5][C@H:4]([C:3]([OH:37])=[O:2])[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29](=[O:36])(=[O:35])[NH:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:21][CH:22]=1)=[O:15]
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)NC(=O)c1c(Cl)cccc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(C[C@H](NC(=O)c2c(Cl)cccc2Cl)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
N-(2,6-Dichlorobenzoyl)-4-[2-[N-(tert-butyl)sulfamoyl]phenyl]-L-phenylalanine methyl ester (75 mg) was dissolved in THF (5 mL) and to this solution was added a solution of LiOH (monohydrate, 10 mg) in water (0.4 mL). Few drops of MeOH were added and the mixture was stirred at room temperature overnight. The mixture was evaporated, water was added to the residue and the mixture was acidified with 10% citric acid. The separated solid was collected by filtration, washed with water and dried to give 60 mg of the title compound. ESMS: m/z 549 (MH+), 547 ((M−H]−).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C@@:10]3([CH2:25][C@H:24]3[C:26](O)=[O:27])[N:9]=2)=[CH:4][CH:3]=1.[CH:29]([N:32](CC)C(C)C)(C)[CH3:30].Cl.C(N)C.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C@@:10]3([CH2:25][C@H:24]3[C:26]([NH:32][CH2:29][CH3:30])=[O:27])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@]1(C[C@H]1C(=O)O)c1nnc(C)n1-2
Agent: CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: ClCCl
Product: CCNC(=O)[C@@H]1C[C@]12N=C(c1ccc(Cl)cc1)c1c(sc(C)c1C)-n1c(C)nnc12
Reaction time: 0.33 h
Yield: 35.4 %

Procedure:
To a solution of crude (1S,2R)-4′-(4-chlorophenyl)-2′,3′,9′-trimethylspiro[cyclopropane-1,6′-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine]-2-carboxylic acid (Compound 228; 0.09 g, 0.218 mmol) in DCM (2.4 mL) was added N,N-diisopropylethylamine (0.190 ml, 1.090 mmol), ethylamine hydrochloride (0.071 g, 0.872 mmol) and HOBt (0.017 g, 0.109 mmol). The mixture was stirred for 10 min at rt (still heterogeneous) before HATU (0.166 g, 0.436 mmol) was added, still at rt. After 20 min, the reaction was filtered on a pad of silica gel. The silica gel was successively rinsed with EtOAc/hexane (5:5) to (10:0) and DCM/MeOH (9:1). The filtrate was concentrated to dryness, and the residue was purified by reverse phase chromatography to give the desired product as an off-white solid (34 mg). LRMS (M+H)+: 440 m/z. 1H NMR (major conformer reported only) (400 MHz, DMSO-d6) δ 8.36 (br. s., 1H), 7.37-7.54 (m, 4H), 2.89-3.01 (m, 1H), 2.69-2.82 (m, 1H), 2.62 (s, 3H), 2.36 (s, 3H), 2.07 (dd, J=5.15, 8.81 Hz, 1H), 1.92 (t, J=6.40 Hz, 1H), 1.78 (t, J=8.00 Hz, 1H), 1.43 (s, 3H), 0.84 (t, J=7.10 Hz, 3H).
Reaction SMILES: [CH2:1]1[CH2:5][O:4][CH2:3][CH2:2]1.[NH2:6][C:7]1[C:12]2=CC(C#N)=C[N:11]2[N:10]=[CH:9][N:8]=1.[H-].C([Al+]CC(C)C)C(C)C>CCOC(C)=O>[NH2:6][C:7]1[C:5]2=[CH:1][C:2]([CH:3]=[O:4])=[CH:12][N:11]2[N:10]=[CH:9][N:8]=1
Reactant: N#Cc1cc2c(N)ncnn2c1
Reactant: C1CCOC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOC(C)=O
Product: Nc1ncnn2cc(C=O)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a solution of THF (200 mL) was added 4-aminopyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile (1.00 g, 6.28 mmol). The solution was heated until all starting material was in solution and was then cooled in an ice-water bath. 1 M Diisobutylaluminum hydride in THF (50.3 mL, 50.3 mmol) was then added to the solution which was stirred for 1 h. EtOAc was added to the solution and it was then allowed to warm to rt. Wet silica gel was carefully pipetted into the solution, and the reaction mixture was heated to 50° C. for 30 min, filtered through Celite, and washed with excess EtOAc. The solution was transferred to a separatory funnel and washed with water. The organic layer was collected, dried (MgSO4), filtered, and concentrated to dryness yielding 0.92 g of yellow solid (5.69 mmol, yield 91%). 1H-NMR (DMSO-d6) δ 9.91 (s, 1H) 7.92 (d, J=1.7 Hz, 1H), 8.14 (d, J=35.3 Hz, 2H), 7.89 (s, 1H), 7.30 (d, J=1.8 Hz, 1H); MS [M+H]+=163.3; LCMS RT=1.07 min.
Reaction SMILES: [Mg].BrC1C=CC(C(C)(C)C)=CC=1.II.BrCCBr.[CH2:19]([O:26][C:27](=[O:39])[NH:28][C@@H](C)C(N1CCOCC1)=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([Mg]Cl)(C)C.Cl>O1CCCC1.C(OCC)C>[CH2:19]([O:26][C:27](=[O:39])[NH2:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCOCC1
Agent: CC(C)(C)c1ccc(Br)cc1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: BrCCBr
Solvent: C1CCOC1
Solvent: CCOCC
Product: NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 0.85 g (34.6 mmole) magnesium turnings in 25 mL tetrahydrofuran was added 5 mL of a solution of 5 g (28.8 mmole) 1-bromo-4-tert-butylbenzene in 25 mL tetrahydrofuran. One iodine crystal and 1,2-dibromoethane (0.3 mL) was added and the mixture was heated to reflux to initiate the reaction. The rest of the 1-bromo-4-tert-butylbenzene solution was then added dropwise and the reaction mixture was stirred at room temperature for 1 hr. The remaining magnesium was allowed to settle and the supernatant was added in portions to a cooled, previously prepared mixture of 8 g (27.4 mmole) ((S)-1-methyl-2-morpholin-4-yl-2-oxoethyl)-carbamic acid benzyl ester n in 30 mL tetrahydrofuran and 30 mL (60 mmole) 2M isopropylmagnesium chloride in diethyl ether. The reaction mixture was stirred at room temperature for 16 hrs. The mixture was then added to a well-stirred mixture of 100 mL 5% hydrochloric acid and crushed ice. The mixture was extracted with two 50 mL portions ethyl acetate. The organic phase was washed with 25 mL saturated sodium chloride, dried (magnesium sulfate) and concentrated under reduced pressure. (S)-2-(4-tert-Butylphenyl)-1-methyl-2-oxoethyl]-carbamic acid benzyl ester o was isolated as a solid, 9.2 g. m.p. 156-158° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C@H:12]2[CH2:16][N:15]([C@H:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:18])[C:14](=O)[CH2:13]2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C:9]1([C@@H:12]2[CH2:13][CH2:14][N:15]([C@H:17]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH3:18])[CH2:16]2)[CH2:10][CH2:11]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](c1ccccc1)N1C[C@H](C2(NC(=O)OC(C)(C)C)CC2)CC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C[C@@H](c1ccccc1)N1CC[C@@H](C2(NC(=O)OC(C)(C)C)CC2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.2 %

Procedure:
4-(R)-[1-(tert-butoxycarbonylamino)cyclopropyl]-1-[1-(S)-phenylethyl]pyrrolidin-2-one (10.4 g, 30.2 mmol) was dissolved in anhydrous tetrahydrofuran (100 ml) and a 1.0M borane-tetrahydrofuran complex/tetrahydrofuran solution (90.7 ml, 90.7 mmol) was added dropwise gradually thereto under a nitrogen atmosphere while cooling with ice. After completion of dripping, it was stirred for 16 hours under the condition of from ice-cooling to room temperature. After slowly adding an aqueous solution (100 ml) of potassium carbonate (25.0 g, 181 mmol) to the reaction solution while cooling with ice, it was heated under reflux was for 1.5 hours. After letting the reaction solution cool, it was extracted with ethyl acetate (10 ml×2) and then washed with saturated saline solution (100 ml) The organic layer was then dried over anhydrous sodium sulfate, and after filtering, the filtrate was concentrated under a reduced pressure. The concentrate was applied to a silica gel chromatography and 8.20 g (82%) of the title compound was obtained in the form of colorless crystals from a chloroform:methanol=100:1 to 30:1 eluate.
Reaction SMILES: FC1C=CC(C[N:7]2[CH2:14][CH2:13][C:10]3([CH2:12][CH2:11]3)[CH2:9][CH:8]2[C:15]([NH:17][C@H:18]([C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=2)[CH3:19])=[O:16])=CC=1.C([O-])=O.[NH4+]>CCO.[Pd]>[CH2:11]1[C:10]2([CH2:13][CH2:14][NH:7][CH:8]([C:15]([NH:17][C@H:18]([C:20]3[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)[CH3:19])=[O:16])[CH2:9]2)[CH2:12]1
Reactant: C[C@H](NC(=O)C1CC2(CCN1Cc1ccc(F)cc1)CC2)c1ccc(C(=O)O)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: C[C@H](NC(=O)C1CC2(CCN1)CC2)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.3 %

Procedure:
4-((1S)-1-(6-(4-fluorobenzyl)-6-azaspiro[2.5]octane-5-carboxamido)ethyl)benzoic acid (single unknown enantiomer) (D127a) (14 mg, 0.034 mmol) was dissolved in EtOH (3 ml) prior addition of Pd/C 10% (18 mg, 0.017 mmol) and ammonium formate (6.5 mg, 0.102 mmol). The heterogeneous solution was left stirring at RT for 24 hrs then catalyst was filtered off and the solvent evaporated in vacuo to afford the title compound (D128) (10 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12].[CH2:20]([Sn](CCCC)(CCCC)C=C)[CH2:21]CC>C1(C)C=CC=CC=1.C(OCC)(=O)C.[F-].[K+].CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[C:14]1([S:11]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([CH:20]=[CH2:21])[CH:3]=3)[NH:7][CH:6]=2)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: O=S(=O)(c1ccccc1)c1c[nH]c2ccc(Br)cc12
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=Cc1ccc2[nH]cc(S(=O)(=O)c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.6 %

Procedure:
5-bromo-3-(phenylsulfonyl)-1H-indole (505 mg, 1.50 mmol) and dichlorobis(tri-o-tolylphosphine)-palladium(II) (118 mg, 0.09 mmol) were dissolved in toluene (5 mL) and stirred for 10 minutes at room temperature under a nitrogen atmosphere. Tributyl(vinyl)tin (619 mg, 1.95 mmol) was added and the mixture was refluxed for 1 hour. The mixture was cooled to room temperature, diluted with ethyl acetate (10 mL), 1 M KF (5 mL) and stirred for 12 hours. The resultant tin salt precipitate is removed by suction filtration and the organic layer was washed with water (5 mL), then brine and dried over MgSO4, filtered and concentrated in vacuo. Purification by flash chromatography (40% ethyl acetate/petroleum ether) gave the title compound as a white solid (313 mg, 74%). Mp: 140-145° C. MS (ES+): 284 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:39])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[O:21][C:20]4[CH:28]=[CH:29][CH:30]=[C:31]([O:32][CH2:33][C:34]([O:36]CC)=[O:35])[C:19]=4[CH2:18]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[C:34]([CH2:33][O:32][C:31]1[C:19]2[CH2:18][C:17](=[CH:16][CH2:15][CH2:14][N:11]3[CH2:10][CH2:9][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)([OH:39])[CH2:13][CH2:12]3)[C:27]3[C:22]([O:21][C:20]=2[CH:28]=[CH:29][CH:30]=1)=[N:23][CH:24]=[CH:25][CH:26]=3)([OH:36])=[O:35]
Reactant: CCOC(=O)COc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)COc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
To a solution of product of example 48 (3.0 g) in methanol (50 ml) was added 1N sodium hydroxide solution (8 ml) and the mixture stirred at room temperature for 1 hour. The reaction mixture was distilled off under reduced pressure. The residue was dissolved with water and neutralized with 1N hydrochloric acid. The precipitation was filtered and washed with water to give the titled compound (2.6 g).
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([O:12][C:13]1[CH:26]=[CH:25][C:16]([C:17]([NH:19][C:20]([CH3:24])([CH3:23])[CH2:21][OH:22])=O)=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)(Cl)Cl>[CH2:5]([O:12][C:13]1[CH:26]=[CH:25][C:16]([C:17]2[O:22][CH2:21][C:20]([CH3:24])([CH3:23])[N:19]=2)=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(CO)NC(=O)c1ccc(OCc2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: CC1(C)COC(c2ccc(OCc3ccccc3)cc2)=N1
Yield: 99 %

Procedure:
Thionyl chloride (11 ml, 150 mmol, 3 eq) is added to a solution of 4-(benzyloxy)-N-(2-hydroxy-1,1-dimethylethyl)benzamide ax1 (14.98 g, 50 mmol, 1 eq) in chloroform (400 ml) and the mixture is heated at reflux for 2 h. The solvent is then removed under vacuum, and the residue is dissolved into dichloromethane. The organic layer is washed with a saturated solution of aqueous sodium bicarbonate, dried over magnesium sulfate, and concentrated under vacuum to give 2-[4-(benzyloxy)phenyl]-4,4-dimethyl-4,5-dihydro-1,3-oxazole ax4 (4.3 g).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[CH3:19][O:20][C:21]1[C:26]([O:27][CH3:28])=[C:25]([O:29][CH3:30])[CH:24]=[CH:23][C:22]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:22]3[CH:23]=[CH:24][C:25]([O:29][CH3:30])=[C:26]([O:27][CH3:28])[C:21]=3[O:20][CH3:19])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: COc1ccc(B(O)O)c(OC)c1OC
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3ccc(OC)c(OC)c3OC)cccc2c1N
Yield: 92 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (106 mg, 0.34 mmol) and 2,3,4-trimethoxyphenyl boronic acid (206 mg, 0.97 mmol) were reacted to afford the title compound (124 mg, 92.1% yield) as a pale-yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.56 (br, 1H), 7.88 (dd, J=8.2 Hz, J′=1.5 Hz, 1H), 7.76 d, J=6.3 Hz, 1H), 7.69 (t, J=7.6 Hz, 1H), 7.09 (d, J=8.6 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 3.94 (s, 3H), 3.92 (s, 3H), 3.62 (s, 3H), 3.45 (q, J=6.7 Hz, 2H), 1.65 (m, J=7.2 Hz, 2H), 0.99 (t, J=7.4 Hz, 3H) MS APCI, m/z=397 (M+H) HPLC 1.70 min.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[C@H:47]12[CH2:53][C@H:52]1[CH2:51][C@@H:50]([CH2:54][NH:55][C:56]1[CH:61]=[N:60][C:59]([C:62]([F:65])([F:64])[F:63])=[CH:58][N:57]=1)[NH:49][CH2:48]2.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][C:2]1[N:7]=[C:6]([C:8]([N:49]2[C@H:50]([CH2:54][NH:55][C:56]3[CH:61]=[N:60][C:59]([C:62]([F:65])([F:63])[F:64])=[CH:58][N:57]=3)[CH2:51][C@H:52]3[C@H:47]([CH2:53]3)[CH2:48]2)=[O:10])[C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)n1
Reactant: FC(F)(F)c1cnc(NC[C@@H]2C[C@@H]3C[C@@H]3CN2)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2nccn2)c(C(=O)N2C[C@H]3C[C@H]3C[C@H]2CNc2cnc(C(F)(F)F)cn2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6-methyl-3-(2H-1,2,3-triazol-2-yl)-2-pyridinecarboxylic acid D40 (33.0 mg) was dissolved in 1 ml of DCM, then TBTU (61.3 mg, 0.191 mmol) and DIPEA (0.033 ml, 0.191 mmol) were added. The suspension was stirred for 30 minutes at room temperature. N-[(1S,4S,6S)-3-azabicyclo[4.1.0]hept-4-ylmethyl]-5-(trifluoromethyl)-2-pyrazinamine D31 (40 mg) dissolved in 1 ml of DCM was added and the reaction was stirred overnight at room temperature. 3 ml of NaHCO3 saturated solution were added, and the aqueous layer was extracted with DCM. The organic layers were collected together, dried through a phase separator and concentrated under vacuum to give a crude which was purified by SCX chromatography (column size 5 g). A second purification was performed by Silica —NH chromatography (Biotage SP—column size 25 g, using Cy:EtOAc=5:5 to EtOAc). It was recovered the title compound E6 (30 mg). UPLC: (Acid Final_QC): rt=0.76 and 0.80 minutes (rotamers present), peaks observed: 459 (M+1). C21H21F3N8O requires 458. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.38 (s, 1 H) 8.28-8.22 (m, 1 H) 8.08-8.06 (s, 2 H), 7.90-7.78 (m, 2 H), 7.57-7.51 (m, 1 H) 4.20-4.08 (m, 1 H) 3.76-3.40 (m, 3 H), 2.68-2.61 (m, 1 H), 2.56 (s, 3 H), 2.44-2.35 (m, 1 H), 1.28-0.95 (m, 2 H), 0.92-0.83 (m, 1 H), 0.68-0.60 (m, 1 H), 0.24-0.18 (m, 1 H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:13])([CH3:12])[CH3:11])[CH:3]=[N:2]1.[I:14]I.[OH-].[K+]>CN(C=O)C>[I:14][C:3]1[C:4]2[C:9](=[C:8]([C:10]([OH:13])([CH3:11])[CH3:12])[CH:7]=[CH:6][CH:5]=2)[NH:1][N:2]=1
Reactant: CC(C)(O)c1cccc2cn[nH]c12
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)(O)c1cccc2c(I)n[nH]c12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In a round-bottomed flask, 2-(1H-indazol-7-yl)-propan-2-ol (204 mg, 1.16 mmol) was dissolved in DMF (3 ml) and iodine (588 mg, 2.32 mmol) and potassium hydroxide (251 mg, 4.48 mmol) were added. The dark brown suspension was stirred at room temperature for 5 h then quenched with 10% aqueous NaHSO3 and extracted with a mixture of diethyl ether and EtOAc (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated to afford 2-(3-iodo-1H-indazol-7-yl)-propan-2-ol as a light yellow oil which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:8])=[CH:5][CH:4]=1.[O:17]1CCOCC1>>[O:17]=[C:9]([C:7]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:16][CH:15]=1)=[O:8])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)CC(=O)c1ccc(OC)cc1
Reactant: C1COCCO1
Product: CCOC(=O)C(=O)C(=O)c1ccc(OC)cc1
Temperature: 25 °C

Procedure:
A suspension of ethyl p-methoxybenzoylacetate (16.3 mL, 85 m mol) and SeO2 (9.9 g, 89 m mol) in 80 mL of dioxane was heated to reflux overnight. After being cooled down to rt, the reaction mixture was filtered to remove inorganic solid. The filtrate was concentrated under reduced pressure and treated with benzene. The benzene solution was concentrated to dryness under reduced pressure to yield ethyl 2,3-dioxo-(p-methoxyphenyl) -propionate, which was used in next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[S:8][C:9]([C:12]([O:14]C)=[O:13])=[CH:10][CH:11]=2)=[CH:4][CH:3]=1.[Li+].[OH-].Cl>O1CCOCC1>[CH3:1][C:2]1[S:6][C:5]([C:7]2[S:8][C:9]([C:12]([OH:14])=[O:13])=[CH:10][CH:11]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(-c2ccc(C)s2)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1ccc(-c2ccc(C(=O)O)s2)s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.9 %

Procedure:
The product of Step 14a (0.37 g, 1.54 mmol), dioxane (5 mL) and LiOH (1N, 3.1 mL, 3.1 mmol) are placed in a flask. Additional dioxane (5 mL) is then added for solubility and stirred for 24 h at rt. 1N HCl is added slowly until pH<6, whereupon a precipitate forms. The precipitate is then collected by filtration, rinsed with water, and dried in a 70° C. vacuum oven to provide the product as a yellow solid (0.30 g, 86%). MS for C10H8O2S2 (ESI) (M−H)+ m/z 223.
Reaction SMILES: Cl.[O:2]=[C:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([NH:17][CH:18]([CH3:20])[CH3:19])[CH:16]=1)[C:11]([OH:13])=O.Cl.[CH2:22]([O:29][C:30](=[O:44])[NH:31][CH2:32][C@@H:33]([OH:43])[C@@H:34]([NH2:42])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([O:29][C:30](=[O:44])[NH:31][CH2:32][C@@H:33]([OH:43])[C@@H:34]([NH:42][C:11]([C:10]1[CH:9]=[C:8]([N:4]2[CH2:5][CH2:6][CH2:7][C:3]2=[O:2])[CH:16]=[C:15]([NH:17][CH:18]([CH3:20])[CH3:19])[CH:14]=1)=[O:13])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)Nc1cc(C(=O)O)cc(N2CCCC2=O)c1
Reactant: N[C@@H](Cc1ccccc1)[C@H](O)CNC(=O)OCc1ccccc1
Agent: Cl
Product: CC(C)Nc1cc(C(=O)N[C@@H](Cc2ccccc2)[C@H](O)CNC(=O)OCc2ccccc2)cc(N2CCCC2=O)c1

Procedure:
Description 107 was prepared in an analogous manner to Description 105 from 3-(2-oxo-pyrrolidin-1-yl)-5-isopropylamino-benzoic acid hydrochloride (A44) and ((2R,3S)-3-amino-2-hydroxy-4-phenyl-butyl)-carbamic acid benzyl ester (D104).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:20])[N:11]([CH2:21][C:22](O)=[O:23])[CH2:10][C@H:9]1[CH3:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:26][C:27]([C:31]1[CH:32]=[C:33]2[NH:39][CH2:38][C:37]([CH3:41])([CH3:40])[C:34]2=[N:35][CH:36]=1)([F:30])[CH2:28][CH3:29].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:20])[N:11]([CH2:21][C:22]([N:39]2[C:33]3[C:34](=[N:35][CH:36]=[C:31]([C:27]([F:30])([F:26])[CH2:28][CH3:29])[CH:32]=3)[C:37]([CH3:40])([CH3:41])[CH2:38]2)=[O:23])[CH2:10][C@H:9]1[CH3:25])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: C[C@@H]1CN(CC(=O)O)[C@@H](CN2CCCC2=O)CN1C(=O)OC(C)(C)C
Reactant: CCC(F)(F)c1cnc2c(c1)NCC2(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(F)(F)c1cnc2c(c1)N(C(=O)CN1C[C@@H](C)N(C(=O)OC(C)(C)C)C[C@@H]1CN1CCCC1=O)CC2(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.4 %

Procedure:
(2R,5S)-4-Carboxymethyl-2-methyl-5-(2-oxo-pyrrolidin-1-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (0.20 g, 0.56 mmol) and 6-(1,1-difluoro-propyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (0.15 g, 0.6 mmol) were dissolved in DMF (2.8 mL). N,N-Diisopropylethylamine (0.36 g, 2.8 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.43 g, 1.1 mmol) were added and the reaction stirred at room temperature for 18 h. Saturated aqueous sodium bicarbonate (10 mL) was added and the aqueous phase extracted with EtOAc (3×10 mL). The combined organic extracts were diluted with petroleum spirit (20 mL), washed with water (3×), dried with sodium sulfate, filtered and concentrated. Chromatography (silica gel, gradient elution, 0-5%, methanol in EtOAc) gave the title compound (0.178 g), MS: [M+H]+=564.
Reaction SMILES: [CH:1]1([C:7](=[O:28])[CH2:8][CH2:9][NH:10][CH:11]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:12]([O:14]CC)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:29]#[C:30][OH:31]>>[CH2:26]([O:25][C:23]([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:11]1[N:10]([CH2:9][CH2:8][C:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[O:28])[C:30](=[O:31])[NH:29][C:12]1=[O:14])=[O:24])[CH3:27]
Reactant: N#CO
Reactant: CCOC(=O)CCCCCCC(NCCC(=O)C1CCCCC1)C(=O)OCC
Product: CCOC(=O)CCCCCCC1C(=O)NC(=O)N1CCC(=O)C1CCCCC1

Procedure:
Reaction of diethyl 2-((3cyclohexyl-3-oxopropyl)amino)nonanedioate (20.8 g) with cyanic acid using the general procedure of Example 2d afforded 5-(6-ethoxycarbonylhexyl)-1-(3-cyclohexyl-3-oxopropyl)hydantoin which was converted to the corresponding acid which crystallised from ether, m.p. 77.5°-78.5° C.