Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1]I.[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.C(=O)([O-])[O-].[K+].[K+].S(=O)(O)[O-].[Na+]>CN(C=O)C.O>[I:1][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:7]=2)[NH:3][CH:4]=1
Reactant: II
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: O=S([O-])O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2[nH]cc(I)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
A brown solution of I2 (3.98 g, 15.70 mmol) in DMF (4.0 mL) was added dropwise over 5 min to a yellow-brown suspension of methyl 1H-indole-5-carboxylate (Aldrich, St. Louis, Mo.; 2.5 g, 14.27 mmol) and potassium carbonate (3.96 g, 28.7 mmol) in DMF (14.0 mL), and the resulting mixture was stirred at 25° C. for 16 h. The mixture was added to a mixture of ice (10 g), H2O (200 mL), and sodium bisulfite (2.228 g, 21.41 mmol). The resulting mixture was extracted with DCM (2×200 mL), and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to provide methyl 3-iodo-1H-indole-5-carboxylate (3.87 g, 12.85 mmol, 90%) as a brown solid: MS (ESI, pos. ion) m/z: 301.9 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 8.22 (s, 1H), 8.00-8.03 (m, 1H), 7.96 (dd, J=8.6, 1.4 Hz, 1H), 7.39 (d, J=8.8 Hz, 1H), 7.37 (d, J=2.3 Hz, 1H), 3.96 (s, 3H).
Reaction SMILES: C(OC([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:22]3[CH:23]=[N:24][N:25]([CH:27]([F:29])[F:28])[CH:26]=3)[C:19]3[C:30](=[O:40])[N:31](C(OC(C)(C)C)=O)[CH2:32][C:18]=3[C:17]=2[F:41])[CH2:13][CH2:12][O:11][CH2:10]1)=O)(C)(C)C.Cl>CC(O)C>[NH2:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:22]3[CH:23]=[N:24][N:25]([CH:27]([F:28])[F:29])[CH:26]=3)[C:19]3[C:30](=[O:40])[NH:31][CH2:32][C:18]=3[C:17]=2[F:41])[CH2:13][CH2:12][O:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(-c2cnn(C(F)F)c2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Agent: Cl
Solvent: CC(C)O
Product: N[C@H]1COCC[C@H]1Nc1nc(-c2cnn(C(F)F)c2)c2c(c1F)CNC2=O
Temperature: 75 °C
Reaction time: 3 h
Yield: 20.7 %

Procedure:
tert-Butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (126 mg, 0.998 mmol) was dissolved in 2-propanol (5 mL) and the solution was heated to 75° C. with a heating block. Then 2M HCl (2.5 mL) was added, the temperature was lowered to 65° C., and the reaction mixture was stirred for 3 h. The solution was concentrated and purified by preparatory HPLC eluting with water (10 mM NH4HCO3) and ACN/water (80/20 v/v, 10-50% gradient, 10 mM NH4HCO3) to give the title compound as a white solid (79 mg, 96%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.75-1.77 (m, 1H), 2.09-2.12 (m, 1H), 3.60-3.63 (m, 1H), 3.76-3.77 (m, 1H), 3.88-3.98 (m, 3H), 4.44 (d, J=6.35 Hz, 2H), 4.54-4.55 (m, 1H), 7.17 (d, J=5.86 Hz, 1H), 7.89 (br s, 1H), 8.54 (s, 1H), 8.58 (s, 1H), 9.43 (s, 1H). [M+H] calc'd for C16H17F3N6O2, 383. found, 383.
Reaction SMILES: Cl.CO[C:4]1[CH:9]=[CH:8][C:7]([C@H:10]([NH:12][C@@H:13]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[CH3:14])[CH3:11])=[CH:6][CH:5]=1.C1(C(N)C)C=CC=CC=1.C(C1C2C(=CC=CC=2)C=CC=1)(=O)C.C([BH3-])#N.[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[C:15]1([CH:13]([NH:12][CH:10]([C:7]2[CH:8]=[CH:9][CH:4]=[CH:5][CH:6]=2)[CH3:11])[CH3:14])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: COc1ccc([C@@H](C)N[C@H](C)c2cccc3ccccc23)cc1
Agent: [Ti+4]
Agent: CC(=O)c1cccc2ccccc12
Agent: CC(C)[O-]
Product: CC(NC(C)c1cccc2ccccc12)c1ccccc1

Procedure:
In a similar fashion equal molar amounts of (R))-1-phenylethylamine, 1′-acetonaphthone and 1.25 equivalents of titanium(IV) isopropoxide were mixed and the resulting intermediate imine was reduced with ethanolic sodium cyanoborohydride. Work-up and chromatography yielded N-[1-(1-naphthyl)ethyl)-1-phenylethylamine, 4G, as a clear, colorless oil; m/z (rel. int.) 275 (M+, 16), 260 (79), 155 (100), 127 (27), 105 (70), 77 (32).
Reaction SMILES: C1(NC2CCCCC2)CCCCC1.Br[C:15]1[CH:23]=[CH:22][C:18]([N:19]([CH3:21])[CH3:20])=[CH:17][CH:16]=1.[CH3:24][C:25]([OH:29])([C:27]#[CH:28])[CH3:26].[Cl-].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Cu]I.C1([B-](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.C1(C)C=CC=CC=1.O1CCCC1>[CH3:20][N:19]([C:18]1[CH:22]=[CH:23][CH:15]=[CH:16][C:17]=1[C:28]#[C:27][C:25]([CH3:26])([OH:29])[CH3:24])[CH3:21]
Reactant: C#CC(C)(C)O
Reactant: CN(C)c1ccc(Br)cc1
Agent: [Cu]I
Agent: [Pd+2]
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CN(C)c1ccccc1C#CC(C)(C)O
Yield: 86.2 %

Procedure:
A 50-ml four-necked flask was equipped with a stirrer, a thermometer and a reflux condenser. 0.034 g (0.15 mmol) of palladium (II) acetate, 0.019 g (0.1 mmol) of copper (I) iodide, 1.088 g (6 mmol) of dicyclohexylamine and 5 ml of tetrahydrofuran were weighed in the flask, followed by stirring. Further, 0.157 g (0.3 mmol) of tri-tert-butylphosphonium tetraphenylborate obtained in Example A-1 was weighed in air and added into the flask. The flask was purged with argon, followed by stirring at 30° C. for 30 minutes. 1.000 g (5 mmol) of 4-bromo-N,N-dimethylaniline and 0.505 g (6 mmol) of 2-methyl-3-butyne-2-ol were added, followed by stirring at 30° C. for 17 hours. After the completion of the reaction, 10 ml of tetrahydrofuran, 5 ml of toluene and 15 ml of saturated sodium chloride solution were added, followed by separation. The organic phase was purified by column chromatography to afford 0.876 g of 4-(N,N-dimethylaminophenyl)-2-methyl-3-butyne-2-ol (yield: 86 mol % based on 4-bromo-N,N-dimethylaniline). The identification of the product was made by mass spectroscopy, 1H-NMR and 13C-NMR.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:9][CH2:10][CH3:11])[NH:5][C:6]=1[CH:7]=[O:8].[C:12]([O:16][C:17]([C:19]1[C:20]([C:25]2[CH:30]=[CH:29][C:28]([CH2:31]Br)=[C:27]([F:33])[CH:26]=2)=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:12]([O:16][C:17]([C:19]1[C:20]([C:25]2[CH:30]=[CH:29][C:28]([CH2:31][N:5]3[C:6]([CH:7]=[O:8])=[C:2]([Cl:1])[N:3]=[C:4]3[O:9][CH2:10][CH3:11])=[C:27]([F:33])[CH:26]=2)=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)c(F)c1
Reactant: CCOc1nc(Cl)c(C=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1F
Yield: 76.7 %

Procedure:
A solution of 4-chloro-2-ethoxyimidazole-5-carboxaldehyde (295.0 mg, 1.7 mmol), 4′-bromomethyl-3′-fluorobiphenyl-2-carboxylic acid t-butyl ester (617 mg, 1.7 mmol) and potassium carbonate (467 mg, 3.4 mmol) in DMF (6 mL) was stirred overnight. The mixture was filtered and concentrated in vacuo. Silica gel chromatography (hexane:EtOAc) afforded intermediate (27a) (598 mg).
Reaction SMILES: FC(F)(F)C([O-])=O.[NH2:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][CH2:11][CH2:12][NH:13][C:14](=[NH:16])[NH2:15].[NH:20](C(OC(C)(C)C)=O)[C@H:21]([C:23](O)=[O:24])[CH3:22].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[NH2:20][C@H:21]([C:23]([NH:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][CH2:11][CH2:12][NH:13][C:14](=[NH:15])[NH2:16])=[O:24])[CH3:22]
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])C(F)(F)F
Solvent: CN(C)C=O
Product: C[C@H](N)C(=O)N[C@@H](CCCNC(=N)N)C(=O)O

Procedure:
443 g of trifluoroacetate of H-Arg (NO2) Leu-NH2 are dissolved in 2 l of DMF. 200 g of Boc-Ala-OH, then 500 g of BOP are added. The pH is adjusted to 7 with pH paper (on small samples of the reaction medium) with the aid of NEM. The medium is stirred and the development of the reaction is followed by TLC. The reaction is terminated after 4 hrs. The medium is evaporated to dryness in vacuo at 25°. The residue is taken up in 2 l of water and 2 l of ethyl acetate. The organic phase is washed with a 5% aqueous solution of NaHCO3, with water, dried and evaporated. The tripeptide is recrystallized in ethyl-acetate/ether, and finally dried in vacuo. It is monitored by TLC and NMR.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]5[C:28](=[O:40])[N:29]([C:33]6[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=6)[N:30]=[CH:31][CH:32]=5)=[O:26])=[CH:20][C:19]=4[F:41])=[C:11]3[C:10]([C:42]3[N:43]([CH3:47])[CH:44]=[CH:45][N:46]=3)=[N:9]2)=CC=1.C(O)(C(F)(F)F)=O>>[F:41][C:19]1[CH:20]=[C:21]([NH:24][C:25]([C:27]2[C:28](=[O:40])[N:29]([C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)[N:30]=[CH:31][CH:32]=2)=[O:26])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:8][N:9]=[C:10]([C:42]3[N:43]([CH3:47])[CH:44]=[CH:45][N:46]=3)[C:11]=12
Reactant: COc1ccc(Cn2nc(-c3nccn3C)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cn1ccnc1-c1n[nH]c2nccc(Oc3ccc(NC(=O)c4ccnn(-c5ccc(F)cc5)c4=O)cc3F)c12
Temperature: 60 °C
Yield: 60.2 %

Procedure:
N-(4-(1-(4-Methoxybenzyl)-3-(1-methyl-1H-imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (127 mg, 0.192 mmol) and TFA (2 mL) were charged in a 50 mL single-neck, round-bottomed flask. The reaction mixture was stirred at 60° C. until the starting material had been consumed (overnight). Then the reaction was cooled to room temperature and the CF3COOH was removed under reduced pressure. The residue was partitioned between DCM (50 mL) and saturated NaHCO3 (50 mL). The phases were separated and the aqueous phase was extracted with DCM (3×50 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford product (62.5 mg, 60.2%). LRMS (APCI pos): >99% purity, 254 nm, m/e 541 (M+1). 1H NMR (400 MHz, DMSO-d6 δ 14.01 (s, 1H), 11.71 (s, 1H), 8.37 (m, 2H), 8.27 (d, 1H), 8.06 (m, 1H), 7.76 (d, 1H), 7.68 (m, 2H), 7.52-7.63 (m, 2H), 7.47 (d, 1H), 7.41 (m, 2H), 6.36 (d, 1H), 3.31 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[O:13])[CH:5]=[CH:4][N:3]=1.[CH2:29]([N:36]=[C:37]=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[CH2:29]([NH:36][C:37](=[O:38])[NH:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:24])[F:23])[CH:16]=2)=[O:13])[CH:5]=[CH:4][N:3]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Nc1cc(CNc2ccccc2C(=O)Nc2cccc(C(F)(F)F)c2)ccn1
Reactant: O=C=NCc1ccccc1
Solvent: ClCCl
Product: O=C(NCc1ccccc1)Nc1cc(CNc2ccccc2C(=O)Nc2cccc(C(F)(F)F)c2)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
100 mg (0.26 mmol) of 2-[(2-amino-pyridin-4-ylmethyl)-amino]-N-(3-trifluoromethyl-phenyl)-benzamide is mixed in 2.5 ml of methylene chloride with 37.9 mg (0.29 mmol) of benzyl isocyanate, and it is stirred overnight at room temperature. After concentration by evaporation, the residue is chromatographed. 66 mg (49% of theory) of 2-{[2-(3-benzyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(3-trifluoromethyl-phenyl)-benzamide with a melting point of 153° C. is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:17][CH:16]3[N:18]([CH3:19])[CH:13]([CH2:14][CH2:15]3)[CH2:12]1)[CH:6]=[CH:5]2.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C[Si]([N-:37][Si](C)(C)C)(C)C.[Li+]>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].O1CCCC1>[CH3:19][N:18]1[CH:16]2[CH2:15][CH2:14][CH:13]1[CH2:12][CH:11]([N:7]1[C:8]3[C:4](=[CH:3][C:2]([NH2:37])=[CH:10][CH:9]=3)[CH:5]=[CH:6]1)[CH2:17]2
Reactant: CN1C2CCC1CC(n1ccc3cc(Br)ccc31)C2
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CN1C2CCC1CC(n1ccc3cc(N)ccc31)C2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
Compound 84 (73 mg, 0.2287 mmol), tris(dibenzylideneacetone)dipalladium (0) (20.9 mg, 0.0229 mmol) and anhydrous tetrahydrofuran (10 mL) were charged to a dry argon purged flask fitted with magnetic stir bar and condenser. A solution of tri-tert-butylphosphine (10 wt % in hexane, 92.5 mg, 0.0457 mmol) is added followed by dropwise addition of a 1M tetrahydrofuran solution of lithium bis(trimethylsilyl)amide (0.686 ml, 0.686 mmol) and mixture refluxed for a period of 90 minutes. The mixture was cooled to room temperature then to 0° C., quenched with 1M HCl (10 mL) and stirred for 15 minutes. The solution was diluted with ethyl acetate and conc. NH4OH added to adjust pH to 9. The mixture was transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulphate, filtered, concentrated to yield crude. The crude amine was combined with a second crude from an identical reaction and the residue purified via chromatography on silica gel (EtOAc:methanol:Et3N, 8:1:1) to yield a brown solid 85 (52 mg, 37.6%) as a 5:1 or 1:5 mixture of endo/exo stereoisomers. 1H NMR (major isomer-DMSO-d6) δ 1.53-1.70 (m, 4H), 2.00-2.09 (m, 2H), 2.18 (s, 3H), 3.17-3.32 (m, 2H), 4.54 (quintuplet, 1H, J=8.2 Hz), 6.11 (d, 1H, J=3.1 Hz), 6.49 (dd, 1H, J=8.6, 2.1 Hz), 6.65 (d, 1H, J=1.9 Hz), 7.05 (d, 1H, J=8.7 Hz), 7.26 (d, 1H, J=3.2 Hz); ESI-MS (m/z, %): 256 (MH+, 100%).
Reaction SMILES: Cl.O.[C:3]([O:7][C:8]1[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[CH:11]=[CH:10][C:9]=1[C:17]1([NH:31][C:32](=[O:35])[CH2:33][CH3:34])[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[N+:27]([O-])=O)[C:18]1=[O:30])(=[O:6])[CH2:4][CH3:5]>C(O)C.[Fe]>[C:3]([O:7][C:8]1[CH:13]=[C:12]([CH:14]([CH3:15])[CH3:16])[CH:11]=[CH:10][C:9]=1[C:17]1([NH:31][C:32](=[O:35])[CH2:33][CH3:34])[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[NH2:27])[C:18]1=[O:30])(=[O:6])[CH2:4][CH3:5]
Reactant: CCC(=O)NC1(c2ccc(C(C)C)cc2OC(=O)CC)C(=O)c2cccc([N+](=O)[O-])c2C1=O
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCC(=O)NC1(c2ccc(C(C)C)cc2OC(=O)CC)C(=O)c2cccc(N)c2C1=O
Yield: 82.8 %

Procedure:
Iron powder (0.03 g, 0.5 mmol), conc. HCl (0.05 ml), and water (0.5 ml) were added in that order to a solution of 5-isopropyl-2-(4-nitro-1,3-dioxo-2-propionamido-2,3-dihydro-1H-inden-2-yl)phenyl propionate (40 mg, 0.08 mmol) in ethanol (5 ml). The reaction mixture was heated for 1 hrs under reflux. The reaction mixture was hot filtered off, the filtrate was concentrated in a vacuum and purified by column chromatography (ethylacetate:hexane=1:4 to 1:2) to afford the title compound (28 mg, 75%).
Reaction SMILES: [Na].[OH:2][C:3]([C:10]([F:13])([F:12])[F:11])([C:6]([F:9])([F:8])[F:7])[C:4]#[N:5].[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1>CN(C)C=O>[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][O:2][C:3]([C:6]([F:7])([F:9])[F:8])([C:10]([F:11])([F:12])[F:13])[C:4]#[N:5])=[CH:17][CH:16]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: N#CC(O)(C(F)(F)F)C(F)(F)F
Agent: [Na]
Solvent: CN(C)C=O
Product: N#CC(OCc1ccc(Cl)cc1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C

Procedure:
A mixture of 2-hydroxy-3,3,3-trifluoro-2-trifluoromethylpropionitrile sodium salt (43 g.), 4-chlorobenzyl chloride (25.6 g.) and dimethylformamide (200 ml.) is stirred at ambient temperature for 5 dayus, then evaporated in vacuo. Water is added to the residue, and the mixture is extracted with 1,2,2-trichloro-1,1,2-trifluoroethane. The extract is dried with sodium sulphate, and evaporated. The residue is distilled to give 2-(4-chlorobenzyloxy)-3,3,3-trifluoro-2-trifluoromethylpropionitrile, b.p. 54°-64° C. at 1 mm. pressure (41.0 g.).
Reaction SMILES: [Br:1][C:2]1[C:7]([Cl:8])=[C:6]([F:9])[CH:5]=[C:4]([Br:10])[C:3]=1N.C(ON=O)CC(C)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([Br:10])[CH:5]=[C:6]([F:9])[C:7]=1[Cl:8]
Reactant: Nc1c(Br)cc(F)c(Cl)c1Br
Agent: CC(C)CCON=O
Solvent: CN(C)C=O
Product: Fc1cc(Br)cc(Br)c1Cl
Temperature: 70 °C
Yield: 80.2 %

Procedure:
A solution of 2,6-dibromo-3-chloro-4-fluoro-phenylamine (1a, 4.85 g, 16 mmol, 1 eq.) in DMF (20 mL) was added to a solution of isoamylnitrite (3.46 mL, 25.6 mmol, 1.6 eq.) in DMF (12 mL) at 70° C. The mixture was heated at 70° C. for 3 h before it was cooled to room temperature, quenched with 1 N NaOH aqueous solution (150 mL), and extracted with EtOAc (200 mL). The EtOAc extract was washed with brine (100 mL×2), dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (heptane) to give desired product 2a as colorless oil (3.70 g, 80%).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[CH2:4][S:5][CH2:6][CH3:7].[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]Br>CCCCCC.C1COCC1>[CH2:10]([Br:9])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:8][CH2:3][CH2:4][S:5][CH2:6][CH3:7]
Reactant: CCSCCO
Reactant: BrCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCSCCOCCCCCCBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
NaH (1.85 g, 0.046 mol) was washed with hexane and then suspended in dry THF (60 mL). 3-Thiapentane-1-ol (4.67 g, 0.04 mol ) in THF (20 mL) was added and stirred for 1 h at room temperature. 1,6-Dibromohexane (9.76 g, 0.04 mol) in THF (20 mL) was added and the mixture was refluxed for 20 h. After evaporation of the solvent, the residue was dissolved in ethyl acetetate (200 mL). The organic phase was washed with water (2×50 mL), and dried (Na2SO4). The crude product was purified by Kugelrohr distillation to give 7-oxa-10-thiadodecyl bromide (3.34 g, 31%); bp 48°-56° C./0.04 torr; NMR: 1.25 (3H, t, J=7 Hz), 1.2-1.9 (8H, m), 2.59 (2H, q, J=7 Hz), 2.68 (2H, t, J=7 Hz), and 3.2-3.7 ppm (6H, m ).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]3[CH2:11][C:12]4[C:17]([C:9]3=[C:8]([CH:18]=O)[C:7]=2[N:20]=1)=[CH:16][CH:15]=[CH:14][CH:13]=4.[H-].[Na+].C(OP([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])(OCC)=O)C>C1COCC1>[CH2:36]([O:35][C:33](=[O:34])[CH2:32][CH:31]=[CH:18][C:8]1[C:7]2[N:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[N:10]2[CH2:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]=12)[CH3:37]
Reactant: CCOC(=O)CCP(=O)(OCC)OCC
Reactant: COc1ccc2c(n1)c(C=O)c1n2Cc2ccccc2-1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC=Cc1c2n(c3ccc(OC)nc13)Cc1ccccc1-2

Procedure:
10.7 mmol of the compound obtained in Step E of Preparation 1 in 20 ml of anhydrous THF are placed in the presence of 1.2 eq of NaH (60% in oil) in 25 ml of anhydrous THF and of 1.2 eq of ethyl 3-(diethoxyphosphoryl)propanoate. The title compound is obtained after 3 hours' stirring at room temperature and gentle refluxing overnight.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[CH:20]=[C:19]([OH:21])[CH:18]=[C:17]([F:22])[C:15]=4[N:16]=3)=[CH:8][C:7]=2[F:23])[CH2:3][CH2:2]1.O[CH2:25][C@@H:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH3:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[CH:20]=[C:19]([O:21][CH2:27][C@@H:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:34])[CH3:33])[CH3:25])[CH:18]=[C:17]([F:22])[C:15]=4[N:16]=3)=[CH:8][C:7]=2[F:23])[CH2:2][CH2:3]1
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: Oc1cc(F)c2nc(-c3ccc(OCC4CC4)c(F)c3)oc2c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C[C@@H](COc1cc(F)c2nc(-c3ccc(OCC4CC4)c(F)c3)oc2c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
To a solution of 2-(4-(cyclopropylmethoxy)-3-fluorophenyl)-4-fluoro-1,3-benzoxazol-6-ol (110 mg), tert-butyl ((2S)-1-hydroxypropan-2-yl)carbamate (91.0 mg) and triphenylphosphine (136 mg) in THF (5 mL) was added dropwise diisopropyl azodicarboxylate toluene solution (1.9 M, 0.274 mL) at 0° C., and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to give the title compound (159 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16](=[O:36])[NH:17][C:18]3[CH:19]=[C:20]4[CH2:35][C:25]5([C:33]6[C:28](=[N:29][CH:30]=[CH:31][CH:32]=6)[NH:27][C:26]5=[O:34])[CH2:24][C:21]4=[N:22][CH:23]=3)[C:13](=[O:37])[C:12]3([CH2:43][O:42][CH2:41][CH2:40][O:39][CH2:38]3)[N:11](C(OC(C)(C)C)=O)[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl>>[F:8][C:6]1[CH:5]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([NH:17][C:18]3[CH:19]=[C:20]4[CH2:35][C:25]5([C:33]6[C:28](=[N:29][CH:30]=[CH:31][CH:32]=6)[NH:27][C:26]5=[O:34])[CH2:24][C:21]4=[N:22][CH:23]=3)=[O:36])[C:13](=[O:37])[C:12]3([CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43]3)[NH:11][CH2:10]2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](c2cc(F)cc(F)c2)N(CC(=O)Nc2cnc3c(c2)CC2(C3)C(=O)Nc3ncccc32)C(=O)C12COCCOC2
Agent: Cl
Product: O=C(CN1C(=O)C2(COCCOC2)NC[C@H]1c1cc(F)cc(F)c1)Nc1cnc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Temperature: 50 °C
Reaction time: 1 h

Procedure:
0.18 g (0.26 mmol) (3R)-tert-butyl 3-(3,5-difluorophenyl)-5-oxo-4-(2-oxo-2-(2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridin-6,3′-pyrrolo[2,3-b]pyridin]-3-ylamino)ethyl)-8,11-dioxa-1,4-diazaspiro[5.6]dodecane-1-carboxylate were combined with 30 ml of a 1N methanolic hydrochloric acid solution and stirred for 1 h at 50° C. The reaction mixture was concentrated by rotary evaporation and purified by HPLC. The product fractions were evaporated down, neutralised with sodium hydrogen carbonate and the aqueous phase was extracted with DCM. The organic phase was concentrated by rotary evaporation. The residue was triturated with diethyl ether, suction filtered, washed with diethyl ether and dried.
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]2[N:21]=[C:20]([C:22]([NH:24][C:25]3[C:34]([CH3:35])=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][C:26]=3[CH3:36])=[O:23])[C:19]([CH3:37])=[CH:18][CH:17]=2)[CH2:11]1)(C(C)(C)C)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]2[N:21]=[C:20]([C:22]([NH:24][C:25]3[C:26]([CH3:36])=[CH:27][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:33][C:34]=3[CH3:35])=[O:23])[C:19]([CH3:37])=[CH:18][CH:17]=2)[CH2:11]1
Reactant: COC(=O)c1cc(C)c(NC(=O)c2nc(N3CCCC(CO[Si](C)(C)C(C)(C)C)C3)ccc2C)c(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1cc(C)c(NC(=O)c2nc(N3CCCC(CO)C3)ccc2C)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.7 %

Procedure:
To a solution of methyl 4-[[6-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-piperidyl]-3-methyl-pyridine-2-carbonyl]amino]-3,5-dimethyl-benzoate (0.22 g, 0.873 mmol) in THF (3 ml) is added Bu4NF 1.0 M in THF (2.00 ml) at 0° C. The reaction mixture is gradually warmed to ambient temperature. After 8 hours, the reaction mixture is diluted with ice-water and extracted twice with ethyl acetate. The organic layers are combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue is purified by flash chromatography (silica gel) over a gradient using 0-40% ethyl acetate in hexanes to afford the title compound as a white solid (0.06 g, 30%). Mass spectrum (m/z): 412.2 (M+1).