Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([F:14])[CH:13]=2)=[CH:6][C:5]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)=[O:16])=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH3:38][N:39]([CH3:46])[C@H:40]1[CH2:44][NH:43][CH2:42][C@@H:41]1[OH:45]>CC(O)C>[CH3:38][N:39]([CH3:46])[C@@H:40]1[C@@H:41]([OH:45])[CH2:42][N:43]([C:2]2[C:7]([C:8]3[CH:9]=[N:10][CH:11]=[C:12]([F:14])[CH:13]=3)=[CH:6][C:5]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:27])([F:28])[F:26])=[CH:20][CH:19]=3)=[O:16])=[CH:4][N:3]=2)[CH2:44]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(-c2cncc(F)c2)c1
Reactant: CN(C)[C@H]1CNC[C@@H]1O
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)[C@H]1CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2cncc(F)c2)C[C@@H]1O
Temperature: 110 °C
Reaction time: 16 h

Procedure:
2-Chloro-5′-fluoro-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide (Stage 236.1, 60 mg, 0.137 mmol) and DIPEA (0.167 mL, 0.959 mmol) were added to a vial containing iPrOH (1 mL). (3S,4S)-4-(dimethylamino)pyrrolidin-3-ol (50 mg, 0.246 mmol) was added. The mixture was stirred at 110° C. for 16 h. The solvent was evaporated off under reduced pressure and the residue was purified by preparative SFC (Column DEAP, from 15% to 20% in 6 min) to afford the title product as a beige foam. HPLC (Condition 10) tR=5.93 min, UPLC-MS (Condition 3) tR=0.81 min, m/z=506.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.14 (s, 6H) 2.52-2.58 (m, 1H) 2.88 (dd, J=11.14, 5.28 Hz, 1H) 3.21 (dd, J=11.34, 5.86 Hz, 1H) 3.28 (dd, J=10.56, 5.86 Hz, 1H) 3.44 (dd, J=11.34, 7.00 Hz, 1H) 4.07 (quin, J=5.28 Hz, 1H) 5.07 (d, J=5.08 Hz, 1H) 7.35 (d, J=9.38 Hz, 2H) 7.85 (d, J=9.38 Hz, 3H) 8.09 (d, J=2.35 Hz, 1H) 8.52 (s, 1H) 8.61 (d, J=2.35 Hz, 1H) 8.78 (d, J=2.35 Hz, 1H) 10.19 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].[C:12](OC=O)(=O)C.CN1C2C(O)=CC=CC=2N=C1.CN1C2C(O)=CC=CC=2N=N1>C1COCC1.C(Cl)(Cl)Cl>[CH3:12][NH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11]
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Reactant: CC(=O)OC=O
Agent: Cn1cnc2cccc(O)c21
Agent: Cn1nnc2cccc(O)c21
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CNc1c(O)cccc1[N+](=O)[O-]
Reaction time: 3 h

Procedure:
The title compound was prepared from 2-amino-3-nitrophenol according to a procedure adapted from Tet. Lett. 23, 3315 (1982). 2-Amino-3-nitrophenol (7.7 g, 50 mmol) in dry THF (20 mL) was treated dropwise with formic-acetic anhydride (130 mmol) in THF (10 mL) at about -5° C. under N2 (g). After stirring 3 hours the mixture was concentrated in vacuo to a viscous oil which was redissolved in THF (12 mL) and treated dropwise with 2M borane-dimethylsulfide in THF (63 mL) at about -5° C. When the addition was complete the mixture was heated to reflux (2 hours), cooled in ice and quenched with MeOH (20 mL). After stirring for 1 hour at about 22° C., anhydrous HCl was bubbled into the solution to acidity it to about pH 2. The mixture was refluxed for 1 hour and concentrated in vacuo. The residue was dissolved in H2O, neutralized with conc. NH4OH and cooled (16 hours) to produce a dark brown solid. This wet material was dissolved in CHCl3, dried over Na2SO4 and concentrated in vacuo to afford a red-brown solid (6.72 g; >95% purity) which was used directly in the syntheses of 3-methylbenzimidazol-4-ol and 3-methylbenzotriazol-4-ol (below).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1B(O)O.[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([Cl:22])[C:20]=1I)[CH2:16][OH:17].ClC1C=C(C=C(Cl)C=1)CO>>[Cl:12][C:13]1[CH:14]=[C:15]([CH2:16][OH:17])[CH:18]=[C:19]([Cl:22])[C:20]=1[C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1]
Reactant: OCc1cc(Cl)c(I)c(Cl)c1
Reactant: OB(O)c1ccc(F)cc1F
Agent: OCc1cc(Cl)cc(Cl)c1
Product: OCc1cc(Cl)c(-c2ccc(F)cc2F)c(Cl)c1
Yield: 72.5 %

Procedure:
Using essentially the same coupling procedure as for Example 8-1, Step 1, but heating 2,4-difluorophenylboronic acid (456 mg, 2.89 mmol) and 3,5-dichloro-4-iodobenzyl alcohol (350 mg, 1.155 mmol) in a microwave at 115° C. for 120 minutes, afforded the title intermediate (242 mg) without formation of any appreciable 3,5-dichlorobenzyl alcohol.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C@H:17]([NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:18](=[O:22])[C:19]([CH3:21])=[CH2:20])=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].C(O)(=O)C>CO>[CH2:26]([O:25][C:24](=[O:33])[NH:23][C@H:17]([C@H:18]([OH:22])[C:19]([CH3:21])=[CH2:20])[CH2:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[CH:15][CH:14]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: C=C(C)C(=O)[C@H](Cc1ccc(CNC(=O)OC(C)(C)C)cc1)NC(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: C=C(C)[C@@H](O)[C@H](Cc1ccc(CNC(=O)OC(C)(C)C)cc1)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Ketone 12 (2.81 g, 4.30 mmol) was dissolved in MeOH (25 mL) and cooled to 0° C. To this were added CeCl3.7H2O (1.5 eq., 6.45 mmol, 2.43 g) and NaBH4 (1.4 eq., 6.0 mmol, 227 mg) portion-wise and the mixture was stirred for 5 minutes. after which TLC analysis indicated a complete conversion. Glacial acetic acid (10 mL) was added and the mixture was concentrated under reduced pressure. The resulting residue was dissolved in EtOAc and extracted with half saturated aq. NaHCO3 (2×) and brine, dried over MgSO4 and concentrated in vacuo. The title compound was obtained as a colourless oil (yield: 1.79 g, 3.94 mmol, 92%). 1H NMR (400 MHz, CDCl3): δ=7.31-7.01 (m, 9H), 5.30 (d, J=9.18 Hz, 1H), 5.06 (s, 1H), 5.00 (d, J=5.19 Hz, 1H), 4.96-4.91 (m, 3H), 4.21 (d, J=4.41 Hz, 1H), 4.16-4.11 (m, 1H), 4.07-3.98 (m, 1H), 2.85 (d, J=12.55 Hz, 1H), 2.65 (dd, J=13.60, 10.41 Hz, 1H), 1.77 (s, 3H), 1.44 (s, 9H) ppm. 13C NMR (100 MHz, CDCl3): δ=155.96, 155.85, 144.44, 137.34, 136.44, 129.34, 128.19, 127.77, 127.66, 127.25, 112.17, 79.25, 76.65, 66.27, 54.06, 44.15, 33.69, 28.22, 18.73 ppm. [α]D23=−18.7 (c=1, CHCl3). HRMS: calcd. for C26H34N2O5 455.25405 [M+H]+. Found 455.25392.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][CH:20]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[O:19][C:18]3=[O:27])=[CH:13][C:12]=2[F:28])=[CH:7][CH:6]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[NH2:1][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][CH:20]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[O:19][C:18]3=[O:27])=[CH:13][C:12]=2[F:28])=[CH:7][CH:6]=1
Reactant: CC(=O)NCC1CN(c2ccc(-c3ccc(CN=[N+]=[N-])cc3)c(F)c2)C(=O)O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)NCC1CN(c2ccc(-c3ccc(CN)cc3)c(F)c2)C(=O)O1
Temperature: 52.5 °C
Yield: 87.1 %

Procedure:
A solution of 53 (7.16 g, 18.69 mmol) in tetrahydrofuran (THF) (100 mL) was treated with triphenylphosphine (PPh3, 5.88 g, 22.43 mmol, 1.2 equiv) and H2O (3.6 g, 3.6 mL, 0.2 mmol, 11.0 equiv) at 25° C., and the resulting reaction mixture was warmed to 50-55° C. for 12 h. When TLC and HPLC showed the reduction reaction was complete, the reaction mixture was cooled to room temperature before the solvents were removed in vacuo. The residue was directly purified by flash column chromatography (0-15% MeOH—CH2Cl2 gradient elution) to afford the desired N-[3-(4′-Aminomethyl-2-fluoro-biphenyl-4-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide 54 (5.82 g, 87% yield) as off-white crystals, which were of sufficient purity to be directly used in subsequent reactions. 1H NMR (300 MHz, DMSO-d6) δ 1.85 (s, 3H, COCH3), 3.04 (br. s, 2H, NH2), 3.44 (t, 2H, J=5.4 Hz), 3.78 (m, 3H), 4.18 (t, 1H, J=9.1 Hz), 4.77 (m, 1H), 7.25-7.60 (m, 7H, aromatic-H), 8.20 (t, 1H, J=5.8 Hz, NHCOCH3). LCMS (ESI) m/e 359 (M+2H)2+.
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10]Cl)=[CH:6][CH:5]=1>CC#N>[CH3:1][NH:2][CH2:10][C:7]1[CH:8]=[N:9][C:4]([CH3:3])=[CH:5][CH:6]=1
Reactant: CN
Reactant: Cc1ccc(CCl)cn1
Solvent: CC#N
Product: CNCc1ccc(C)nc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 16.6 g of 40% aqueous MeNH2 solution and 52 ml of CH3CN was cooled with ice and 6.08 g (0.043 mole in terms of pure product) of crude (6-methyl-3-pyridyl)methyl chloride was added dropwise with constant stirring. After completion of dropwise addition, the mixture was stirred at room temperature for 1.5 hours, at the end of which time the solvent was distilled off. The solid residue was extracted with CH2Cl2 and the CH2Cl2 layer was dried over MgSO4. The CH2Cl2 was distilled off and the residue was diluted with 70 ml of Et2O and filtered to remove the insoluble matter. Finally the filtrate was concentrated to recover 4.60 g of the title compound as a crude oil.
Reaction SMILES: CO[C:3]([C:5]1[C:14]([C:15]([O:17]C)=O)=[C:13]([OH:19])[C:12]2[C:7](=[CH:8][C:9]([Cl:20])=[CH:10][CH:11]=2)[N:6]=1)=[O:4].Cl.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][NH2:30])=[CH:25][CH:24]=1.C(N(CC)CC)C>C(O)C>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[C:3](=[O:4])[C:5]3[NH:6][C:7]4[CH:8]=[C:9]([Cl:20])[CH:10]=[CH:11][C:12]=4[C:13](=[O:19])[C:14]=3[C:15]([OH:17])=[N:30]2)=[CH:25][CH:24]=1
Reactant: NNc1ccc(Br)cc1
Reactant: COC(=O)c1nc2cc(Cl)ccc2c(O)c1C(=O)OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=c1c2ccc(Cl)cc2[nH]c2c(=O)n(-c3ccc(Br)cc3)nc(O)c12
Temperature: 25 °C
Yield: 62.8 %

Procedure:
To a stirred suspension of dimethyl-7-chloro-4-hydroxyquinoline-2,3-dicarboxylate (1.90 g, 6.40 mM) and 4-bromophenylhydrazine hydrochloride (10.0 g, 44.7 mM) in ethanol (35 mL) was added triethylamine (7.1 mL, 51.1 mM). The resulting brown solution was refluxed for 22 hours during which time a tan precipitate formed. This mixture was cooled to room temperature and filtered to give the 4-bromophenylhydrazine salt of the title compound as a white powder (1.69 g). This material was refluxed in glacial acetic acid (20 mL) for 3 hours and cooled to room temperature. The resulting tan suspension was filtered and the solids washed with glacial acetic acid and then ether to give the title compound (1.15 g, 43%) as a tan powder, mp 393-394° C.; MS(CI): 420 (M+H).
Reaction SMILES: [C:1](OC)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16].[H][H]>>[OH:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16]
Reactant: [H][H]
Reactant: COC(=O)CCCCCCCCCCCCCC(=O)OC
Product: COC(=O)CCCCCCCCCCCCCCO
Reaction time: 8 h
Yield: 61 %

Procedure:
150 g (499 mmol) of dimethyl 1,15-pentadecandioate and 12 g (8.0% by weight per the diester) of the catalyst prepared in Preparative Example 1 were added to an autoclave and subjected to hydrogenation reaction at the hydrogen pressure of 20.0 Mpa at 250° C. After 8 hours, the degree of the conversion was 63% and the selectivity was 87%. The reaction was further continued, and after 10 hours, methyl 15-hydroxypentadecanoate was obtained in 61% yield. The results are shown in Table 2.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:8][CH2:7][NH:6][S:5]1(=[O:10])=[O:9].Br[C:12]1[N:17]=[C:16]([CH3:18])[C:15]([Br:19])=[CH:14][N:13]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CN(C=O)C.O>[Br:19][C:15]1[C:16]([CH3:18])=[N:17][C:12]([N:6]2[CH2:7][CH2:8][N:4]([CH3:3])[S:5]2(=[O:10])=[O:9])=[N:13][CH:14]=1
Reactant: Cc1nc(Br)ncc1Br
Reactant: CN1CCNS1(=O)=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1nc(N2CCN(C)S2(=O)=O)ncc1Br
Temperature: 80 °C

Procedure:
Sodium hydride (0.128 g, 60% disp. in oil) was added to a stirred solution of 2-methyl-1,2,5-thiadiazolidine 1,1-dioxide (0.433 g) in THF (10 ml). DMF (10 ml) was added and the mixture heated at 80° C. for 5 min then a solution of the product from step (i) (0.8 g) in DMF (5 ml) was added. The mixture was heated at 60° C. for 10 min, poured into water (100 ml), acidified with citric acid and extracted with ethylacetate. The organics were evaporated under reduced pressure and the residue purified by chromatography on silica eluting with diethylether, yield 0.58 g.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[NH2:6].C(N(CC)CC)C.Cl.[C:24]1([CH2:30][C:31](Cl)=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O.ClCCl>[OH:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][C@H:5]([NH:6][C:31](=[O:32])[CH2:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:4]([O:3][CH3:2])=[O:15])=[CH:13][CH:12]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)Cc1ccccc1
Yield: 88.4 %

Procedure:
200 ml of dichloro methane (DCM) was added to (L)-tyrosine methyl ester HCl salt (23.16 g, 0.1 mol), and 28 ml of triethyl amine (TEA, 0.2 mol) was added thereto, thereby dissolving HCl salt. The reactor was temperature-lowered to 0° C. by using an ice bath, and 15.46 g of phenylacetyl chloride (0.1 mol) was slowly added, following by stirring for 3˜4 hours. 200 ml of water was added to the reacted material, followed by extraction with 400 ml of ethyl acetate. Drying over sodium sulfate followed by filtering was carried out. The solvent was removed from the filtrate by rotary evaporation, followed by solidification with hexane and ethyl acetate, thereby obtaining a white solid (27.7 g, 88.1% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([P:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)(=[O:11])[OH:10])=[CH:5][CH:4]=1.[OH-].[CH2:21]([N+:25]([CH2:34][CH2:35][CH2:36][CH3:37])([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH3:24].CC(O)C>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([P:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)(=[O:10])[O-:11])=[CH:7][CH:8]=1.[CH2:34]([N+:25]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:30][CH2:31][CH2:32][CH3:33])[CH2:35][CH2:36][CH3:37]
Reactant: COc1ccc(P(=O)(O)c2ccc(OC)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: COc1ccc(P(=O)([O-])c2ccc(OC)cc2)cc1

Procedure:
To a flask were added 2.0 g bis(4-methoxyphenyl)phosphinic acid, 3.0 g of a 55-60% solution of tetrabutylammonium hydroxide in water, 2.0 g of water and 18 ml 2-propanol. After heating to 50 C under nitrogen for 1 hour, the solvent was removed and another 20 ml of 2-propanol were added and removed by distillation under reduced pressure. A waxy solid was obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[CH:9][C:10]=2[O:12][CH3:13])[CH:5]=[C:4]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)[N:3]=1>C(O)(C)C>[CH:10]([O:12][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[CH:9][C:10]=2[O:12][CH3:13])[CH:5]=[C:4]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)[N:3]=1)([CH3:11])[CH3:9]
Reactant: COc1cc(OC)c2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Solvent: CC(C)O
Product: COc1cc(OC)c2c(OC(C)C)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 400 was used, starting from isopropyl alcohol and (1-Chloro-6,8-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine (example 9F) to give (1-Isopropoxy-6,8-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS: m/e 343(MH+).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[O:22][N:21]=[C:20]([CH3:23])[CH:19]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[O:22][N:21]=[C:20]([CH3:23])[CH:19]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(Nc2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)on1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(Nc2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)on1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.7 %

Procedure:
N-tert-Butyl-2-(3-methylisoxazol-5-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (33 mg, 74.2 mol) was dissolved in dichloromethane (1.3 mL) and treated with trifluoroacetic acid (169 mg, 114 μL, 1.48 mmol). The mixture was stirred at room temperature for 16 h, then concentrated and re-dissolved in dichloromethane (1.3 mL), methanol (0.65 mL) and ammonium hydroxide (0.2 mL) and stirred at room temperature for 1 h. The mixture was concentrated and diluted with water, triturated and filtered. The solid obtained was washed with ether and dried to give N-tert-butyl-2-(3-methylisoxazol-5-ylamino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (16 mg, 45.8 mol, 62%) as a yellow solid. 1H NMR (400 MHz, DMSO-d) δ ppm: 12.53 (s, 1H), 11.06 (s, 1H), 8.14 (d, J=3.0, 1 H), 8.09 (s, 1H), 7.57 (s, 1H), 6.18 (s, 1H), 2.17 (s, 3H), 1.48 (s, 9H); MS (EI/CI) m/z: 315.1 [M+H].
Reaction SMILES: [C:1]([NH:8][C:9]([CH3:14])([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH2:16]([O:18][C:19](=[O:31])[C@H:20]([CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[NH2:21])[CH3:17].C(N=C=NCCCN(C)C)C.ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl>[CH2:16]([O:18][C:19](=[O:31])[C@H:20]([CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[NH:21][C:11](=[O:13])[C:9]([NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])([CH3:10])[CH3:14])[CH3:17]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: CCOC(=O)[C@@H](N)COCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@H](COCc1ccccc1)NC(=O)C(C)(C)NC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
To a solution of BOC-α-methylalanine (3.05 g, 15 mmol), O-benzyl-L-serine ethyl ester hydrochloride (3.89 g, 15 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI, 2.88 g, 15 mmol) and 1-hydroxy-7-azabenzotriazole (HOAT, 2.04, 15 mmol) in methylene chloride (150 mL) is added triethylamine (1.52 g, 15 mmol). The mixture is stirred overnight and then concentrated in vacuo. The residue is re-dissolved in ethyl acetate and washed with water, 1 N HCl, water, and brine. The solution is dried over sodium sulfate and concentrated to yield N-[2-(BOC-amino)-2-methylpropionyl]-O-benzyl-L-serine ethyl ester of the formula
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[CH2:4][CH:5]1[C:12]2[CH:11]=[C:10]([C:13]([O:15]C)=[O:14])[NH:9][C:8]=2[CH2:7][CH2:6]1.[OH-].[Li+].CO>C1COCC1>[F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[CH2:4][CH:5]1[C:12]2[CH:11]=[C:10]([C:13]([OH:15])=[O:14])[NH:9][C:8]=2[CH2:7][CH2:6]1
Reactant: COC(=O)c1cc2c([nH]1)CCC2Cc1ccc(F)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc2c([nH]1)CCC2Cc1ccc(F)cc1F

Procedure:
The title compound was synthesized from methyl 4-(2,4-difluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.062 g, 0.213 mmol) and lithium hydroxide (0.045 g, 1.07 mmol), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (6 mL) was used. The resulting product was purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-100% EtOAc/heptane to afford the title compound. 41 mg. 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.12 (m, 1H), 2.56 (m, 1H), 2.65 (m, 2H), 2.78 (d, J=7.37 Hz, 2H), 3.20-3.30 (m, 1H), 6.29 (s, 1H), 6.81-6.95 (m, 2H), 7.22 (m, 1H); 19F NMR δ ppm −116.13 (m), −116.30 (m); LCMS-MS (ESI−) 276.0 (M−H); HPLC (UV=99.0%), (ELSD=100%).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[O:18]1[CH2:20][CH:19]1[CH2:21][N:22]1[C:30]2[C:25](=[CH:26][C:27]([C:31]#[N:32])=[CH:28][CH:29]=2)[CH:24]=[CH:23]1.[Na+].[Cl-]>CN(C=O)C>[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:20][CH:19]([OH:18])[CH2:21][N:22]2[C:30]3[C:25](=[CH:26][C:27]([C:31]#[N:32])=[CH:28][CH:29]=3)[CH:24]=[CH:23]2)=[CH:13][CH:12]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: N#Cc1ccc2c(ccn2CC2CO2)c1
Reactant: CCCCCCCOc1ccc(O)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc(OCC(O)Cn2ccc3cc(C#N)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.13 g (2.47 mmol) sodium hydride as 60% dispersion in mineral oil is suspended in 10 ml absolute DMF under nitrogen, stirred at room temperature for 10 min and mixed with the solution of 0.5 g (2.39 mmol) 4-heptyloxyphenol in 5 ml absolute DMF. Having stirred for 1 hour, a solution of 475 mg (2.39 mmol) 1-oxiranylmethylindole-5-carbonitrile in 5 ml absolute DMF is added and stirring is continued at room temperature overnight. Thereafter, the suspension is hydrolyzed with semi-saturated NaCl solution and extracted three times with ethyl acetate. The extracts are washed with saturated NaCl solution, dried on sodium sulfate and the solvent is distilled off. The residue is purified on silica gel by means of column chromatography (flow agent: hexane/ethyl acetate 1:1), the product accruing as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:6]2[C:7]([O:11]C)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1.B(Br)(Br)Br.O>ClCCl>[CH3:1][C:2]1([CH3:13])[C:6]2=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=[C:5]2[O:4][CH2:3]1
Reactant: COc1cccc2c1C(C)(C)CO2
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CC1(C)COc2cccc(O)c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
To a solution of 3,3-dimethyl-4-(methyloxy)-2,3-dihydro-1-benzofuran (Intermediate 5, 4.0 g) in dichloromethane (100 ml, SCRC) was added BBr3 (6.37 ml, 67.3 mmol, SCRC) dropwise under ice-cooling. After the addition was complete, the reaction mixture was stirred for 2 hours at room temperature and then water (20 ml) was added. The resulting mixture was extracted with ethyl acetate (3 times 100 ml, SCRC) and the combined organic layers were dried, evaporated and purified by silica gel chromatography with EtOAc/PE as eluents (1/20) to afford the title compound (2.8 g).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:51])([CH:26]([C@H:37]2[CH2:42][CH2:41][C@@H:40]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])[CH2:39][CH2:38]2)[C:27]([O:29]CC2C=CC=CC=2)=[O:28])[C:16]([O:18]CC2C=CC=CC=2)=[O:17])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd].[C]>[Si:1]([O:8][C@@H:9]1[CH2:10][CH2:11][C@H:12]([C:15]([OH:51])([CH:26]([C@H:37]2[CH2:38][CH2:39][C@@H:40]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:45])[CH3:46])[CH2:41][CH2:42]2)[C:27]([OH:29])=[O:28])[C:16]([OH:18])=[O:17])[CH2:13][CH2:14]1)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](C(C(=O)OCc2ccccc2)C(O)(C(=O)OCc2ccccc2)[C@H]2CC[C@@H](O[Si](C)(C)C(C)(C)C)CC2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](C(C(=O)O)C(O)(C(=O)O)[C@H]2CC[C@@H](O[Si](C)(C)C(C)(C)C)CC2)CC1
Reaction time: 24 h

Procedure:
To a solution of dibenzyl 2,3-bis(cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)-2-hydroxysuccinate (500 mg, 0.38 mmol) in ethanol (15 ml) was added 10% Pd-carbon (150 mg) under a nitrogen gas stream. The atmosphere in the reaction vessel was replaced five times with nitrogen gas and was filled with hydrogen gas, and the contents in the reaction vessel were stirred under a hydrogen gas stream for 24 hr. The catalyst was collected by filtration through Celite pad and was washed with ethanol (50 ml×2). The filtrate was concentrated under reduced pressure to give the title compound as a colorless solid (275 mg, yield 73%).