Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:14]2[C:22]3[C:17](=[CH:18][C:19]([OH:23])=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:25][CH2:26][CH2:27][OH:28].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]1([CH:7]([C:14]2[C:22]3[C:17](=[CH:18][C:19]([O:23][CH2:25][CH2:26][CH2:27][OH:28])=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CC(c1ccccc1)c1c[nH]c2cc(O)ccc12
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CC(c1ccccc1)c1c[nH]c2cc(OCCCO)ccc12

Procedure:
1.2 g (3.88 mmol) of 4 are refluxed overnight in 30 ml of acetone together with 0.66 ml (7.6 mmol) of 3-bromo-1-propanol and 2.1 g (15.2 mmol) of potassium carbonate. After cooling, the insoluble residue is filtered off, and the filtrate is evaporated. The crude product can be purified by chromatography on silica gel (eluent gradient toluene/acetone 9:1→4:1), giving ethyl 3-phenyl-3-[6-(3-hydroxypropoxy)indol-3-yl]propionate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[CH2:6][NH:7][CH:8]([CH2:17]NCC1C=CC(OC)=C(OC)C=1)[CH:9]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[OH:10]>C(O)C.O=[Pt]=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[CH2:6][NH:7][C:8]([NH:7][CH2:6][C:5]1[CH:30]=[CH:31][C:32]([O:33][CH3:34])=[C:3]([O:2][CH3:1])[CH:4]=1)([CH3:17])[CH:9]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[OH:10]
Reactant: COc1ccc(CNCC(NCc2ccc(OC)c(OC)c2)C(O)C2CCCCO2)cc1OC
Agent: O=[Pt]=O
Solvent: CCO
Product: COc1ccc(CNC(C)(NCc2ccc(OC)c(OC)c2)C(O)C2CCCCO2)cc1OC
Reaction time: 24 h
Yield: 100 %

Procedure:
A solution of 83 g of (5) in 200 ml of absolute ethanol, containing 0.3 g of PtO2 was hydrogenated at atmospheric pressure and room temperature. After 24 hours, the catalyst was filtered off and the solvent evaporated. The crude product was chromatographed on a silica gel column with EtOAc-Et3N-MeOH (90:5:5) to give diamine (6) (41.5 g) with a 47.6% yield from (4).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH3:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12](Cl)(=[O:14])=[O:13].O.C(OCC)(=O)C>O1CCCC1>[CH3:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([N:2]([CH3:3])[CH3:1])(=[O:14])=[O:13]
Reactant: CNC
Reactant: COc1ccccc1S(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccccc1S(=O)(=O)N(C)C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
72 ml (144 mmol, 3 eq) of a 2 M solution of dimethylamine in tetrahydrofuran were added dropwise to a solution of 9.90 g (47.9 mmol, 1 eq) of 2-methoxybenzenesulfonyl chloride in 300 ml of tetrahydrofuran at 0° C. under nitrogen. After 30 minutes, the reaction medium was hydrolyzed with water, and ethyl acetate was added. The organic phase was again washed with water, and then dried over anhydrous sodium sulfate, filtered and concentrated. 8.78 g of product were obtained in the form of a brown oil. Yield=85%.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([OH:17])=O)[CH2:10][CH2:9]1.[NH2:18][C@@H:19]([CH2:37][O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[CH:25][CH:24]=1)=[O:21]>>[CH2:39]([O:38][CH2:37][C@H:19]([NH:18][C:15](=[O:17])[CH2:14][N:11]1[CH2:10][CH2:9][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=2)[CH2:13][CH2:12]1)[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[CH:25][CH:24]=1)=[O:21])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=C(O)CN1CCN(c2ccccn2)CC1
Agent: Cl
Product: O=C(CN1CCN(c2ccccn2)CC1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 33.6 %

Procedure:
Proceeding as in Example 1, but substituting 2-(4-(pyridin-2-yl)piperazin-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 126, (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(4-(pyridin-2-yl)piperazin-1-yl)acetamido)propanamide (15.7 g, 33.6%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.23 (s, 1H), 8.11-8.12 (m, 1H), 8.05 (d, 1H), 7.60 (d, 2H), 7.51-7.55 (m, 1H), 7.28-7.33 (m, 5H), 7.19-7.25 (m, 2H), 6.98-7.04 (m, 4H), 6.81 (d, 1H), 6.63-6.66 (m, 1H), 4.71 (m, 1H), 4.52 (s, 2H), 3.72-3.78 (m, 2H), 3.47-3.49 (m, 4H), 3.06 (s, 2H), 2.55-2.59 (m, 4H). MS (EI) for C33H34FN5O4. found 584.6 (MH+).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5](/[C:9](=[CH:12]/[CH2:13][CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=3[CH:16]=2)/[CH2:10][OH:11])[CH:6]=[CH:7][CH:8]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:31]([O:11][CH2:10]/[C:9](/[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:29])([F:30])[F:1])[CH:4]=1)=[CH:12]\[CH2:13][CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:21]([CH3:25])([CH3:26])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=2[CH:16]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)CCC(C)(C)c2cc(CC/C=C(\CO)c3cccc(C(F)(F)F)c3)ccc21
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)OC/C(=C\CCc1ccc2c(c1)C(C)(C)CCC2(C)C)c1cccc(C(F)(F)F)c1
Reaction time: 2 h
Yield: 99 %

Procedure:
A solution of (Z)-2-(3-trifluoromethylphenyl)-5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-2-pentenol 5r (0.99 g, 2.4 mmol) in anhydrous pyridine (25 mL) at room temperature under argon was treated with 4-dimethylaminopyridine (0.01 g) and acetic anhydride (0.32 g, 3.1 mmol). The reaction mixture was stirred for 2 h and then partitioned between diethyl ether (100 mL) and 1N HCl solution (50 mL). The ether layer was washed further with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to give 1.09 g (100%) of the product as a colorless oil. The acetate was used without purification in the next reaction. 1H NMR (300 MHz, CDCl3) δ7.50 (d, J=8 Hz, 1H, 2-ArH), 7.36-7.41 (m, 2H, 2-ArH), 7.17 (d, J=8 Hz, 1H, 2-ArH), 7.11 (d, J=8 Hz, 1H, 5-ArH), 6.98 (d, J=2 Hz, 1H, 5-ArH), 6.82 (dd, J=2, 8 Hz, 1 Hz, 5-ArH), 5.89 (t, J=7.5 Hz, 1H, C=CH), 4.73 (s, 2H, CH2OAc), 2.61 (t, J=7 Hz, 2H, ArCH2), 2.24 (q, J=7 Hz, 2H, ArCH2CH2), 1.99 (s, 3H, CH3C=O), 1.64 (s, 4H, CH2CH2), 1.24 (s, 6H, 2'CH3), and 1.22 (s, 6H, 2×CH3); 13C NMR (75 MHz, CDCl3) δ170.66 (C=O), 144.70, 142.52, 138.81, 137.91, 134.89, 133.09, 131.95, 128.67, 126.48, 126.45, 125.73, 125.36, 125.31, 124.02, 68.68 (CH2OAc), 35.33, 35.14, 35.09, 34.12, 31.87, 31.81, 30.67, and 20.89; IR (film) 2960, 2925, 2860, 1745 (C=O), 1325, 1225, 1165, and 1130 cm-1 ; MS (DCI) m/e 399 (M+ --OAc).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[NH:9][C:8](=O)[N:7]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:6]=2[C:5]([CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:8]1[N:7]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:6]2[C:5]([CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:4][CH:3]=[C:2]([Cl:1])[C:10]=2[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)Cn1c(=O)[nH]c2c(Cl)ccc(C(CC)CC)c21
Product: CCOC(=O)Cn1c(Cl)nc2c(Cl)ccc(C(CC)CC)c21
Temperature: 90 °C
Reaction time: 72 h
Yield: 92 %

Procedure:
A mixture of ethyl [4-chloro-7-(1-ethylpropyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]acetate (2.57 g, 7.91 mmol) and phosphorus oxychloride (15 mL) was stirred at 90° C. for 3 days. After cooling, phosphorus oxychloride was evaporated in vacuo. The residue was poured into ice-cold 2N aqueous sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 10-20% ethyl acetate/n-hexane gradient mixture to give the title compound (2.49 g, 7.25 mmol, 92%) as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C@@H:5]([NH:13][C:14]([C:16]1S[C:18]([Br:21])=[CH:19][CH:20]=1)=[O:15])[CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2].BrC1[O:28]C(C(O)=O)=CC=1>>[CH2:1]([O:3][C:4](=[O:22])[C@@H:5]([NH:13][C:14]([C:16]1[O:28][C:18]([Br:21])=[CH:19][CH:20]=1)=[O:15])[CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2]
Reactant: O=C(O)c1ccc(Br)o1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(Br)s1)C(=O)OCC
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(Br)o1)C(=O)OCC
Yield: 72 %

Procedure:
Compound 13 was prepared using the general method described for the preparation of compound 9 and 13, from 12 (1.91 g, 10 mmol) to give 2.71 g (72%) of 13 as yellow oil. 1H NMR (DMSO-d6): δ 1.13-1.19 (m, 6H), 1.88-2.11 (m, 2H), 2.37-2.41 (t, J=7.2 Hz, 2H), 4.00-4.12 (m, 4H), 4.36-4.41 (m, 1H), 6.77-6.78 (d, J=3.6 Hz, 1H), 7.20-7.21 (d, J=3.6 Hz, 1H), 8.72-8.74 (d, J=7.6 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([S:12]([NH2:15])(=[O:14])=[O:13])[CH:5]=[CH:4][CH:3]=1.[Cl-].N1C=CC=CC=1.[C:23](Cl)(Cl)=[O:24]>ClCCCl>[Cl:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([S:12]([N:15]=[C:23]=[O:24])(=[O:13])=[O:14])[CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(Cl)cccc1S(N)(=O)=O
Reactant: O=C(Cl)Cl
Agent: [Cl-]
Solvent: ClCCCl
Solvent: c1ccncc1
Product: COC(=O)c1c(Cl)cccc1S(=O)(=O)N=C=O
Temperature: 55 °C

Procedure:
100 g of methyl 6-chloro-2-aminosulfonyl-benzoate were suspended in 300 ml of 1,2-dichloroethane, 123 g of thionuyl chloride were added with stirring, and the mixture was slowly heated to the reflux temperature. After it had been stirred for 5 hours under reflux, it was cooled to 55° C., 1.5 ml of pyridine were added and the mixture again heated to the reflux temperature, while introducing phosgene. After 4 hours' treatment with phosgene gas, the reaction mixture was concentrated under reduced pressure and flushed with nitrogen. The oil which remained (105 g) was used, without further purification, for the subsequent stages.
Reaction SMILES: [CH2:1]([N:8]1[CH:14]2[CH2:15][CH2:16][CH2:17][CH:9]1[CH2:10][NH:11][C:12](=O)[CH2:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1.ClCCl>[CH2:1]([N:8]1[CH:14]2[CH2:15][CH2:16][CH2:17][CH:9]1[CH2:10][NH:11][CH2:12][CH2:13]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC2CCCC(CN1)N2Cc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: c1ccc(CN2C3CCCC2CNCC3)cc1
Temperature: 0 °C
Reaction time: 14 h

Procedure:
A solution obtained by dissolving 0.50 g of 10-benzyl-3,10-diazabicyclo[4.3.1]decan-4-one (1py1) in THF (4 ml) is dripped in a suspension of LiAlH4 (0.19 g) in anhydrous THF (9 ml), cooled at 0° C., kept under an argon inert atmosphere. The mixture is kept under stirring at room temperature for 14 hours. At the end the mixture is cooled to 0° C. About 0.9 ml of H2O are cautiously added while stirring for 10 min. A precipitate is obtained which is filtered under vacuum and washed with dichloromethane. The recovered filtrate is evaporated, obtaining an oil which is dissolved in dichloromethane. The organic solution is dehydrated with sodium sulphate and the solvent then evaporated. 0.47 g of the compound 10-benzyl-3,10-diazabicyclo[4.3.1]decane are recovered. Yield: quantitative; Rf: 0.62 (CH2Cl2-MeOH 8:2); 1H-NMR (CDCl3): δ (ppm) 1.17-2.18 (m, 8H), 2.62 (bs, 1H), 2.76-2.92 (m, 2H), 2.99-3.18 (m, 4H), 3.97 (s, 2H), 7.20-7.42 (m, 5H).
Reaction SMILES: [OH:1][C@H:2]([C@H:18]1[O:23][CH2:22][CH2:21][N:20]([C:24]2[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=2)[C:19]1=[O:31])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:16][C:15](=[O:17])[O:14][N:13]=2)=[CH:8][CH:7]=1)=[O:4].CC([Si](C)(C)[O:37][CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1B(O)O)(C)C.S1C=CC=C1B(O)O>>[OH:1][C@H:2]([C@H:18]1[O:23][CH2:22][CH2:21][N:20]([C:24]2[CH:29]=[CH:28][C:27]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=3[CH2:39][CH2:38][OH:37])=[CH:26][CH:25]=2)[C:19]1=[O:31])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:16][C:15](=[O:17])[O:14][N:13]=2)=[CH:8][CH:7]=1)=[O:4]
Reactant: O=C(Nc1ccc(-c2noc(=O)[nH]2)cc1)[C@H](O)[C@H]1OCCN(c2ccc(I)cc2)C1=O
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccccc1B(O)O
Agent: OB(O)c1cccs1
Product: O=C(Nc1ccc(-c2noc(=O)[nH]2)cc1)[C@H](O)[C@H]1OCCN(c2ccc(-c3ccccc3CCO)cc2)C1=O
Yield: 33.7 %

Procedure:
According to the Step 22-1 in synthetic method for EXAMPLE 22, compound 106-2 (30 mg) and [2-[2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]ethyl]phenyl]boronic acid (31.4 mg) were used instead of 14-4 and 2-thiopheneboronic acid to obtain compound 106-3 (10 mg) as a colorless amorphous solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[ClH:10].[CH3:11][OH:12]>>[ClH:10].[Br:1][C:2]1[CH:3]=[C:4]([C:5](=[NH:6])[O:12][CH3:11])[CH:7]=[CH:8][CH:9]=1
Reactant: CO
Reactant: N#Cc1cccc(Br)c1
Agent: Cl
Product: COC(=N)c1cccc(Br)c1
Reaction time: 3 h

Procedure:
A solution of m-bromobenzonitrile (1.82 g; 10 mmol) in MeOH (20 mL) at 0° C. was sparged with HCl gas for 30 min, the reaction flask was stoppered and aged in a refrigerator (ca. 5° C.) for 3 h. The mixture was sparged with N2 to remove excess HCl, concentrated in vacuo (2×PhMe chase) and dried under high vacuum ca. 45 min, affording the title compound as a colorless solid which was used directly for Step 2 below. LC/MS (method A) tR 0.81 min, m/z 214, 216 (M+H, Br isotopes).
Reaction SMILES: [C:1]1(=O)[NH:6][CH2:5][CH2:4][N:3]2[CH2:7][CH2:8][NH:9][CH2:10][CH:2]12.B.C1COCC1>C1COCC1>[CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[CH2:7][CH2:8][NH:9][CH2:10][CH:2]12
Reactant: O=C1NCCN2CCNCC12
Agent: B
Solvent: C1CCOC1
Product: C1CN2CCNCC2CN1
Temperature: 50 °C
Reaction time: 3 h
Yield: 81.4 %

Procedure:
To a suspension of hexahydro-2H-pyrazino[1,2-a]pyrazin-1(6H)-one (D78, 339 mg, 2.184 mmol) in 3.5 mL of THF kept at 0° C. were added dropwise 21.84 mL of a 1M borane-THF solution. The reaction was kept at 75° C. under nitrogen atmosphere for 3 h, then quenched by slow addition MeOH at 0° C. After 30 min at room temperature, 5 mL of a 37% HCl aqueous solution diluted in 10 mL of MeOH were added and the resulting solution was heated to 50° C. for 2.5 h. The solvent was removed and the residue purified by SCX, leaving 251 mg of the title compound.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][C:5]([F:8])([F:7])[F:6].II.[Cl-].[Zn+2:12].[Cl-]>C1COCC1>[Zn:12]([CH2:3][CH2:4][C:5]([F:8])([F:7])[F:6])[CH2:3][CH2:4][C:5]([F:8])([F:7])[F:6]
Reactant: [Zn+2]
Reactant: FC(F)(F)CCBr
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: FC(F)(F)CC[Zn]CCC(F)(F)F
Temperature: 25 °C
Reaction time: 1.08 h

Procedure:
To magnesium (1.373 g, 56.5 mmol) in a 500 mL tear-shaped flask applied vacuum then nitrogen, added 50 mL THF, added 3-bromo-1,1,1-trifluoropropane (6.02 mL, 56.5 mmol), and then 1 crystal of iodine. Within 1 minute the mixture became warm and by 5 minutes was refluxing. The mixture was cooled for 2 minutes with an ice bath to control the exothermic reaction then allowed to warm back up to rt. By 65 minutes, nearly all of the Mg had dissolved. Added zinc(II) chloride (3.85 g, 28.3 mmol) which caused a small amount of heat to be generated. Nearly all was dissolved within 10 minutes to provide ˜1.1 M of Zn(CH2CH2CF3)2 in THF. To 5-bromo-2-chloropyrimidine (7.72 g, 39.9 mmol) and bis(tri-t-butylphosphine)palladium(0) (404 mg, 0.791 mmol) applied vacuum then placed under an atmosphere of nitrogen, added 80 mL THF, and then added over ˜2 minutes 60 mL of the ˜1.1 M of Zn(CH2CH2CF3)2 in THF. The reaction was quenched after 23 hour)s with 300 mL saturated NH4Cl+300 mL EtOAc, the organic layer was then washed with 300 mL saturated NaHCO3 then 300 mL water, dried with MgSO4, filtered, then concentrated to 7.6 g brown oily solids. This material was purified by flash chromatography (0-10% EtOAc/hexanes) to yield product (3.86 g, 18.4 mmol, 46% yield) as a pale yellow solid. MS (ESI) 211.1 (M+1).
Reaction SMILES: [C:1](=[O:20])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.[NH2:21][C@H:22]([C:30]([OH:32])=[O:31])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(#N)C>C(#N)C.O.[OH-].[Na+].O>[N:7]1[CH:6]=[CH:5][C:4]([CH2:3][O:2][C:1]([NH:21][C@H:22]([C:30]([OH:32])=[O:31])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:20])=[CH:9][CH:8]=1
Reactant: O=C(OCc1ccncc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccncc1
Reaction time: 8 h

Procedure:
8 g of 4-pyridylmethyl 4-nitrophenyl carbonate and 4.82 g of L-phenylalanine were dissolved in 350 ml of acetonitrile/water 1:1, and about 45 ml of 2N NaOH were added to pH 10. The mixture was stirred overnight and was freed from the acetonitrile in vacuo. The aqueous solution was brought to pH 6, washed three times with diethyl ether, subsequently brought to pH 1 and concentrated to give a solid residue. This was dissolved in water and the solution was extracted intensively with ethyl acetate and then brought to pH 2 and the precipitate which had separated out was filtered off with suction. After drying, the precipitate weighed 7.3 g.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:26]=[CH:25][CH:24]=[CH:23][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[C:21]([F:22])=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][N:14]=2)[CH2:8]1)[CH3:2].[NH2:27][C@H:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C:33]([O:35]C)=[O:34].CCN=C=NCCCN(C)C.Cl.[Li+].[OH-]>>[CH2:1]([O:3][C:4]1[CH:26]=[CH:25][CH:24]=[CH:23][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[C:21]([F:22])=[CH:20][C:16]([C:17]([NH:27][C@H:28]3[CH2:32][CH2:31][CH2:30][C@H:29]3[C:33]([OH:35])=[O:34])=[O:18])=[CH:15][N:14]=2)[CH2:8]1)[CH3:2]
Reactant: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)O)cc2F)C1
Reactant: COC(=O)[C@@H]1CCC[C@@H]1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Li+]
Product: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)N[C@H]3CCC[C@H]3C(=O)O)cc2F)C1

Procedure:
(1R,2S)-2-(6-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)-5-fluoronicotinamido)cyclopentane-1-carboxylic acid was prepared from (R)-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)-5-fluoronicotinic acid and methyl (1R,2S)-2-aminocyclopentane-1-carboxylate using Amidation Method 2 (EDCl) and Ester Hydrolysis Method 1 (LiOH). 1H NMR (400 MHz, DMSO-d6) δ 11.3 (s, 1H), 8.35 (s, 1H), 7.59 (dd, 1H), 7.03 (d, 1H), 6.91 (m, 3H), 4.38 (m, 1H), 4.05 (dd, 1H), 3.93 (m, 3H), 3.69 (m, 1H), 3.50 (m, 2H), 2.33 (m, 1H), 1.98 (m, 4H), 1.79 (m, 1H), 1.60 (m, 3H), 1.45 (m, 2H), 1.25 (t, 3H). MS (ES+) 472.0 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]#[C:14][C:15]([OH:28])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:11]([CH:29]=[O:30])[CH:10]=[C:9]1[C:31]([O:33]C)=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl>CO.O>[CH2:1]([N:8]1[C:12]([C:13]#[C:14][C:15]([OH:28])([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:11]([CH:29]=[O:30])[CH:10]=[C:9]1[C:31]([OH:33])=[O:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(C=O)c(C#CC(O)(c2ccccc2)c2ccccc2)n1Cc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=Cc1cc(C(=O)O)n(Cc2ccccc2)c1C#CC(O)(c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 6 (0.49 g, 1.1 mmol) in MeOH (20 mL) and water (6 mL) was added KOH (0.18 g, 3.3 mmol) and stirred at 60° C. for 2 hours. The solvent was then removed in vacuo. The residue obtained was acidified with 2N HCl to pH 2-3 and extracted with EtOAc (3×15 mL). The combined organic layer was dried over MgSO4, filtered and then concentrated in vacuo to give 7 as a light brown solid. The crude product was subjected to the next reaction without further purification. 1H NMR (CDCl3) δ 9.82 (s, 1H), 7.50-7.52 (m, 4H), 7.45 (s, 1H), 7.21-7.26 (m, 7H), 7.02-7.03 (m, 2H), and 5.64 (s, 2H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)O1.[Br:19][C:20]1[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=1.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[Br:19][C:20]1[CH:25]=[CH:24][C:23]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)=[CH:22][CH:21]=1
Reactant: Brc1ccc(Br)cc1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Brc1ccc(-c2cccc3[nH]ccc23)cc1
Temperature: 70 °C
Reaction time: 15 h
Yield: 55.1 %

Procedure:
To a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (3, 2.43 g, 10 mmol), and 1,4-dibromobenzene (1.8 g, 50 mmol) in THF (34 mL)) were added Palladium catalyst Pd(PPh3)4 (347 mg, 0.3 mmol) and the freshly prepared sodium hydroxide solution (1.20 g, 30 mmol in 14 mL water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 70° C. oil bath for 15 hours. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4, and concentrated. The crude product was purified by a silica gel column eluting with hexanes—EtOAc (9:1) to provide 1.50 g (55%) of the product 4-(4-bromo-phenyl)-1H-indole as a white solid.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][C:20]([F:23])([F:22])[F:21])[CH:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.C(#N)C.C(=O)([O-])[O-].[K+].[K+].[CH3:35][C:36]([OH:53])([CH3:52])[CH2:37][N:38]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[N:39]1>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:35][C:36]([OH:53])([CH3:52])[CH2:37][N:38]1[CH:42]=[C:41]([C:2]2[CH:25]=[CH:24][C:5]3[C:6]4[N:7]=[C:8]([C:14]5[N:15]([CH2:19][C:20]([F:23])([F:21])[F:22])[CH:16]=[CH:17][N:18]=5)[S:9][C:10]=4[CH2:11][CH2:12][O:13][C:4]=3[CH:3]=2)[CH:40]=[N:39]1
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: FC(F)(F)Cn1ccnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(O)Cn1cc(-c2ccc3c(c2)OCCc2sc(-c4nccn4CC(F)(F)F)nc2-3)cn1
Temperature: 25 °C

Procedure:
8-Bromo-2-[1-(2,2,2-trifluoro-ethyl)-1H-imidazol-2-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (110.0 mg, 0.2557 mmol) dissolved in Acetonitrile (0.534 mL, 10.2 mmol) and with dissolved 2.00 M of Potassium carbonate in Water (0.256 mL). Degas by bubbling nitrogen for 5 min. The reaction was charged with 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol (102 mg, 0.384 mmol) then Tetrakis(triphenylphosphine)palladium(0) (41.36 mg, 0.03579 mmol). The reaction was heated in microwave at 140 C for 10 min. The reaction was cooled to r.t. then extracted with ethyl acetate. Combined organics concentrated and purified by reverse phase HPLC to give 355. MS: (ESI+)=490.1. 1H NMR (400 MHz, DMSO) δ 8.24 (d, J=8.3 Hz, 1H), 8.17 (s, 1H), 7.95 (s, 1H), 7.55 (s, 1H), 7.41 (dd, J=8.3, 1.8 Hz, 1H), 7.29 (d, J=1.8 Hz, 1H), 7.18 (d, J=1.2 Hz, 1H), 5.74 (q, J=8.9 Hz, 2H), 4.71 (s, 1H), 4.37 (t, J=5.0 Hz, 2H), 4.03 (s, 2H), 3.40 (t, J=5.0 Hz, 2H), 1.09 (s, 6H)