Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:18]([CH:19]=O)=[C:17]([CH:21]([CH3:23])[CH3:22])[CH:16]=[C:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:14]=2)=[CH:9][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:19][C:18]1[C:13]([C:10]2[CH:9]=[CH:8][C:7]([F:6])=[CH:12][CH:11]=2)=[N:14][C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:16][C:17]=1[CH:21]([CH3:23])[CH3:22]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)c1cc(-c2ccccc2)nc(-c2ccc(F)cc2)c1C=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)c1cc(-c2ccccc2)nc(-c2ccc(F)cc2)c1C=C(Br)Br
Reaction time: 0.33 h
Yield: 98.7 %

Procedure:
A solution of carbon tetrabromide (2.866 gm, 8.64 mmol) in CH2Cl2 (8 ml) was added over a 10 minute period to a cold (-10° C.) solution of 2-(4-Fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinecarboxaldehyde (1.840 gm, 5.76 mmol) (the preparation of which is described in Example 3) and triphenylphosphine (4.590 gm, 17.5 mmol) in CH2Cl2 (30 ml). After the addition was complete, the cooling bath was removed and the mixture was stirred for 20 minutes. The solution was quenched with saturated NaHCO3 and extracted 2× with CH2Cl2. The combined organic layers were washed with saturated NaHCO3, dried (Na2SO4), filtered and concentrated. The concentrate was chromatographed (flash, Merck, SiO2, 1:1 CH2Cl2 : hexane) to give 3-(2,2-Dibromoethenyl)-2-(4-fluorophenyl)-4-(1-methylethyl)-6-phenylpyridine as a white solid (2.701 gm, 99%).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[C:6]([O:26][CH3:27])=[C:7]([CH:13]([N:15]3[C:19]4=[N:20][CH:21]=[N:22][C:23]([NH2:24])=[C:18]4[C:17]([CH3:25])=[N:16]3)[CH3:14])[CH:8]=[C:9]([Cl:12])[C:10]=2[Cl:11])[CH2:2]1.C([BH3-])#N.[Na+].[CH:32](=O)[CH3:33].C(O)(=O)C>CO>[Cl:11][C:10]1[C:9]([Cl:12])=[CH:8][C:7]([CH:13]([N:15]2[C:19]3=[N:20][CH:21]=[N:22][C:23]([NH2:24])=[C:18]3[C:17]([CH3:25])=[N:16]2)[CH3:14])=[C:6]([O:26][CH3:27])[C:5]=1[CH:3]1[CH2:2][N:1]([CH2:32][CH3:33])[CH2:4]1
Reactant: CC=O
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(Cl)c1C1CNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCN1CC(c2c(Cl)c(Cl)cc(C(C)n3nc(C)c4c(N)ncnc43)c2OC)C1
Temperature: 20 °C
Reaction time: 0.33 h

Procedure:
A solution of 1-[1-(3-azetidin-3-yl-4,5-dichloro-2-methoxyphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (40 mg, 0.098 mmol) in methanol (2.6 mL) was treated with sodium cyanoborohydride (15 mg, 0.25 mmol) followed by acetaldehyde (22 μL, 0.39 mmol) and stirred at 20° C. for 20 min. The reaction mixture was quenched with acetic acid (130 μL, 2.3 mmol), diluted with methanol, and purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product as a mixture of enantiomers. This racemic mixture was separated by chiral HPLC (RT=18.6 min and 22.0 min; Phenomenex Lux Cellulose C-4 column, 21.2×250 mm, 5 micron particle size, eluting with 5% ethanol in hexanes at 18 ml/min, 2.5 mg/inj) to give the desired peak 1 isomer (11 mg, 26%). 1H NMR (300 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.45 (s, 1H), 7.33 (br s, 2H), 6.21 (q, J=6.9 Hz, 1H), 3.98-3.77 (m, 3H), 3.57 (s, 3H), 2.92-2.83 (m, 1H), 2.79-2.72 (m, 1H), 2.55 (s, 3H), 2.35-2.22 (m, 2H), 1.70 (d, J=7.1 Hz, 3H), 0.86 (t, J=7.1 Hz, 3H). LCMS for C20H25Cl2N6O (M+H)+: m/z=435.1; Found: 435.0.
Reaction SMILES: [Br:1][C:2]1[N:6]([C@@H:7]2[O:24][CH2:23][C@@H:18]([O:19]C(=O)C)[C@@H:13]([O:14]C(=O)C)[C@H:8]2[O:9]C(=O)C)[C:5]2[CH:25]=[C:26]([Cl:30])[C:27]([Cl:29])=[CH:28][C:4]=2[N:3]=1.[Li+].[OH-]>O1CCOCC1>[Br:1][C:2]1[N:6]([C@@H:7]2[O:24][CH2:23][C@@H:18]([OH:19])[C@@H:13]([OH:14])[C@H:8]2[OH:9])[C:5]2[CH:25]=[C:26]([Cl:30])[C:27]([Cl:29])=[CH:28][C:4]=2[N:3]=1
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](OC(C)=O)CO[C@H]1n1c(Br)nc2cc(Cl)c(Cl)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O[C@@H]1[C@H](O)[C@H](O)CO[C@H]1n1c(Br)nc2cc(Cl)c(Cl)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
3.0 g (5.7 mmol) 2-Bromo-5,6-dichloro-1-(2,3,4-tri-O-acetyl-β-D-ribopyranosyl) -1H-benzimidazole was deprotected as using the general procedure summarized in the foregoing description by being dissolved in 60 ml dioxane and the resultant solution cooled in an ice bath between 0 and 5° C. To this solution was added all at once, 22 ml (22 mmol) of 1M aq. LiOH. The mixture was removed from the ice bath and allowed to stir at ambient temperature for 1 h. The mixture was diluted with 120 ml of pH 7 phosphate buffer and extracted with ethyl acetate. The ethyl acetate layer was dried over magnesium sulfate (anhyd.), filtered and solvents evaporated. The residue was triturated in dichloromethane and 1.7 g (4.3 mmol, 75% yield) of 2-bromo-5,6-dichloro-1-β-D-ribopyranosyl-1H-benzimidazole was collected by vacuum filtration. The product was dried in a vacuum oven at 50° C. overnight; m.p. 175° C. (decomposes); 1H NMR (DMSO-d6) δ 7.96 (s, 1H), 7.07 (s, 1H), 5.64-5.62 (d, J=9.2 Hz), 5.19-5.17 (d, 1H, J=6.4 Hz), 5.13-5.12 (d, 1H, J=3.2 Hz), 4.86-4.84 (d, 1H, J=6.5 Hz), 4.12-4.06 (m, 1H), 3.98-3.92 (m, 2H), 3.68-3.63 (m, 2H).
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH:16]([F:18])[F:17])[C:5]=2[CH2:19][O:20][CH:21]2[CH2:27][CH:26]3[N:28]([C:29]4[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][C:30]=4[F:37])[CH:23]([CH2:24][CH2:25]3)[CH2:22]2)[CH2:3][CH2:2]1.[N-:38]=[N+:39]=[N-:40].[Na+].[Cl-].[NH4+]>CN(C)C(=O)C.C(OCC)(=O)C>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH:16]([F:17])[F:18])[C:5]=2[CH2:19][O:20][CH:21]2[CH2:22][CH:23]3[N:28]([C:29]4[CH:36]=[CH:35][C:32]([C:33]5[N:38]=[N:39][NH:40][N:34]=5)=[CH:31][C:30]=4[F:37])[CH:26]([CH2:25][CH2:24]3)[CH2:27]2)[CH2:3][CH2:2]1
Reactant: N#Cc1ccc(N2C3CCC2CC(OCc2c(-c4ccccc4OC(F)F)noc2C2CC2)C3)c(F)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Fc1cc(-c2nn[nH]n2)ccc1N1C2CCC1CC(OCc1c(-c3ccccc3OC(F)F)noc1C1CC1)C2
Temperature: 120 °C
Reaction time: 8 h

Procedure:
4-(3-((5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)isoxazol-4-yl)methoxy)-8-azabicyclo[3.2.1]octan-8-yl)-3-fluorobenzonitrile (70 mg, 0.14 mmol) was dissolved in N,N-dimethylacetamide (2 ml), sodium azide (91 mg, 10 eq, 1.40 mmol) and ammonium chloride (75 mg, 10 eq, 1.40 mmol) were added, and the mixture was stirred at 120° C. overnight. Upon cooling to room temperature, the reaction mixture was diluted with ethyl acetate (30 mL) and washed with brine (2×20 mL). The combined organics were separated, dried (MgSO4), and evaporated in vacuo. The product was purified by mass directed reverse phase HPLC to give a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[C:7]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Br:21])[CH:6]=1.CCN(CC)CC.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[Br:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][O:13][C:7]1[CH:6]=[C:5]([CH:12]=[CH:11][C:8]=1[CH:9]=[O:10])[O:4][CH2:3][CH2:2][NH:1][C:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NCCOc1ccc(C=O)c(OCc2ccccc2Br)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=Cc1ccc(OCCNC(=O)c2ccccc2)cc1OCc1ccccc1Br

Procedure:
4-(2-Aminoethoxy)-2-(2-bromobenzyloxy)benzaldehyde (200 mg, 0.43 mmol) was dissolved in CH2Cl2 (20 ml) and Et3N (87.02 mg, 0.12 ml, 0.86 mmol) was added to the solution, followed by stirring for 2˜3 min. Benzoyl chloride (60.45 mg, 50 μl, 0.43 mmol) was also added before additionally stirring at room temperature for 2 hours. After completion of the reaction, the reaction solution was extracted with brine and CH2Cl2 (×3). The organic layer was dried over anhydrous MgSO4 and filtered. The filtrate was concentrated in a vacuum. The residue was purified using column chromatography (ethyl acetate/n-hexane=1/5→1/3) to afford the object compound (white solid, 78 mg, 40%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH:9]([C:13]([F:26])([F:25])[C:14]([N:16]([F:24])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[CH2:8][CH2:7]2)([O-])=O>C1COCC1.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH:9]([C:13]([F:26])([F:25])[C:14]([N:16]([F:24])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15])[CH2:8][CH2:7]2
Reactant: O=C(N(F)Cc1ccccc1)C(F)(F)C1CCc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc2c(c1)CCC2C(F)(F)C(=O)N(F)Cc1ccccc1
Reaction time: 1 h

Procedure:
To a stirred solution of 2-(5-nitroindanyl)-N-(phenylmethyl)trifluoroacetamide (1.17 g, 3.21 mmol) in THF/MeOH (100 ml, 1:1) was added a catalytic amount of 10% Pd/C. The mixture was hydrogenated at 50 psi for 1 hr, filtered through celite, and concentrated to give 2-(5-aminoindanyl)-N-(phenylmethyl)trifluoroacetamide which was homogeneous by TLC and used immediately in step (f).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10]([C:12]1[C:16](Br)=[C:15]([N+:18]([O-:20])=[O:19])[S:14][CH:13]=1)=[O:11])[CH3:8].[CH2:21]([SH:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)C>[CH2:7]([O:9][C:10]([C:12]1[C:16]([S:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:15]([N+:18]([O-:20])=[O:19])[S:14][CH:13]=1)=[O:11])[CH3:8]
Reactant: SCc1ccccc1
Reactant: CCOC(=O)c1csc([N+](=O)[O-])c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1csc([N+](=O)[O-])c1SCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.8 %

Procedure:
An aqueous solution of potassium carbonate (9.90 g, 71.6 mmol, dissolved in 40 mL water) was added to a suspension of 4-bromo-5-nitro-thiophene-3-carboxylic acid ethyl ester (20.06 g, 71.6 mmol) in ethanol at 25° C. Benzyl mercaptan (8.41 mL, 71.6 mmol) was added via pipette, and the dark red reaction mixture was stirred at 25° C. for 4 h and then was concentrated in vacuo to near-dryness. The remaining orange-brown solid was triturated with water (200 mL) and was collected by filtration. After washing with water (200 mL), the resulting solid was air-dried overnight to afford the desired product, 4-benzylsulfanyl-5-nitro-thiophene-3-carboxylic acid ethyl ester (22.63 g, 70.0 mmol, 98%), as a yellow/brown solid. 1H NMR (400 MHz, CDCl3) δ: 1.41 (3H, t, J=7.1 Hz), 4.25 (2H, s), 4.39 (2H, q, J=7.0 Hz), 7.18-7.23 (5H, m), 8.07 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([F:20])[C:17]([N:21]2[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[N:23]([CH3:32])[C:22]2=[O:33])=[CH:16][C:3]=1[O:4][C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH2:8][C:9]([OH:11])=[O:10].S(Cl)(Cl)=O.O1C[CH2:41][CH2:40][CH2:39]1>>[Cl:1][C:2]1[CH:19]=[C:18]([F:20])[C:17]([N:21]2[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:29])([F:30])[F:31])[N:23]([CH3:32])[C:22]2=[O:33])=[CH:16][C:3]=1[O:4][C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH2:8][C:9]([O:11][CH2:41][CH:40]=[CH2:39])=[O:10]
Reactant: C1CCOC1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccccc3OCC(=O)O)c(Cl)cc2F)c1=O
Solvent: O=S(Cl)Cl
Product: C=CCOC(=O)COc1ccccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl

Procedure:
1.0 g of [2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]acetic acid was dissolved in tetrahydrofuran, to this was added 0.7 ml of thionyl chloride while stirring, then, the mixture was heated while stirring under reflux condition for 2 hours. Then, the solution was allowed to cool, concentrated, then, dissolved in 3 ml of tetrahydrofuran (hereinafter, referred to as Solution B). 0.7 ml of tetrahydrofuran was added to 0.05 g of allyl alcohol, and trisected portions of Solution B were added, then, 0.17 ml of pyridine was added. The mixture was stirred for 2 hours at room temperature, then, 2% aqueous hydrochloric acid was poured into the reaction solution, and extracted with ethyl acetate. The organic layer was washed with saturated saline, and dried over magnesium sulfate, then, concentrated. The residue was subjected to silica gel column chromatography (eluent: hexane/ethyl acetate=5/1) to obtain 0.08 g of allyl [2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]acetate [compound 3-20 of the present invention].
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[CH2:14][OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.O=[Mn]=O>[O:1]([C:8]1[C:9]([CH:14]=[O:15])=[CH:10][N:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1cnccc1Oc1ccccc1
Agent: O=[Mn]=O
Solvent: C1CCOC1
Product: O=Cc1cnccc1Oc1ccccc1
Reaction time: 8 h
Yield: 106.5 %

Procedure:
MnO2 (289 mg, 3.33 mmol) was added to a solution of (4-phenoxypyridin-3-yl)methanol (70 mg, 0.33 mmol) in THF (10 mL). After stiffing overnight the reaction mixture was filtered (celite). Removal of the solvent provided 4-phenoxynicotinaldehyde (70 mg, 95%). MS [M+H]+=200.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:13]([O-:15])=[O:14])=[C:7]([S:9](O)(=[O:11])=[O:10])[CH:8]=1.O=S(Cl)[Cl:18]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:13]([O-:15])=[O:14])=[C:7]([S:9]([Cl:18])(=[O:11])=[O:10])[CH:8]=1
Reactant: COc1ccc([N+](=O)[O-])c(S(=O)(=O)O)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])c(S(=O)(=O)Cl)c1

Procedure:
In a similar fashion using route 39 general procedure 96, 5-methoxy-2-nitro-benzenesulfonic acid 447 (2.0 g, 8.58 mmol), SOCl2 (9.4 ml) and (0.2 ml) DMF gave the title compound (2.5 g) which was used in the next step without further purification. The structure was confirmed by 1H NMR.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:18][CH2:17][S:16](=[O:20])(=[O:19])[CH2:15]1.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1B(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:19]=[S:16]1(=[O:20])[CH2:17][CH2:18][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:22]4[S:21][CH:25]=[CH:24][CH:23]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:15]1
Reactant: OB(O)c1cccs1
Reactant: NC(=O)c1cc(Br)cc2c(C3CCS(=O)(=O)C3)c[nH]c12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)c1cc(-c2cccs2)cc2c(C3CCS(=O)(=O)C3)c[nH]c12
Temperature: 100 °C
Yield: 36 %

Procedure:
5-bromo-3-(1,1-dioxidotetrahydro-3-thienyl)-1H-indole-7-carboxamide (0.050 g, 0.140 mmol) and 2-thienylboronic acid (0.018 g, 0.14 0 mmol) was dissolved in a 6:1 solution of 1,4 dioxane/water in a 20 mL microwave reaction vessel. Potassium carbonate (0.097 g, 0.70 mmol) was added and the solution was degassed with Argon. PdCl2(dppf) (0.017 g, 0.024 mmol) was added and the reaction was heated in a microwave at 100° C. for 10 min. The solution was passed through a StratoSpheres SPE PL-Thiol MP SPE column to remove palladium and purified on Gilson preparative HPLC using Acetonitrile/0.1% NH4OH/H20. The desired fractions were concentrated, giving 0.017 g (36%) of the title compound.
Reaction SMILES: [SH:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28].C(N(CC)CC)C>C(O)C>[C:19]1(=[O:28])[N:18]([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][S:1][C:2]2[N:7]3[CH:8]=[CH:9][N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]12
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCBr
Reactant: Sc1cccc2nccn12
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CCCCCCSc1cccc2nccn12
Temperature: 25 °C
Reaction time: 12 h
Yield: 75.4 %

Procedure:
To a suspension of 5-mercaptoimidazo[1,2-a]pyridine (1.50g, 10 mmoles) and N-[6-(bromo)hexyl]phthalimide (3.10 g, 10 mmoles) in ethanol (100 ml) was added triethylamine (2.1 ml, 15 mmoles) and the mixture was stirred at room temperature for 12 hours. After the solvent was distilled off, chloroform was added to the residue, which was washed with water, dried over anhydrous magnesium sulfate and the solvent was distilled off. Then the residue was purified by column chromatography (eluent: ethyl acetate) to obtain 2.86 g of the desired product (75.5%, light tan solid).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:15][C@@H:14]([NH:16]C(OCC2C=CC=CC=2)=O)[C:13]2[C:8](=[CH:9][C:10]([O:29][CH3:30])=[C:11]([O:27][CH3:28])[CH:12]=2)[N:7]1[C:31]([O:33][CH:34]([CH2:36][CH3:37])[CH3:35])=[O:32])=[O:5])[CH3:2]>[Pd].C(O)C.C1CCCCC=1>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:15][C@@H:14]([NH2:16])[C:13]2[C:8](=[CH:9][C:10]([O:29][CH3:30])=[C:11]([O:27][CH3:28])[CH:12]=2)[N:7]1[C:31]([O:33][CH:34]([CH2:36][CH3:37])[CH3:35])=[O:32])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1C[C@@H](NC(=O)OCc2ccccc2)c2cc(OC)c(OC)cc2N1C(=O)OC(C)CC
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: CCOC(=O)[C@H]1C[C@@H](N)c2cc(OC)c(OC)cc2N1C(=O)OC(C)CC
Temperature: 70 °C
Yield: 84.5 %

Procedure:
cis-4-Benzyloxycarbonylamino-6,7-dimethoxy-3,4-dihydro-2H-quinoline-1,2-dicarboxylic acid 2-butyl ester 1-ethyl ester (Example 2) (800 mg), 10% palladium on carbon (800 mg), and a mixture of ethanol-cyclohexene (2:1, 60 mL) was heated to 70° C. for 2 h. The reaction mixture was cooled to room temperature, filtered through Celite®, and concentrated in vacuo. Purification by silica gel chromatography using to 5% methanol/ethyl acetate afforded the title compound (500 mg). 1H NMR (CDCl3) δ 0.9 (t, 3H), 1.4 (m, 5H), 2.5 (m, 1H), 3.9 (d, 6H), 6.9 (s, 1H), 7.2 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:38])([CH2:34][CH2:35][CH2:36][CH3:37])[C:3](=[O:33])[CH2:4][CH2:5][C@H:6]1[C@H:10]([O:11]C2CCCCO2)[CH2:9][C:8](=[O:18])[C@@H:7]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28].C(O)(=O)C.O>C1COCC1>[F:1][C:2]([F:38])([CH2:34][CH2:35][CH2:36][CH3:37])[C:3](=[O:33])[CH2:4][CH2:5][C@H:6]1[C@H:10]([OH:11])[CH2:9][C:8](=[O:18])[C@@H:7]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH:30]([CH3:31])[CH3:32])=[O:28]
Reactant: CCCCC(F)(F)C(=O)CC[C@H]1[C@H](OC2CCCCO2)CC(=O)[C@@H]1CCCCCCCCC(=O)OC(C)C
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CCCCC(F)(F)C(=O)CC[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCCCC(=O)OC(C)C
Reaction time: 3.5 h

Procedure:
The compound (59) (0.288 g) was dissolved in a mixed solvent (30 ml) consisting of acetic acid, water and THF (4:2:1) and the solution was kept at 45° C. for 3.5 hours. The resultant mixture was worked up with the conventional procedure and the obtained crude product was subjected to silicagel column chromatography to give the titled compound (60). Yield: 0.184 g (76%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][N:10]=2)=[CH:5][CH:4]=1.[BH4-].[Na+]>CO>[F:20][C:2]([F:1])([F:19])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1ccc(C2=NCCc3ccccc32)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: FC(F)(F)c1ccc(C2NCCc3ccccc32)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline (4.69 g, 17 mmol) in MeOH (24 mL) was added sodium borohydride (1.94 g, 51.1 mmol) slowly at 0° C. Then, the mixture was stirred at 0° C. for 15 min and at RT for 2 h. The solvent was then removed and H2O (20 mL) was added to the residue. A saturated NaHCO3 solution (150 mL) was added slowly and the mixture was extracted with EtOAc (2×200 mL). The combined organic extracts were dried over MgSO4 and concentrated. The residue was mixed with silica gel (4:1; residue:silica gel) and purified by silica gel chromatography (20%-100% EtOAc/hexane) to give the title compound as a white solid. MS (ESI, positive ion) m/z: 278 (M+H).
Reaction SMILES: C([C:5]1[CH:37]=[CH:36][C:8]([C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:26]=[C:25]4[C:21]([CH2:22][N:23]([C@@H:28]([CH:33]([CH3:35])[CH3:34])[C:29]([O:31][CH3:32])=[O:30])[C:24]4=[O:27])=[CH:20][CH:19]=3)=[N:16][CH:17]=2)=[O:10])=[CH:7][CH:6]=1)(C)(C)C.NC1C=CC(C2C=[C:52]3[C:48](CN([C@@H](C(C)C)C(OC)=O)[C:51]3=[O:54])=[CH:47]C=2)=NC=1.C(OC1C=CC(C(Cl)=O)=CC=1)CCC>>[CH2:51]([O:54][C:5]1[CH:37]=[CH:36][C:8]([C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:26]=[C:25]4[C:21]([CH2:22][N:23]([C@@H:28]([CH:33]([CH3:34])[CH3:35])[C:29]([O:31][CH3:32])=[O:30])[C:24]4=[O:27])=[CH:20][CH:19]=3)=[N:16][CH:17]=2)=[O:10])=[CH:7][CH:6]=1)[CH2:52][CH2:48][CH3:47]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cn3)cc2C1=O
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C(C)(C)C)cc4)cn3)cc2C1=O
Agent: CCCCOc1ccc(C(=O)Cl)cc1
Product: CCCCOc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)OC)C(C)C)C4)nc2)cc1
Yield: 69 %

Procedure:
The compound of example 411 was prepared analogous to the compound of example 403 by reaction of the compound of example 392 with 4-n-butoxy benzoyl chloride.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[CH:39][C:40](=[O:45])[N:41]([CH2:43][CH3:44])[CH:42]=1>>[CH2:43]([N:41]1[C:40](=[O:45])[CH:39]=[CH:38][C:37]([C:16]2[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:9][C:8]3=[O:10])[CH3:12])=[CH:18][CH:17]=2)=[CH:42]1)[CH3:44]
Reactant: CCn1cc(Br)ccc1=O
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: CCn1cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)ccc1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 5-bromo-1-ethylpyridin-2(1H)-one following a procedure analogous to that described in Example 6 Step 1. LC-MS Method 2 tR=1.224 min, m/z=475.1; 1H NMR (CDCl3) 1.11 (s, 3H), 1.19 (s, 3H), 1.39 (t, 3H), 1.56 (d, 3H), 2.20 (s, 2H), 2.26 (m, 1H), 2.36-2.57 (m, 2H), 2.87 (m, 1H), 4.03 (m, 2H), 5.69 (m, 1H), 6.62 (d, 1H), 7.00 (d, 2H), 7.17 (d, 2H), 7.28-7.51 (m, 6H), 7.50 (d, 1H). Recrystallization from isopropyl acetate following a procedure analogous to that described for Example 37 in Recrystallization Method B afforded a crystalline solid with mp 167-168° C.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Li]CCCC.[F:16][C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1.[Cl:23][C:24]1[N:29]=[C:28]([C:30](OC)=[O:31])[CH:27]=[CH:26][CH:25]=1>C1COCC1>[Cl:23][C:24]1[N:29]=[C:28]([C:30]([C:22]2[C:17]([F:16])=[N:18][CH:19]=[CH:20][N:21]=2)=[O:31])[CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1cccc(Cl)n1
Reactant: Fc1cnccn1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(c1cccc(Cl)n1)c1nccnc1F
Temperature: -30 °C
Reaction time: 0.17 h
Yield: 46.2 %

Procedure:
2,2,6,6-tetramethylpiperidine (1.729 g, 2.066 mL, 12.24 mmol) was dissolved in THF (20.00 mL) and cooled to −30° C. under nitrogen. BuLi (4.488 mL of 2.5 M, 11.22 mmol) was added dropwise and the reaction allowed to warm to 0° C. Stir at this temperature for 10 minutes then cooled to −78° C. A solution of 2-fluoropyrazine (1 g, 10.20 mmol) in THF (4.000 mL) was added slowly and the mixture stirred at −78° C. for 1 h. Methyl 6-chloropyridine-2-carboxylate (1.750 g, 10.20 mmol) in THF (6.000 mL) was added dropwise at between −78 and −70° C., stirred at −78° C. for 1 h. Reaction quenched with 5% citric acid at −78° C. then allow to warm to ambient temperature. Diluted with EtOAc and separated layers. Extracted with EtOAc (x1) then wash combined organics with NaHCO3 (x1), brine (x1). Dried (MgSO4), filtered and concentrated. Crude product purified by ISCO companion (80 g SiO2, 0 to 50% EtOAc/petrol) to leave title compound as an orange oil (1.12 g, 46%). 1H NMR (DMSO-d6) δ 7.90 (dd, 1H), 8.22-8.15 (dd, 2H), 8.67 (dd, 1H), 8.84 (dd, 1H). ES+238.13.