Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)[C:15](=[O:29])[CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]1.Cl.O1CCOCC1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:27])([F:28])[F:26])=[CH:20][CH:19]=2)[C:15](=[O:29])[CH2:14][NH:13][CH2:12]1
Reactant: COc1cccc(OC)c1C1CN(C(=O)OC(C)(C)C)CC(=O)N1Cc1ccc(OC(F)(F)F)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cccc(OC)c1C1CNCC(=O)N1Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A cooled (0° C.) solution of tert-butyl 3-(2,6-dimethoxyphenyl)-5-oxo-4-(4-(trifluoromethoxy)-benzyl)piperazine-1-carboxylate (540 mg; 1.05 mmol) in anh. DCM (10 ml) was treated dropwise with 4 M HCl in dioxane (4.00 ml; 16.00 mmol), and the resulting mixture was further stirred at rt, under nitrogen, for 16 h. The reaction mixture was concentrated to dryness under reduced pressure, the resulting residue was dissolved in DCM, and washed successively with 1 M aq. NaOH, aq. sat. NaHCO3, and brine. The organic layer was dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=10/1) afforded 6-(2,6-dimethoxyphenyl)-1-(4-(trifluoromethoxy)benzyl)piperazin-2-one as an orange oil. LC-MS (conditions D): tR=0.85 min.; [M+H]+: 411.13 g/mol.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)=O.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[BH4-].[Na+]>CO>[CH2:19]([NH:26][CH2:1][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCc1ccccc1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc(CNCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.9 %

Procedure:
Combine 4-(4-Formyl-phenoxy)-benzamide from Example 247, step 2 (0.1 g, 0.41 mmol), benzylamine (0.040 g, 0.38 mmol), 4 {acute over (Å)} molecular sieves (1 g) in methanol (5 mL) and stir for 18 h at ambient temperature. Add sodium borohydride (0.058 g, 1.52 mmol), agitate 66 h at ambient temperature. Filter through a 5 g SCX column, eluting first with 1:1 dichloromethane/methanol. Discard the first washings, then elute with 1:1 dichloromethane/2 M ammonia in methanol. Collect the eluants and concentrate in vacuo. Purify by Chromatotron, on a 2 mm silica plate, eluting with 90:10:1 dichloromethane/ethanol/ammonium hydroxide to afford the title compound (0.058 g, 46%): mass spectrum (ion spray): m/z=333.06 (M+1); 1H NMR (DMSO-d6): 7.82 (m, 3H), 7.39-7.18 (m, 8H), 7.02-6.97 (m, 4H), 3.67-3.66 (2s, 4H).
Reaction SMILES: CO.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]([F:13])[F:12])=[C:6]([O:14]CC2CC2)[C:5]=1[I:19].Cl>O>[Br:3][C:4]1[C:5]([I:19])=[C:6]([OH:14])[C:7]([O:10][CH:11]([F:13])[F:12])=[CH:8][CH:9]=1
Reactant: FC(F)Oc1ccc(Br)c(I)c1OCC1CC1
Agent: Cl
Solvent: CO
Solvent: O
Product: Oc1c(OC(F)F)ccc(Br)c1I
Yield: 85.9 %

Procedure:
To 59.5 ml of methanol solution containing 8.1 g (22 mmol) of 1-bromo-3-cyclopropylmethoxy-4-difluoromethoxy-2-iodobenzene obtained in Reference example 12-(e) was added 59.5 ml of conc. hydrochloric acid, and the mixture was refluxed for 4 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=9:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 6.9 g of the title compound as a colorless solid. (Yield: 87%)
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]([CH3:13])[CH:7]=1>S(=O)(=O)(O)O>[N+:1]([C:11]1[CH:10]=[C:9]([NH2:12])[C:8]([CH3:13])=[CH:7][C:6]=1[CH3:5])([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(N)c(C)c1
Agent: O=S(=O)(O)O
Product: Cc1cc(C)c([N+](=O)[O-])cc1N
Temperature: 15 °C
Reaction time: 1 h
Yield: 71117.9 %

Procedure:
Conc. nitric acid (33 g) was added dropwise over 3 h to a stirred solution of m-xylidine (40 g, 0.33 mmol) in conc. sulfuric acid (400 g) at <15° C. After complete addition the reaction was stirred at 15° C. for 1 h then poured onto ice (600 mL), stirred for 30 min and filtered. The yellow filter-cake was neutralised with saturated aqueous sodium hydrogen carbonate solution (500 mL) and extracted with ethyl acetate (3×200 mL). The combined organic extracts were dried (Magnesium sulfate), filtered and the solvent removed under vacuum to leave a crude solid. The solid was recrystallised (ethanol-water) to give the product as an orange solid (39 g, 71%, contains 20% di-nitro). IR νmax (Nujol)/cm−1 3469, 3386, 3239, 2956, 2925, 2855, 1719, 1636, 1514, 1461, 1377, 1339, 1297, 1273, 1222, 1170, 1034, 992, 885, 870, 849, 805, 758, 745, 723, 640, 607 and 571; NMR δH (400 MHz; CDCl3) 7.15 (1H, s), 6.87 (1H, s), 4.99 (2H br. s), 2.21 (3H, s), 1.97 (3H, s).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:10][NH:11][C@H:12]([C:14]([NH:16][C@H:17]([C:21]([NH:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH3:13])=O)(C)(C)C.FC(F)(F)C(O)=O.ClCCl>C(O)C>[NH2:8][C@@H:9]([CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:10][NH:11][C@H:12]([C:14]([NH:16][C@H:17]([C:21]([NH:23][CH2:24][CH:25]([CH3:26])[CH3:27])=[O:22])[CH:18]([CH3:19])[CH3:20])=[O:15])[CH3:13]
Reactant: CC(C)CNC(=O)[C@@H](NC(=O)[C@H](C)NC[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: ClCCl
Product: CC(C)CNC(=O)[C@@H](NC(=O)[C@H](C)NC[C@@H](N)Cc1ccccc1)C(C)C

Procedure:
N-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropyl]-L-alanyl-N1-isobutyl-L-valinamide (84 mg, 0.176 mmol) is stirred with 1 mL of trifluoroacetic acid and 3 mL of dichloromethane for 30 min. It is then concentrated on a rotary evaporator and then neutralized with several mL of saturated aqueous sodium bicarbonate. The product is taken up in 70 mL of ethyl ether, washed with several more mL of bicarbonate solution, and then dried over anhydrous sodium sulfate. Concentration from ethyl ether, and then from absolute ethanol, afforded 75 mg of a slightly yellow oil, whose NMR spectrum was consistent with the title compound, along with a small amount of residual ethanol. NMR (CDCl3) δ 7.96 (d, J=9 Hz, 1H), 7.3-7.17 (m, 5H), 6.88 (br t, 1H), 4.13 (m, 1H), 3.27 (m, 1H), 3.13 (m, 1H), 3.05 (m, 1H), 2.94 (m, 1H), 3.83 (m, 2H), 2.7 (dd, 1H), 2.57 (dd, 1H), 2.08 (m, 1H), 1.72 (m, 1H), 1.31 (d, J=7 Hz, 3H), 0.93-0.86 (overlapping d, 12H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([N+:17]([O-])=O)[C:11]=2[N:10]([CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:9]1=[O:27])([CH3:4])([CH3:3])[CH3:2]>CCO.CCOC(C)=O.[Pd]>[NH2:17][C:16]1[C:11]2[N:10]([CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:9](=[O:27])[N:8]([CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:28])[C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)CCCn1c(=O)n(CC(=O)OC(C)(C)C)c2cccc([N+](=O)[O-])c21
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)CCCn1c(=O)n(CC(=O)OC(C)(C)C)c2cccc(N)c21
Reaction time: 1 h

Procedure:
A mixture of methyl 4-[3-(2-tert-butoxy-2-oxoethyl)-7-nitro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]butanoate from Step B (129 mg, 0.33 mmol) and 10% Pd/C (40 mg) in EtOH (30 mL) and EtOAc (15 mL) was stirred under an atmosphere of hydrogen (ca. 1 atm). After 1 h, the reaction was filtered through a Celite pad and concentrated in vacuo to give the title compound. MS: m/z=364 (M+1).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:6]=1[N+:12]([O-])=O.[H][H]>C1C=CC=CC=1.[Pd]>[CH3:11][C:8]1[CH:7]=[C:6]2[C:5]([CH:4]=[CH:3][NH:12]2)=[CH:10][CH:9]=1
Reactant: Cc1ccc(/C=C/N(C)C)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: c1ccccc1
Product: Cc1ccc2cc[nH]c2c1
Reaction time: 5 h
Yield: 83 %

Procedure:
A glass-lined rocking autoclave was charged with a solution of 300 g (1.45 moles) of trans-β-dimethylamino-4-methyl-2-nitrostyrene in 3 l of benzene and 15 g of 5% palladium on carbon. The autoclave was pressurized with 20 psi of hydrogen and rocked for 5 hours. The mixture was filtered through a bed of Celite, which was washed thoroughly with benzene. The filtrate was concentrated to half its volume and washed with 1 l of 0.25 N hydrochloric acid, 500 ml of saturated sodium bicarbonate and 500 ml of brine. The aqueous phases were backwashed with 500 ml of benzene and the combined organic phases were dried over sodium sulfate and concentrated. The residual dark brown oil was distilled at vacuo to afford 157.9 g (83%) of product as a light yellow oil, b.p. 80°-85°/0.05 mmHg, which solidified after seeding to a light yellow solid. m.p. 29°-30.5°.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]([CH3:14])[CH2:10][C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1.S(=O)(=O)(O)O.[CH3:20]O>>[NH2:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]([CH3:14])[CH2:10][C:11]([O:13][CH3:20])=[O:12])=[CH:5][CH:4]=1
Reactant: CO
Reactant: CC(CC(=O)O)c1ccc(N)nc1
Agent: Cl
Agent: O=S(=O)(O)O
Product: COC(=O)CC(C)c1ccc(N)nc1

Procedure:
A solution of (RS) 3-(6-amino-pyrid-3-yl)-butanoic acid hydrochloride (12.0 g, Reference Example 20) in methanol (300 mL) was treated with concentrated sulphuric acid (3.0 mL) then heated at reflux temperature for 8 hours. The reaction mixture was concentrated, then basefied with 5% aqueous sodium bicarbonate and then extracted with ethyl acetate . The extracts were washed with water, then with brine, then dried over magnesium sulphate and then evaporated to give the title compound (7.6 g) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14](B2OCC(C)(C)CO2)[C:8]2[O:9][C:10]([F:13])([F:12])[O:11][C:7]=2[CH:6]=1)=[O:4].[OH:24]O>CO>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([OH:24])[C:8]2[O:9][C:10]([F:13])([F:12])[O:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2c(c(B3OCC(C)(C)CO3)c1)OC(F)(F)O2
Reactant: OO
Solvent: CO
Product: COC(=O)c1cc(O)c2c(c1)OC(F)(F)O2
Reaction time: 0.5 h

Procedure:
6.0 g of 7-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-2,2-difluoro-benzo[1,3]dioxole-5-carboxylic acid methyl ester were dissolved using 200 ml of methanol and 30 ml of a 33% aqueous solution of H2O2 added. Stirring was continued for 30 minutes at room temperature. The reaction mixture was then concentrated to 20 ml and 100 ml of water and 100 ml of a saturated aqueous NaCl-solution added. The reaction mixture was then extracted three times using 100 ml of CH2Cl2 each, dried using MgSO4, and evaporated. Chromatography on silica gel using EA/HEP 1:4 yielded 1.8 g of the title compound, colorless oil.
Reaction SMILES: [C:1]([OH:11])(=O)/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(Cl)(=O)C([Cl:15])=O>C1(C)C=CC=CC=1>[C:1]([Cl:15])(=[O:11])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)/C=C/c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)/C=C/c1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 135.9 %

Procedure:
trans-Cinnamic acid (5 g, 33.7 mmol, Aldrich) was dissolved in toluene (100 mL), and the solution was cooled to 0° C. and flushed with N2. Anhydrous DMF (0.1 mL) was added, followed by oxalyl chloride (8.56 g, 5.88 mL, 67.4 mmol) dropwise over 8 minutes. The mixture was stirred at 0° C. for 1 hour and at room temperature for 1.5 hours. The solvent was removed under vacuum to give the title compound (7.63 g).
Reaction SMILES: O=O.[CH3:3][O:4]/[C:5](=[CH:9]\[C:10]1[C:15]2[S:16][CH:17]=[CH:18][C:14]=2[C:13]([O:19][CH2:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])=[CH:12][CH:11]=1)/[C:6]([OH:8])=[O:7].C1([C@@H](N)C)C=CC=CC=1.[H][H]>C1COCC1.ClCCl>[CH3:3][O:4][C@H:5]([CH2:9][C:10]1[C:15]2[S:16][CH:17]=[CH:18][C:14]=2[C:13]([O:19][CH2:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])=[CH:12][CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: CO/C(=C\c1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)C(=O)O
Reactant: [H][H]
Agent: C[C@H](N)c1ccccc1
Agent: O=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CO[C@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a glove box (O2 content≦2 ppm), a 50-ml stainless steel autoclave was charged with 0.66 mg of [Ru(η5-2,4-DMP)((R)—(S)—PPF—PtBu2)(NCMe)]BF4 (0.0008 mmol, S/C 3,000) and 5 ml of dichloromethane. The resulting violet solution was stirred for 2 h at r.t. Then, 1.00 g of (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylic acid (2.30 mmol), 2.5 ml of dichloromethane, 7.5 ml of THF and 0.06 ml of (S)-1-phenylethylamine (0.47 mmol) were added. The autoclave was sealed and the hydrogenation was run under stirring at 40° C. under 30 bar of hydrogen. After 16 h the autoclave was opened and the yellowish solution was rotary evaporated to dryness (50° C./5 mbar) to afford (R)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid (Acid I) as a white solid with a chemical purity of 99.5% (99.9% conversion) and an enantiomeric purity of 89%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH:11]([Si:14](OS(C(F)(F)F)(=O)=O)([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])([CH3:13])[CH3:12].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([Si:14]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:11]([CH3:13])[CH3:12])[CH:6]=[CH:5]2
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Place a 35% oil dispersion of KH (6 g) in a flask under nitrogen, rinse with 50 mL hexanes and dry under vacuum. Cool the solid suspension in 100 mL anhydrous DMF to 0° C. Add dropwise over 10 minutes a solution of 5-bromoindole (10.3 g, 52.5 mmol) in 25 mL DMF. Stir the mixture 1 hour at 0° C. then treat with triisopropylsilyltrifluoromethane sulfonate (32.2 g, 105.1 mmol). Remove the cooling bath and stir the reaction 72 hours before pouring into 500 mL water and extracting with EtOAc. Dilute the combined extracts with hexanes, wash with brine then dry over MgSO4. Concentration under vacuum and chromatograph on silica gel eluting with 1% EtOAc in hexanes to give 5-Bromo-1-triisopropylsilanyl-1H-indole as a colorless oil: 1H NMR (CDCl3) 7.73-7.72 (d, 1H), 7.36-7.34 (d, 1H), 7.24-7.23 (d, 1H), 7.21-7.19 (m, 1H), 6.55-6.54 (m, 1H), 1.72-1.61 (m, 3H), 1.13-1.10 (m, 18H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[C:4]([N+:10]([O-])=O)[CH:3]=1.[H][H]>CO.[Pt]>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[C:4]([CH:3]=1)[NH2:10]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1CO
Reactant: [H][H]
Agent: [Pt]
Solvent: CO
Product: Nc1cc(Cl)ccc1CO
Yield: 100 %

Procedure:
To a solution of 4-chloro-2-nitro benzyl alcohol (25.00 g) in methanol (1 ltr) under nitrogen at room temperature, was added platinum on sulfided carbon (2.5 g, 10% by wt). The reaction mixture was shaken under 50 psi of hydrogen until the theoretical uptake of hydrogen had occurred. Filtration, then removal of the solvent in vacuo afforded the desired compound as a solid (21.00 g). δ (360 MHz, DMSO-d6) 4.35 (2H, d, J=4.95 Hz, CH2OH), 5.17 (1H, t, J=4.95 Hz, CH2OH), 6.77 (1H, dd, J=7.98 Hz, J=2.18 Hz, 4-H), 7.06 (1H, d, J=2.18 Hz, 6-H), 7.18 (1H, d, J=7.98 Hz, 3-H), 8.08 (1H, bs, NH2), 8.47 (1H, bs, NH).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](F)[C:3]=1[C:4]#[N:5].[CH3:11][NH2:12]>C(O)C.O>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:12][CH3:11])[C:3]=1[C:4]#[N:5]
Reactant: CN
Reactant: N#Cc1c(F)cccc1F
Solvent: CCO
Solvent: O
Product: CNc1cccc(F)c1C#N
Temperature: 80 °C
Yield: 99.6 %

Procedure:
To a stirred solution of 2,6-difluorobenzonitrile (3.5 g, 25.2 mmol) in ethanol (40 mL) was added 2 mL of methylamine (40 wt %, in H2O) and heated at 80° C. for 2 h. The mixture was then diluted with water and the resulting slurry extracted with dichloromethane (3×50 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated to give the title product as a white solid (3.77 g, 99.6% yield). 1HNMR (500 MHz, CDCl3) δ: 7.35–7.31 (1H, m), 6.41–6.38 (2H, m), 4.74 (1H, br s), 2.93 (3H, d, J=5.19 Hz). LCMS calcd for C8H8FN2 (M+H): 151.07.
Reaction SMILES: [ClH:1].[OH:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:18]=1[C:17]1=[C:19]3[C@@H:9]([N:10]([CH3:20])[CH2:11][CH2:12][C:13]3=[CH:14][CH:15]=[CH:16]1)[CH2:8]2.C[Mg+].[Br-].CN(C)P(N(C)C)N(C)C.C=O.Cl.[C:37]([O-])(O)=[O:38].[Na+]>C1C=CC=CC=1>[ClH:1].[CH:37]([C:4]1[C:3]([OH:2])=[C:18]2[C:7]([CH2:8][C@H:9]3[C:19]4[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=4)[CH2:12][CH2:11][N:10]3[CH3:20])=[CH:6][CH:5]=1)=[O:38]
Reactant: O=C([O-])O
Reactant: CN1CCc2cccc3c2[C@@H]1Cc1cccc(O)c1-3
Agent: C=O
Agent: CN(C)P(N(C)C)N(C)C
Agent: C[Mg+]
Solvent: c1ccccc1
Product: CN1CCc2cccc3c2[C@@H]1Cc1ccc(C=O)c(O)c1-3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
This reaction was performed in a dry box under N2 (10% relative humidity). A suspension of 0.228 g (0.908 mmol) of 9 in 10 mL of benzene was added in 0.5 mL portions over 20 min to a solution of 0.45 mL (1.36 mmol) of MeMgBr (3.0M in Et2O) in 10 mL of benzene. The mixture was stirred at room temperature for 30 min. A solution of 0.243 g (1.36 mmol) of hexamethylphosphorous triamide in 1 mL of benzene was added. The mixture was stirred for 15 min, then a suspension of 0.273 g (9.08 mmol) of paraformaldehyde in 2 mL of benzene was added. The mixture was heated under reflux for 4 h, cooled, and transferred to a 1 L beaker. Two hundred milliliters of 5% HCl was added and the resulting mixture was stirred for 10 min. The mixture was made basic with solid NaHCO3 and was extracted with 100 mL of Et2O, then with four 75 mL portions of CHCl3. The combined extracts were dried (Na2SO4) and volatiles were removed under reduced pressure to produce a green oil which was converted into its HCl salt with ethereal HCl. The salt was washed with two 5 mL portions of abs EtOH to give 0.130 g (46%) of a white solid, mp 255°-258° C. (decomp). Lit1 mp of (R) enantiomer 260°-262° C. (decomp).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:12])[N:10]=2)[CH:7]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].C(#N)C>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.C1(C)C=CC=CC=1>[C:13]1([C:11]([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:7][N:6]3[CH:8]=2)=[O:12])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C(c1ccccc1)c1cn2cc(Br)ccc2n1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CC#N
Product: O=C(c1ccccc1)c1cn2cc(-c3ccccc3)ccc2n1
Reaction time: 0.33 h
Yield: 41.3 %

Procedure:
0.391 g of (6-bromoimidazo[1,2-a]pyridin-2-yl)(phenyl)methanone, 0.237 g of phenylboronic acid, 45 mg of tetrakis(triphenylphosphine)palladium, 4 mL of aqueous 2M sodium carbonate solution, 6 mL of acetonitrile and 6 mL of toluene are introduced into a 20 mL microwave tube. The mixture is stirred for 20 minutes in a microwave machine set at 150° C. After cooling, the organic phase is separated out, dried and evaporated. The residue is taken up in a mixture of dichloromethane and pentane. The solid is filtered off and then purified by trituration in methanol to give 0.16 g of phenyl(6-phenylimidazo[1,2-a]pyridin-2-yl)methanone in the form of an off-white solid.
Reaction SMILES: [Si]([O:8][C@@H:9]([C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][C:66]=1[C:71]1[CH:76]=[CH:75][C:74]([Cl:77])=[CH:73][CH:72]=1)[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:64]=[CH:63][C:19]([C:20]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][C:29]([NH:32][C@H:33]([CH2:42][CH2:43][N:44]4[CH2:49][CH2:48][O:47][CH:46]([CH2:50][N:51]([CH2:54][CH3:55])[CH2:52][CH3:53])[CH2:45]4)[CH2:34][S:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[C:28]([S:56]([C:59]([F:62])([F:61])[F:60])(=[O:58])=[O:57])[CH:27]=3)(=[O:25])=[O:24])=[O:21])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)(C(C)(C)C)(C)C.Cl.CCN(CC)CC>O1CCOCC1.C(Cl)Cl>[Cl:77][C:74]1[CH:75]=[CH:76][C:71]([C:66]2[CH:67]=[CH:68][CH:69]=[CH:70][C:65]=2[C@H:9]([OH:8])[CH:10]2[CH2:11][CH2:12][N:13]([C:16]3[CH:17]=[CH:18][C:19]([C:20]([NH:22][S:23]([C:26]4[CH:31]=[CH:30][C:29]([NH:32][C@H:33]([CH2:42][CH2:43][N:44]5[CH2:49][CH2:48][O:47][CH:46]([CH2:50][N:51]([CH2:54][CH3:55])[CH2:52][CH3:53])[CH2:45]5)[CH2:34][S:35][C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)=[C:28]([S:56]([C:59]([F:62])([F:61])[F:60])(=[O:57])=[O:58])[CH:27]=4)(=[O:24])=[O:25])=[O:21])=[CH:63][CH:64]=3)[CH2:14][CH2:15]2)=[CH:72][CH:73]=1
Reactant: CCN(CC)CC1CN(CC[C@H](CSc2ccccc2)Nc2ccc(S(=O)(=O)NC(=O)c3ccc(N4CCC([C@@H](O[Si](C)(C)C(C)(C)C)c5ccccc5-c5ccc(Cl)cc5)CC4)cc3)cc2S(=O)(=O)C(F)(F)F)CCO1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCN(CC)CC1CN(CC[C@H](CSc2ccccc2)Nc2ccc(S(=O)(=O)NC(=O)c3ccc(N4CCC([C@@H](O)c5ccccc5-c5ccc(Cl)cc5)CC4)cc3)cc2S(=O)(=O)C(F)(F)F)CCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(4-((R)-(tert-butyldimethylsilyloxy)(4′-chlorobiphenyl-2-yl)methyl)piperidin-1-yl)-N-(4-((2R)-4-(2-((diethylamino)methyl)morpholino)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)phenylsulfonyl)benzamide, single diastereomer (INTERMEDIATE 117, 199 mg, 0.17 mmol) in dioxane (2.027 ml) was added drop wise HCl (4M in dioxane, 0.430 ml, 1.72 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was neutralized with Et3N (2 ml), diluted with DCM and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (ISCO, eluting with 0→100% DCM to 10% MeOH/0.1% NH3 in DCM) to provide the title product as a substantially separated diastereomer (0.06 g, 30%).
Reaction SMILES: [C:1]([Si:5]([CH3:21])([CH3:20])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][Si](C)(C)C)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].S([O-])([O-])(=O)=O.[Mg+2]>CO>[C:1]([Si:5]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[CH:15])=[CH:10][CH:9]=1)([CH3:21])[CH3:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(C#C[Si](C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.5 %

Procedure:
Under argon condition, tert-butyldimethyl((4-((trimethylsilyl)-ethynyl)benzyl)oxy)silane (383 mg, 2.40 mmol) and potassium carbonate (332 mg, 2.40 mmol) were dissolved in 4 mL of methanol, and then stirred for 2 hours at room temperature. Upon completion of the reaction, the reaction was terminated by adding 10 mL of aqueous saturated ammonium chloride solution. The reaction mixture was extracted with ethyl acetate (5 mL×4) and the organic layer thus obtained was treated with anhydrous magnesium sulfate to remove water. The precipitate was filtered out and the resulting solution was concentrated by distillation under reduced pressure, and purified by column chromatography to obtain 280 mg (1.14 mmol, 95%) of the desired compound.