Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1.[F:20][C:21]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=1[C@H:28]([CH2:37][CH2:38][CH:39]=[CH2:40])/[CH:29]=[N:30]/[S@@:31]([C:33]([CH3:36])([CH3:35])[CH3:34])=[O:32]>O1CCCC1.C(OCC)(=O)C.CCCCCC>[Br:13][C:14]1[C:19]([C@@H:29]([NH:30][S@@:31]([C:33]([CH3:36])([CH3:35])[CH3:34])=[O:32])[C@H:28]([C:22]2[CH:23]=[CH:24][CH:25]=[C:26]([F:27])[C:21]=2[F:20])[CH2:37][CH2:38][CH:39]=[CH2:40])=[N:18][CH:17]=[CH:16][N:15]=1
Reactant: Brc1cnccn1
Reactant: C=CCC[C@H](/C=N/[S@](=O)C(C)(C)C)c1cccc(F)c1F
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: C=CCC[C@@H](c1cccc(F)c1F)[C@H](N[S@](=O)C(C)(C)C)c1nccnc1Br
Temperature: -30 °C
Reaction time: 0.08 h
Yield: 62.3 %

Procedure:
In an oven-dried 250 mL round-bottomed flask was dissolved diisopropylamine (1.7 mL, 12 mmol) in tetrahydrofuran (40 mL) to give a colorless solution under nitrogen. After cooling to −30° C., n-BuLi (4.3 mL, 11 mmol) was added, and the mixture was briefly warmed up to rt for 3 min. After cooling down to −78° C., 2-bromopyrazine (0.98 mL, 10.7 mmol) was added dropwise via syringe. The resulting yellow solution was stirred at −78° C. for 5 min. (R,E)-N—((S)-2-(2,3-difluorophenyl)hex-5-enylidene)-2-methylpropane-2-sulfinamide (2.089 g, 6.67 mmol) in 4 mL anhydrous tetrahydrofuran (plus 3 mL rinse) was added via canuula, and the mixture was stirred for 2 h at −75° C. The reaction was quenched with saturated sodium bicarbonate solution and diluted with ethyl acetate. The layers were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried, and concentrated to give a tan oil. Flash column chromatography up to 80% ethyl acetate/hexane afforded the desired product (1.964 g, 62%) as a dense tan oil: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.33 (d, J=2.26 Hz, 1H) 8.26 (d, J=2.26 Hz, 1H) 6.99-7.22 (m, 3H) 5.74 (d, J=6.53 Hz, 1H) 5.18 (dd, J=9.29, 5.27 Hz, 1H) 4.85-4.99 (m, 2H) 4.30 (d, J=9.54 Hz, 1H) 3.66-3.77 (m, 1H) 2.17 (br. s., 1H) 1.80-2.04 (m, 3H) 1.05 (s, 9H); 19F NMR (376 MHz, CHLOROFORM-d) δ ppm −138.41 (d, J=15.61 Hz, 1F) −144.20-−143.20 (m, 1F); 13C NMR (101 MHz, CHLOROFORM-d) δ ppm 155.19 (s, 1C) 151.32-149.72 (dd, J=13.87 and 249.47 Hz, 1C) 150.24-147.67 (dd, J=12.72 and 246.95 Hz, 1C) 142.89 (s, 1C) 141.44 (br. s., 1C) 140.47 (s, 1C) 136.93 (d, J=10.02 Hz, 1C) 127.54 (d, J=10.79 Hz, 1C) 124.12-124.96 (m, 1C) 123.41-123.97 (m, 1C) 115.23-115.83 (m, 1C) 115.09 (s, 1C) 59.93-60.56 (m, 1C) 56.10-56.69 (m, 1C) 40.72-41.81 (m, 1C) 30.81 (s, 1C) 30.34 (br. s., 1C) 21.94 (q, J=6.17 Hz, 3C).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.C(O)(=O)C.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[F:31][C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[CH:34][N:33]=1>C(#N)C.O>[Cl:1][CH2:38][C:36]1[CH:35]=[CH:34][N:33]=[C:32]([F:31])[CH:37]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1ccnc(F)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: CC(=O)O
Solvent: CC#N
Product: Fc1cc(CCl)ccn1
Temperature: 25 °C

Procedure:
N-Chlorosuccinimide (8.8 g, 66 mmol), acetic acid (0.15 mL) and benzoyl peroxide (220 mg, 0.91 mmol) were added to a solution of 2-fluoro-4-picoline (5.0 g, 45 mmol) in acetonitrile (25 mL) at room temperature, and the mixture was refluxed for 2 hours. The reaction mixture was cooled to room temperature, water (200 mL) was added thereto, and then the mixture was extracted with ethyl acetate (300 mL). The organic layer was washed with brine (200 mL) and dried over anhydrous magnesium sulfate. The organic layer was evaporated under reduced pressure, hexane/ethyl acetate (1:1) was added to the resulting residue, and then the insoluble matter was filtered out. The filtrate was evaporated under reduced pressure to give 6.5 g of the title reference compound as a crude product.
Reaction SMILES: C(O)(=O)C(O)=O.[NH:7]1[CH2:11][CH2:10][C@@H:9]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8]1.Cl[C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([F:34])[CH:32]=2)[N:27]=[C:26]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[OH:41])[N:25]=1.C(N(CC)CC)C>C(Cl)Cl>[F:34][C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][CH:30]=1)[N:27]=[C:26]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[OH:41])[N:25]=[C:24]2[N:7]1[CH2:11][CH2:10][C@@H:9]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:8]1
Reactant: Oc1ccccc1-c1nc(Cl)c2cc(F)ccc2n1
Reactant: O=C(N[C@@H]1CCNC1)OCc1ccccc1
Agent: O=C(O)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1CCN(c2nc(-c3ccccc3O)nc3ccc(F)cc23)C1)OCc1ccccc1
Reaction time: 2 h
Yield: 83 %

Procedure:
A solution of (R)-benzyl pyrrolidin-3-ylcarbamate oxalate (1.35 g, 4.38 mmol) in CH2Cl2 (5 mL) was added dropwise to a solution of 2-(4-chloro-6-fluoroquinazolin-2-yl)phenol (1.0 g, 3.6 mmol) and triethylamine (1.22 mL, 8.76 mmol) in CH2Cl2 (10 mL). After stirring the mixture for 2 h, the reaction was quenched with H2O, the layers were separated, and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were dried over MgSO4, filtered, and concentrated. The residue was purified via silica gel chromatography using 5-10% EtOAc in CH2Cl2 to give (R)-benzyl 1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-ylcarbamate (1.37 g, 82%). 1H NMR (400 MHz, CDCl3) δ 8.39 (d, J=6.9 Hz, 1H), 7.80 (s, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.46 (m, 1H), 7.37 (m, 6H), 7.01 (d, J=7.8 Hz, 1H), 6.90 (t, J=7.5 Hz, 1H), 5.17 (m, 2H), 4.51 (s, 1H), 4.25 (m, 1H), 4.10 (m, 2H), 3.91 (m, 1H), 2.37 (m, 1H), 2.12 (m, 1H). LC/MS: m/z 459.5 (M+H)+ at 2.80 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: O=S(Cl)Cl.[OH:5][C:6]1[C:11]2[CH2:12][C@@H:13]3[C:18]([CH3:20])([CH3:19])[C@:17]([CH3:21])([C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH2:16][CH2:15][N:14]3[C:22]([C@@H:24]1[CH2:29][CH2:28][C@H:27]([C:30]([OH:32])=[O:31])[CH2:26][CH2:25]1)=[O:23]>C(O)(C)(C)C>[C:10]([C:7]1[CH:8]=[CH:9][C:10]2[C@@:17]3([CH3:21])[C:18]([CH3:20])([CH3:19])[C@H:13]([N:14]([C:22]([C@@H:24]4[CH2:29][CH2:28][C@H:27]([C:30]([OH:32])=[O:31])[CH2:26][CH2:25]4)=[O:23])[CH2:15][CH2:16]3)[CH2:12][C:11]=2[C:6]=1[OH:5])([CH3:17])([CH3:11])[CH3:9]
Reactant: CC1(C)[C@H]2Cc3c(O)cccc3[C@]1(C)CCN2C(=O)[C@H]1CC[C@@H](C(=O)O)CC1
Solvent: O=S(Cl)Cl
Solvent: CC(C)(C)O
Product: CC(C)(C)c1ccc2c(c1O)C[C@H]1N(C(=O)[C@H]3CC[C@@H](C(=O)O)CC3)CC[C@]2(C)C1(C)C
Temperature: -10 °C
Reaction time: 8 h

Procedure:
SOCl2 (1 mL) is added dropwise to a solution of cis-4-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carbonyl]-cyclohexane carboxylic acid (100 mg) in tert-butanol (5 mL) cooled to −10° C. Then, the cooling bath is removed and the resulting solution is stirred at ambient temperature overnight before another portion of SOCl2 (1 mL) is added. After stirring for additional 12 h more SOCl2 (2 mL) is added and the solution is heated to 50° C. The solution is stirred at this temperature for 48 h before HCl in 1,4-dioxane (1 mL) is added. The resulting solution is stirred at reflux temperature overnight and then treated with concentrated H2SO4 (3 mL). After stirring at reflux temperature for additional 3 h, the solution is cooled to ambient temperature and concentrated under reduced pressure. The residue is treated with water and the precipitate is separated by filtration. The precipitate is taken up in ethyl acetate and washed with water and dried (MgSO4). After removing the solvent, the residue is purified by HPLC (water/MeCN/F3CCO2H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:30])[C:8]([CH:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22]CC)=[O:21])=[C:9]2[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[CH2:31]([Sn](CCCC)(CCCC)C=C)[CH2:32]CC.C(N(CC)CC)C>CC#N.O>[C:26]([O:25][CH:19]([C:8]1[C:7]([CH3:30])=[CH:6][C:5]2[C:10](=[CH:11][C:2]([CH:31]=[CH2:32])=[CH:3][CH:4]=2)[C:9]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:20]([OH:22])=[O:21])([CH3:27])([CH3:28])[CH3:29]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccc(Br)cc2c1-c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: C=Cc1ccc2cc(C)c(C(OC(C)(C)C)C(=O)O)c(-c3ccc(Cl)cc3)c2c1

Procedure:
2-tert-Butoxy-2-(1-(4-chlorophenyl)-3-methyl-7-vinylnaphthalen-2-yl)acetic acid (76) was prepared by the method of Example 67 from ethyl 2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate using tributyl(vinyl)tin and without triethylamine. 1H-NMR: 400 MHz, (CD3OD) δ: 7.74 (d, J=9 Hz, 1H), 7.65 (m, 2H), 7.55 (m, 3H), 7.32 (d, J=9 Hz, 1H), 7.13 (s, 1H), 6.65 (dd, J=18, 11 Hz, 1H), 5.71 (d, J=18 Hz, 1H), 5.19 (d, J=11 Hz, 1H), 5.17 (s, 1H), 2.59 (s, 3H), 0.98 (s, 9H). HPLC (Kinetex 2.6u, 50×4.6 mm, 2-100% MeCN/H2O+0.05% HOAc, 5 min run): tR (min)=3.99.
Reaction SMILES: [C:1]([O:4][CH:5]1[O:9][C:8](=[O:10])[C:7]2[CH:11]=[C:12]3[C:17](=[CH:18][C:6]1=2)[C:16]([CH:19]=[O:20])=[CH:15][CH:14]=[CH:13]3)(=[O:3])[CH3:2].OO.[O-:23]Cl=O.[Na+]>CC#N.O.[NH4+].[Cl-]>[C:1]([O:4][CH:5]1[O:9][C:8](=[O:10])[C:7]2[CH:11]=[C:12]3[C:17](=[CH:18][C:6]1=2)[C:16]([C:19]([OH:23])=[O:20])=[CH:15][CH:14]=[CH:13]3)(=[O:3])[CH3:2]
Reactant: [O-][Cl+][O-]
Reactant: CC(=O)OC1OC(=O)c2cc3cccc(C=O)c3cc21
Agent: OO
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: CC(=O)OC1OC(=O)c2cc3cccc(C(=O)O)c3cc21
Yield: 80 %

Procedure:
To a solution of 3-acetoxy-5-formylnaphtho[2,3-c]furan-1(3H)-one (100 mg, 0.377 mmol) in MeCN (0.373 mL) and H2O (0.150 mL) at rt was added NaH2PO4 (15.3 mg, 0.097 mmol) followed by 50% H2O2 (0.026 mL). NaClO2 (1.0 M in H2O, 0.518 mL) was added over the course of 2 h via syringe pump. The reaction mixture was then diluted with saturated aqueous NH4Cl and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give the title compound (87 mg, 80%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:9]=2[F:17])[C:3]=1[C:18]#[N:19].O.O.[Sn](Cl)Cl>O1CCCC1.C(O)C>[NH2:14][C:12]1[CH:11]=[CH:10][C:9]([F:17])=[C:8]([C:4]2[C:3]([C:18]#[N:19])=[C:2]([F:1])[CH:7]=[CH:6][CH:5]=2)[CH:13]=1
Reactant: N#Cc1c(F)cccc1-c1cc([N+](=O)[O-])ccc1F
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: N#Cc1c(F)cccc1-c1cc(N)ccc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3,2′-Difluoro-5′-nitrobiphenyl-2-carbonitrile (3.25 g, 12.5 mmol) in tetrahydrofuran (20 mL) and ethanol (20 mL) was treated with tin(II) chloride dihydrate (9.86 g, 43.8 mmol) and the mixture left to stir at ambient temperature for 18 h. The solvent was evaporated and the residue stirred with 2 N sodium hydroxide solution (40 mL) for 2 h. The resulting suspension was diluted with water (100 mL) and extracted with dichloromethane (3×200 mL). The combined organics were washed with water (200 mL), brine (200 mL), dried over anhydrous sodium sulfate, filtered and evaporated to give 5′-amino-3,2′-difluorobiphenyl-2-carbonitrile as a brown solid (2.87 9, 100%): δH (360 MHz, CDCl3) 3.74 (2H, s), 6.66-6.75 (2H, m), 7.01 (1H, dd, J 9 and 9), 7.19-7.30 (2H, m), 7.59-7.65 (1H, m).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C@H:8]([N:13]2[CH2:17][CH2:16][C:15]([CH3:19])([OH:18])[CH2:14]2)[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[NH2:20][NH2:21]>C(O)(CC)C>[CH3:19][C:15]1([OH:18])[CH2:16][CH2:17][N:13]([C@@H:8]([C:5]2[CH:6]=[N:7][C:2]([NH:20][NH2:21])=[CH:3][CH:4]=2)[C:9]([F:12])([F:11])[F:10])[CH2:14]1
Reactant: CC1(O)CCN([C@@H](c2ccc(Cl)nc2)C(F)(F)F)C1
Reactant: NN
Solvent: CCC(C)O
Product: CC1(O)CCN([C@@H](c2ccc(NN)nc2)C(F)(F)F)C1
Temperature: 125 °C
Reaction time: 8 h
Yield: 107.1 %

Procedure:
To a solution of Diastereomer 1 of 1-((S)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl)-3-methylpyrrolidin-3-ol (0.550 g, 1.866 mmol) in sec-butanol (10 mL) was added hydrazine (0.8786 mL, 27.99 mmol) and stirred at 125° C. overnight. The reaction was concentrated from methanol (3×30 mL) to give Diastereomer 1 of 3-methyl-1-((S)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ol (0.580 g, 1.998 mmol, 107.1% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[N:12]=[C:11]([CH2:13][C:14]#[N:15])[O:10][N:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH:18]S(O)(=O)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[N:12]=[C:11]([CH2:13][C:14]([NH2:15])=[O:18])[O:10][N:9]=2)=[O:7])=[CH:16][CH:17]=1
Reactant: N#CCc1nc(C(=O)c2ccc(Cl)cc2)no1
Reactant: O=S(=O)(O)O
Product: NC(=O)Cc1nc(C(=O)c2ccc(Cl)cc2)no1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2.8 g of [3-(4-chlorobenzoyl)-1,2,4-oxadiazol-5-yl]acetonitrile and 25 ml of 98% H2SO4 was stirred at room temperature overnight. The resulting solution was added slowly to 500 ml of ice water with mechanical stirring to precipitate a solid. The collected solid was washed with excess water and dried in vacuo to give 2.6 g of a solid. Recrystallization from isopropanol yielded 2.12 g (71%) of crystals, m.p. 156°-158°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:13][NH:12][C:11](=[O:14])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C[O:16][C:17]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)=[O:18].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:14]=[C:11]1[NH:12][CH2:13][C@@H:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([C:22]3[CH:23]=[CH:24][C:19]([C:17]([OH:18])=[O:16])=[CH:20][CH:21]=3)[CH:3]=2)[CH2:10]1
Reactant: O=C1C[C@H](c2ccc(Cl)c(Br)c2)CN1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1C[C@H](c2ccc(Cl)c(-c3ccc(C(=O)O)cc3)c2)CN1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
(4R)-4-(3-Bromo-4-chlorophenyl)pyrrolidin-2-one (0.5 g, 0.55 mmol) and 4-methoxycarbonylphenyl boronic acid (0.144 g, 0.55 mmol) were mixed in DMF (2 mL). The mixture was degassed by alternately applying a vacuum and flushing with nitrogen gas. Palladium acetate (0.025 g, 0.11 mmol) and tetrabutylammonium bromide (0.053 g, 0.165 mmol) were added followed by potassium phosphate (0.35 g, 1.65 mmol). The mixture was stirred overnight at 90° C. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), washed with 10% aqueous HCl solution then brine, and concentrated in vacuo to provide 4-[5-((3R)-5-oxopyrrolidin-3-yl)-2-chlorophenyl]benzoic acid. 4-[5-((3R)-5-Oxopyrrolidin-3-yl)-2-chlorophenyl]benzoic acid was then treated with HCl as described for the preparation of (3R)-4-amino-3-(3-bromo-4-chlorophenyl)butanoic acid hydrochloride to provide the title compound (24). MS (ESI) m/z 334.07 (M+H)+.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:21])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:29](Cl)(=[O:33])[CH:30]([CH3:32])[CH3:31]>C1(C)C=CC=CC=1>[C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:21][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: CC(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)C(=O)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1

Procedure:
(R)—N2-indan-1-yl-quinoline-2,6-diamine (0.05 g, 0.18 mmol), triethylamine (0.028 mL, 0.2 mmol) and isobutyryl chloride (0.021 mL, 0.2 mmol) were dissolved in toluene (2.0 mL).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN([CH:9]=[O:10])C.[Br:11][C:12]1[CH:13]=[C:14]([O:21][CH3:22])[C:15]2[N:16]([N:18]=[CH:19][CH:20]=2)[CH:17]=1>>[Br:11][C:12]1[CH:13]=[C:14]([O:21][CH3:22])[C:15]2[N:16]([N:18]=[CH:19][C:20]=2[CH:9]=[O:10])[CH:17]=1
Reactant: CN(C)C=O
Reactant: COc1cc(Br)cn2nccc12
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(Br)cn2ncc(C=O)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Phosphorous oxychloride (513 μl, 5.51 mmol) was added to DMF (8.52 ml, 110 mmol) at 0° C. The bath was removed and the solution was allowed the solution to warm to ambient temperature. After 30 minutes, 6-bromo-4-methoxypyrazolo[1,5-a]pyridine (500 mg, 2.202 mmol) was added, and the mixture was allowed to stir at ambient temperature. After 3.5 h, the reaction was quenched by the addition of saturated aqueous sodium bicarbonate (30 mL) and stirred for 60 minutes. The reaction mixture was diluted in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and brine then dried over sodium sulfate, filtered and concentrated. The solid was placed under vacuum overnight to remove excess DMF and afford 6-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carbaldehyde contaminated with about 9% of the starting material.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12](=[O:17])[N:13]([O:15][CH3:16])[CH3:14])(=O)OCC)C.[NH:18]1[C:26]2[C:21](=[CH:22][C:23]([CH:27]=O)=[CH:24][CH:25]=2)[CH:20]=[CH:19]1.N1C2C(=CC=CC=2)C=C1>C1COCC1>[CH3:16][O:15][N:13]([CH3:14])[C:12](=[O:17])[CH:11]=[CH:27][C:23]1[CH:22]=[C:21]2[C:26](=[CH:25][CH:24]=1)[NH:18][CH:19]=[CH:20]2
Reactant: O=Cc1ccc2[nH]ccc2c1
Reactant: CCOP(=O)(CC(=O)N(C)OC)OCC
Agent: [H-]
Agent: [Na+]
Agent: c1ccc2[nH]ccc2c1
Solvent: C1CCOC1
Product: CON(C)C(=O)C=Cc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of sodium hydride (0.44 g of a 60% suspension in mineral oil, 11 mmol) and diethyl-(N-methoxy-N-methyl-carbamoylmethyl)-phosphonate (3.0 g, 3 equiv.) in anhydrous THF was stirred at room temperature for 30 minutes. A solution of indole-5-carboxaldehyde (0.61 g, 4.18 mmol) was added dropwise to the mixture. The reaction was complete after 2 h after the addition of the starting indole. The mixture was quenched with water (50 ml), then diluted with ether. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give N-methoxy-N-methyl-3-(indol-5-yl)acrylamide as a yellow oil which solidified on standing to an off-white solid (1.53 g, quantitative yield. 1H NMR (CDCl3): δ 8.55 (br, 1H), 7.87 (d, J=18.6 Hz, 1H), 7.85 (s, 1H), 7.38 (d, J=8.5 Hz, 1H), 7.25 (d, J=8.5 Hz, 1H), 7.23 (m, 1H), 7.0 (d, J=18.6 Hz, 1H), 6.58 (m, 1H), 3.78 (s, 3H), and 3.32 (s, 3H). FIMS: 229.1 (M−H)−, reverse-phase HPLC purity: 88%.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.O[CH2:14][CH2:15][C:16]1[C:21]([C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[O:23])=[CH:20][N:19]=[CH:18][CH:17]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO>C1COCC1.C(Cl)(Cl)Cl>[CH3:33][O:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][N:24]2[CH2:14][CH2:15][C:16]3[C:21](=[CH:20][N:19]=[CH:18][CH:17]=3)[C:22]2=[O:23])=[CH:27][CH:28]=1
Reactant: COc1ccc(CNC(=O)c2cnccc2CCO)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc(CN2CCc3ccncc3C2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.8 %

Procedure:
DEAD (1.094 g, 6.286 mmol) was added drop wise to a solution of 4-(2-hydroxyethyl)-N-(4-methoxybenzyl)nicotinamide (I-65d: 1.5 g, 5.238 mmol) and PPh3 (2.784 g, 10.477 mmol) in THF (40 mL) at 0° C. and the resulting reaction mass was stirred at room temperature for 1 hour. The reaction was monitored by TLC (10% methanol in CHCl3). The reaction mass was concentrated under reduced pressure and the crude residue was purified by column chromatography on silica gel (3% methanol in DCM) to afford 700 mg of the product (49.82% yield).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:24]1[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]=[C:25]1[CH3:33])=[N:6][C:7]=2[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.Br[C:35]([CH3:41])([CH3:40])[C:36]([NH:38][CH3:39])=[O:37]>>[CH3:39][NH:38][C:36](=[O:37])[C:35]([CH3:41])([N:15]1[CH2:16][CH2:17][CH:12]([CH2:11][C:10]2[N:2]([CH3:1])[C:3]3[C:8]([N:9]=2)=[C:7]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[N:6]=[C:5]([N:24]2[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[N:26]=[C:25]2[CH3:33])[N:4]=3)[CH2:13][CH2:14]1)[CH3:40]
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCNCC3)n(C)c2n1
Reactant: CNC(=O)C(C)(C)Br
Product: CNC(=O)C(C)(C)N1CCC(Cc2nc3c(N4CCOCC4)nc(-n4c(C)nc5ccccc54)nc3n2C)CC1

Procedure:
Following General Procedure C, 4-(9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-8-(piperidin-4-ylmethyl)-9H-purin-6-yl)morpholine and 2-bromo-N,2-dimethylpropanamide were reacted to give 585. LCMS m/z: 273.8 (2M+H+)
Reaction SMILES: [CH:1]([O:4][P:5]([CH:11]1[O:15][CH:14]([CH2:16][O:17]C(=O)C2C=CC=CC=2)[CH:13]([O:26][CH3:27])[CH2:12]1)([O:7][CH:8]([CH3:10])[CH3:9])=[O:6])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO>[CH:8]([O:7][P:5]([CH:11]1[CH2:12][CH:13]([O:26][CH3:27])[CH:14]([CH2:16][OH:17])[O:15]1)(=[O:6])[O:4][CH:1]([CH3:3])[CH3:2])([CH3:10])[CH3:9]
Reactant: COC1CC(P(=O)(OC(C)C)OC(C)C)OC1COC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC1CC(P(=O)(OC(C)C)OC(C)C)OC1CO
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.9 %

Procedure:
To a solution of Benzoic acid 5-(diisopropoxy-phosphoryl)-3-methoxy-tetrahydro-furan-2-ylmethyl ester (266 mg, 0.66 mmol) in methanol (3 mL) was added potassium carbonate (45 mg, 0.33 mmol) and stirred for 5 hours at RT. Dowex acidic resin was added until neutral pH was attained, the reaction mixture filtered and concentrated to give (5-Hydroxymethyl-4-methoxy-tetrahydro-furan-2-yl)-phosphonic acid diisopropyl ester (168 mg, 85%).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][N:6]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]=[C:7]2[C:15]([N:17]([CH2:39][CH:40]([CH3:42])[CH3:41])[C@H:18]2[CH2:23][C@@H:22]([C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]2)=[O:16])[CH2:3][CH2:2]1.C(OCC)(=O)C.[ClH:49]>>[ClH:49].[ClH:49].[CH:1]1([CH2:4][CH2:5][N:6]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]=[C:7]2[C:15]([N:17]([CH2:39][CH:40]([CH3:42])[CH3:41])[C@H:18]2[CH2:23][C@@H:22]([C:24]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)=[O:25])[CH2:21][NH:20][CH2:19]2)=[O:16])[CH2:2][CH2:3]1
Reactant: CC(C)CN(C(=O)c1nc2ccccc2n1CCC1CC1)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)CN(C(=O)c1nc2ccccc2n1CCC1CC1)[C@@H]1CNC[C@H](C(=O)N2CCOCC2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl (3S,5R)-3-[(1H-benzimidazol-2-ylcarbonyl)(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (257 mg), 2-cyclopropylethanol (86 mg) and triphenylphosphine (263 mg) in toluene (10 ml) was added diisopropyl azodicarboxylate (506 μl) at room temperature, and the mixture was stirred at the same temperature for 17 hr. The reaction mixture was diluted with aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give tert-butyl (3S,5R)-3-[{[1-(2-cyclopropylethyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate. The obtained tert-butyl (3S,5R)-3-[{[1-(2-cyclopropylethyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate was dissolved in 4M hydrogen chloride-ethyl acetate (5 ml), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated, and the residue was subjected to reversed-phase preparative HPLC and the eluted fraction was concentrated under reduced pressure. The residue was diluted with aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. 4M Hydrogen chloride-ethyl acetate (1 ml) was added and the mixture was stirred for 5 min. The solvent was evaporated under reduced pressure to give the object product (220 mg).