Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:29])[C@@H:15]([CH3:28])[C@H:16]([OH:27])[CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)C1C=CC=CC=1.OO.O.[OH-].[Li+].S([O-])([O-])=[O:36].[Na+].[Na+]>C1COCC1.O.O>[OH:27][C@H:16]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C@H:15]([CH3:28])[C:14]([OH:29])=[O:36]
Reactant: O=S([O-])[O-]
Reactant: C[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)CCCCc1ccccc1
Agent: OO
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](C(=O)O)[C@H](O)CCCCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
4-(S)-Benzyl-3-(3-(R)-hydroxy-2-(S)-methyl-7-phenylheptanoyl)oxazolidin-2-one (7.64 g, 19 mmol) is dissolved in 4:1 THF-water (100 mL) and cooled to 0° C. To this is added 30% hydrogen peroxide (8.2 mL, 80 mmol) over 5 minutes, followed by lithium hydroxide monohydrate (1.3 g, 32 mmol) in water (40 mL) added dropwise over 10 minutes, keeping the reaction temperature <10° C. This mixture is stirred for 1 hour. Then sodium sulfite (10 g, 80 mmol), in 60 mL of water, is added carefully to keep the temperature <25° C. The solvent is removed in vacuo and the aqueous residue is washed with CH2Cl2 (3×100 mL). The aqueous layer is then cooled in an ice bath and acidified to pH 1 with 6 N HCl and the product extracted into ethyl acetate (2×100 mL). This solution is dried over MgSO4 and concentrated in vacuo, to yield (+)-(2S, 3R)-3-hydroxy-2-methyl-7-phenylheptanoic acid (3.76 g, 84%): m.p. 75-77° C.; [a]D23 +20° (c=1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.30-7.25 (m, 2H), 7.20-7.16 (m, 3H), 3.95-3.93 (m, 1H), 2.65-2.54 (m, 3H), 1.69-1.34 (m, 6H), 1.20 (d, J=7.2 Hz, 3H); MS (EI) m/e 236 (M+).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C@@H:13]2O)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].[CH3:22][O:23]C1C=C2C(=CC=1)C(N)CC2>>[CH2:1]([C:3]1[C:4]([NH:11][CH:12]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH3:22])=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2]
Reactant: COc1ccc2c(c1)CCC2N
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Product: CCc1cnc(CC)c(NC2CCc3cc(OC)ccc32)n1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 5-methoxyindan-1-amine and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ 1.31, 1.89, 2.58, 2.67, 2.73, 2.91, 3.00, 3.83, 4.51, 5.69, 6.79, 6.85, 7.26, 7.69; 13C NMR (CDCl3) δ 11.08, 13.97, 26.04, 28.55, 30.84, 35.35, 55.79, 55.87, 110.39, 113.15, 125.21, 130.10, 137.12, 140.93, 145.91, 151.82, 153.69, 160.25; HRMS (FAB) calcd for C18H23N3O+H 298.1919, found 298.1900. Anal. Calcd for C18H23N3O: C, 72.70; H, 7.80; N, 14.13. Found: C, 72.51; H, 8.00; N, 13.82.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:14]([N:31]1[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]1)([O:16][CH2:17][CH:18]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15].C(O)C.C([BH3-])#N.[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:34]2[CH2:33][CH2:32][N:31]([C:14]([O:16][CH2:17][CH:18]3[C:19]4[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:25]4[C:30]3=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:15])[CH2:36][CH2:35]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH3-]C#N
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(C2CCN(C(=O)OCC3c4ccccc4-c4ccccc43)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.7 %

Procedure:
N-tert-butoxycarbonyl-piperazine (1.86 g, 10 mmol, Lancaster), N-Fmoc-4-oxo-piperidine (3.21 g, 10 mmol, Aldrich) and titanium(IV) isopropoxide (3.72 mL, Aldrich) were combined, and the mixture was stirred at room temperature for 1 h. Then ethyl alcohol (10 mL) was added followed by sodium cyanoborohydride (0.47 g, 7.48 mmol, Aldrich), and the mixture was stirred overnight. Water (2 mL) was added and the mixture was filtered. The solid was washed with ethyl alcohol and the filtrate was combined. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (ISCO machine, silica gel, eluting with 20% ethyl acetate in hexane for a period of 30 min) to give 4-(1-Fmoc-piperidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester as a white foam (1.02 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:38])[C:22]([N:24]3[CH2:29][CH2:28][CH2:27][CH:26]([NH:30]C(=O)OC(C)(C)C)[CH2:25]3)=[O:23])[C:17]1=[O:39])(=[O:14])=[O:13])[CH:6]=[CH:5]2.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:30][CH:26]1[CH2:27][CH2:28][CH2:29][N:24]([C:22](=[O:23])[C@@H:21]([N:18]2[CH2:19][CH2:20][C@H:16]([NH:15][S:12]([C:7]3[CH:6]=[CH:5][C:4]4[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=4)[CH:8]=3)(=[O:14])=[O:13])[C:17]2=[O:39])[CH3:38])[CH2:25]1
Reactant: C[C@@H](C(=O)N1CCCC(NC(=O)OC(C)(C)C)C1)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](C(=O)N1CCCC(N)C1)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.6 %

Procedure:
tert-Butyl 1-[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-ylcarbamate (0.6 g) was dissolved in DCM (11 ml) and trifluoroacetic acid (11 ml) was added. The mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure. The residue was dissolved in water (5 ml) and ammonia solution (0.88%; 1 ml) added. The resultant aqueous mixture was extracted with DCM. The combined organic extracts were dried (over magnesium sulphate), filtered and concentrated under reduced pressure to give the title compound (0.38 g) as a white foam.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17]CN3C(=O)N4C=CC=CC4=N3)[CH2:14][CH:15]=2)=[CH:2]1.[O:29]=[C:30]1[N:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]2=[N:32][N:31]1CCOS(C1C=CC(C)=CC=1)(=O)=O.N1CCC(C2C3C(=CC=CC=3)NC=2)CC1>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:31]3[C:30](=[O:29])[N:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]4=[N:32]3)[CH2:12][CH2:11]2)=[CH:2]1
Reactant: Cc1ccc(S(=O)(=O)OCCn2nc3ccccn3c2=O)cc1
Reactant: O=c1n(CCCN2CC=C(c3c[nH]c4ccccc34)CC2)nc2ccccn12
Agent: c1ccc2c(C3CCNCC3)c[nH]c2c1
Product: O=c1n(CCN2CCC(c3c[nH]c4ccccc34)CC2)nc2ccccn12

Procedure:
2-{2-[4-(1H-Indol-3-yl)-piperidin-1-yl]-ethyl}-2H-[1,2,4]triazolo[4,3-a]pyridin-3-one was prepared in a similar fashion to of 2-{2-[4-(1H-Indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-ethyl}-2H-[1,2,4]triazolo[4,3-a]pyridin-3-one (example 22) using of toluene-4-sulfonic acid 2-(3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2-yl)-ethyl ester and 3-Piperidin-4-yl-1H-indole. Yield: 70 mg of compound was obtained (39%). mp: 142° C.; M+: 362.1; H-NMR: 8.14 (b, 1H, NH), 7.74 (m, 1H), 7.62 (m, 1H), 7.35(m, 1H), 7.08 (m, 5H), 6.94 (m, 1H), 6.45 (m, 1H), 4.23 (m, CH2), 3.13 (d, CH2), 2.93 (m, CH2), 2.82 (m, 1H) 2.28 (t, CH2), 2.04(m, CH2), 1.86(m, CH2).
Reaction SMILES: O=[C:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3]1[N:10]2[C:6](=[N:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)[S:5][N:4]=1.N1C=CC=CC=1.Cl.[NH2:28][OH:29]>C(O)C>[OH:29][N:28]=[C:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3]1[N:10]2[C:6](=[N:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)[S:5][N:4]=1
Reactant: NO
Reactant: O=C(c1ccccc1)c1nsc2nc3ccccc3n12
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: ON=C(c1ccccc1)c1nsc2nc3ccccc3n12
Yield: 89.2 %

Procedure:
To a solution of 0.5 g (1.79 mmol) of 3-(oxophenyl-methyl)-1,2,4-thiadiazolo[4,5-a]benzimidazole in 7 mL of ethanol was added 0.5 mL (6.46 mmol) of pyridine and 0.5 g (7.20 mmol) of hydroxylamine hydrochloride. The mixture was refluxed for overnight. The precipitate was collected by filtration, and washed with methanol and dichloromethane to give the crude product, which was recrystallized from methanol to yield 0.47 g (89%) of the title compound as white crystals. mp 247° C.; 1H NMR (DMSO-d6) δ 11.89 (s, 1H), 7.81 (d, 1H), 7.73 (dd, 2H), 7.45-7.53 (m, 5H), 7.32 (t, 1H) ppm; 13C NMR (CDCl3) δ 168.25, 155.24, 150.52, 147.95, 136.94, 135.67, 134.30(2C), 133.03, 131.52(2C), 130.35, 127.26, 124.28, 116.91 ppm; IR (KBr) ν 2731, 1549, 1475, 1450, 1251, 1194, 983, 753, 736 cm-1. HRMS calcd for C15H10N4OS 294.0575, found 294.0583.
Reaction SMILES: [OH:1][C@H:2]([CH3:37])[C@H:3]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=4)[N:20]([CH3:28])[N:19]=3)[N:16]=2)[N:11](COCC[Si](C)(C)C)[CH:10]=1)=[O:8])[CH2:4][OH:5].C(O)(C(F)(F)F)=O.C(N)CN>ClCCl>[OH:1][C@H:2]([CH3:37])[C@H:3]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=4)[N:20]([CH3:28])[N:19]=3)[N:16]=2)[NH:11][CH:10]=1)=[O:8])[CH2:4][OH:5]
Reactant: C[C@@H](O)[C@@H](CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](O)[C@@H](CO)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 39.6 %

Procedure:
In a 10 mL round-bottom flask, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((1R,2R)-2-hydroxy-1-hydroxymethyl-propyl)-amide (30 mg, 0.057 mmol) and TFA (0.3 ml, 3.9 mmol) were combined with dichloromethane (1 ml) to give an orange solution. The reaction mixture was stirred at room temperature for 2.5 h then concentrated under reduced pressure. The resultant crude solid was dissolved in dichloromethane (1 mL) and ethylenediamine (0.10 ml, 1.5 mmol) was added. The reaction mixture was stirred at room temperature for 18 h then concentrated and the residue was precipitated with water. The suspension was stirred for 1 h and the crude solid collected by filtration. The crude solid was purified by trituration (hot dichloromethane/heptane) to afford 9 mg (40%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((1R,2R)-2-hydroxy-1-hydroxymethyl-propyl)-amide as a light yellow solid. MS: [M+H]+=399; 1H NMR (DMSO-d6) δ: 12.61 (br. s., 1H), 9.16 (s, 1H), 8.83 (dd, J=8.9, 5.5 Hz, 1H), 8.44 (s, 1H), 8.15 (d, J=9.4 Hz, 1H), 7.64 (dd, J=9.8, 1.9 Hz, 1H), 7.15 (td, J=9.3, 1.9 Hz, 1H), 5.07 (d, J=4.2 Hz, 1H), 4.85 (t, J=4.9 Hz, 1H), 4.15 (s, 3H), 3.98-4.24 (m, 2H), 3.54-3.71 (m, 2H), 1.13 (d, J=6.0 Hz, 3H).
Reaction SMILES: C[Mg]Cl.[Cl:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]#[CH:10].[CH:11](OCC)([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14].[Cl-].[NH4+]>O1CCCC1.C1(C)C=CC=CC=1.O.C(O)(=O)C>[Cl:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]#[C:10][CH:11]([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14]
Reactant: C#CCCCCCl
Reactant: CCOC(OCC)OCC
Agent: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(C#CCCCCCl)OCC
Temperature: 47.5 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
In a reactor equipped with a stirrer, a cooling condenser, a dropping funnel and a thermometer was placed a solution of methyl magnesium chloride (89.7 g:1.2 mol) in tetrahydrofuran (370.0 g), and stirred at a solution temperature of from 45 to 50° C. The 6-chloro-1-hexyne (116.6 g:1.0 mol) was dropwise added thereto at a reaction mixture temperature of from 50 to 60° C. over one hour, and then stirred at from 60 to 65° C. for 5 hours. A solution of triethyl orthoformate (177.8 g:1.2 mol) in toluene (120.0 g) was dropwise added thereto at a reaction mixture temperature of from 80 to 85° C. over 30 minutes, and then stirred at from 90 to 95° C. for 6 hours. After completion of the reaction was confirmed by gas chromatography, acetic acid (57.0 g), ammonium chloride (35.0 g) and water (400.0 g) were added to the reaction mixture. The organic phase separated from the aqueous phase was washed with an aqueous 1.0% sodium hydroxide solution (170.0 g). The organic phase was subjected to removal of the solvent under reduced pressure, and then the residue was distilled under reduced pressure to obtain 7-chloro-1,1-diethoxy-2-heptyne [bp: 100-104° C./0.13 KPa, 133.4 g, 0.61 mol]. [Yield: 61.0%]
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[Cl:7][C:8]1[N:9]=[CH:10][N:11]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]3[N:37]=[C:23]4[C@@H:24]([C:30]5[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=5)[CH2:25][C:26](=C)[CH2:27][CH2:28][N:22]4[N:21]=3)=[CH:15][C:14]=2[O:38][CH3:39])[CH:12]=1>O.C1COCC1.[Cl-].[Na+].O.[Os](=O)(=O)(=O)=O>[Cl:7][C:8]1[N:9]=[CH:10][N:11]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]3[N:37]=[C:23]4[C@@H:24]([C:30]5[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=5)[CH2:25][C:26](=[O:2])[CH2:27][CH2:28][N:22]4[N:21]=3)=[CH:15][C:14]=2[O:38][CH3:39])[CH:12]=1
Reactant: C=C1CCn2nc(Nc3ccc(-n4cnc(Cl)c4)c(OC)c3)nc2[C@@H](c2ccc(F)cc2)C1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(Nc2nc3n(n2)CCC(=O)C[C@@H]3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Reaction time: 1 h
Yield: 95.6 %

Procedure:
A solution of sodium periodate (276 mg, 1.29 mmol) in water (5.0 mL) was added over a 10 min period to a vigorously stirred solution of the (R)—N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-9-(4-fluorophenyl)-7-methylene-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine (200 mg, 0.430 mmol, from example 134) and osmium tetroxide (10.9 mg, 0.043 mmol) in THF (5.0 mL). The reaction was stirred for 1 h and then diluted with water (150 mL)/brine (100 mL) and extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo to afford (R)-2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-9-(4-fluorophenyl)-8,9-dihydro-5H-[1,2,4]triazolo[1,5-a]azepin-7(6H)-one (192 mg, 77% yield). LC-MS (M+H)+ 467.1.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])=[CH:8][CH:7]=1)C.[OH-].[Na+]>CCO.O>[CH2:15]([S:12]([C:9]1[CH:10]=[CH:11][C:6]([CH2:5][C:4]([OH:17])=[O:3])=[CH:7][CH:8]=1)(=[O:14])=[O:13])[CH3:16]
Reactant: CCOC(=O)Cc1ccc(S(=O)(=O)CC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCS(=O)(=O)c1ccc(CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
To a solution of ethyl2-(4-(ethylsulfonyl)phenyl)acetate (10.0 g, 39 mmol) in EtOH (100 mL) was added a solution of NaOH (5.7 g, 142.5 mmol) in water (100 mL). The reaction mixture was stirred at rt for 16 h. EtOH was removed under reduced pressure. The aqueous layer was adjusted to pH=1 with 6 N aq. HCl and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (2×100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the desired product 2-(4-(ethylsulfonyl)phenyl)acetic acid (7.3 g, 82%) as a white solid. LC-MS tR=0.573 min in 5-95AB—1.5 min chromatography (Welch Xtimate C18, 2.1*30 mm, 3 um), MS (ESI) m/z 228.8 [M+H]+. 1H NMR (CDCl3 400 MHz): δ 7.88 (d, J=8.0 Hz, 2H), 7.50 (d, J=8.4 Hz, 2H), 3.77 (s, 2H), 3.12 (q, J=7.6 Hz, 2H), 1.28 (t, J=7.6 Hz, 3H).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:5]2=[N:6][CH:7]=1.[CH3:25][O:26][CH2:27][O:28][C:29]1[CH:30]=[C:31]([N:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[CH:32]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:34]=1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>O>[CH3:25][O:26][CH2:27][O:28][C:29]1[CH:34]=[C:33]([C:2]2[N:3]=[C:4]3[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:5]3=[N:6][CH:7]=2)[CH:32]=[C:31]([N:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[CH:30]=1
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: COCOc1cc(B2OC(C)(C)C(C)(C)O2)cc(N2CCCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COCOc1cc(-c2cnc3c(n2)c(C(=O)C(C)(C)C)cn3COCC[Si](C)(C)C)cc(N2CCCC2)c1
Temperature: 150 °C

Procedure:
A microwave flask was charged with 1-[2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one (705 mg, 1.71 mmol, following the general procedures described in these Examples), 1-[3-methoxymethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-pyrrolidine (570 mg, 1.71 mmol), and K2CO3 (591 mg, 4.28 mmol). Dioxane (13 ml) and water (3.2 ml) were added, and the solution was vacuum degassed under argon. [1,1′-Bis(diphenylphosphino)ferrocene]palladium(ll) dichloride dichloromethane complex (140 mg, 0.17 mmol) was added, and the reaction mixture was heated (150° C.) in a microwave reactor for 45 minutes. The reaction mixture was filtered through a plug of celite using ethyl acetate. The filtrate was transferred to a reparatory funnel and shaken with water (60 ml). The organic phase was collected and the aqueous phase back extracted with ethyl acetate (2×50 ml). The organic phases were combined, dried (MgSO4), filtered and stripped to provide a viscous semi-solid. This material was purified by preparative TLC, eluting with 24% ethyl acetate in hexanes to afford 492 mg of 1-[2-(3-Methoxymethoxy-5-pyrrolidin-1-yl-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one as a red-brown viscous oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:22]=[C:21]([NH2:23])[CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][N:4]=[N:3]1.N1C=CC=CC=1.[O:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[CH2:32][CH:31]1[C:39](Cl)=[O:40]>ClCCl>[CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:22]=[C:21]([NH:23][C:39]([CH:31]3[CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[O:30]3)=[O:40])[CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1C(=NOCc1cccc(N)n1)c1ccccc1
Reactant: O=C(Cl)C1Cc2ccccc2O1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cn1nnnc1C(=NOCc1cccc(NC(=O)C2Cc3ccccc3O2)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a stirred solution of 6-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-amine (100 mg, 0.32 mmol) in dry dichloromethane (4 mL) under argon was added pyridine (39 μL, 0.48 mmol) at room temperature, followed after fifteen minutes by 2,3-dihydro-1-benzofuran-2-carbonyl chloride (88 mg, 0.48 mmol). The reaction mixture was stirred overnight at room temperature and quenched by filtration on bi-layer cartridge filled with 1.4 g of basic alumina and 1 g of silica. The cartridge was rinsed twice by 10 mL of dichloromethane. The combined filtrated solutions were evaporated in vacuo to yield a colorless oil. Purification on silica gel afforded of N-{6-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}-2,3-dihydro-1-benzofuran-2-carboxamide as a colorless oil [150 mg, yield 96%; HPLC/MS: nm/z=456 (M+H); log P(HCOOH)=3.67].
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([NH:10][C:11]([C:13]2[CH:35]=[CH:34][C:16]([O:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]([C:28]([O:30]CC)=[O:29])[CH2:23][CH2:24][O:25]4)=[CH:20][C:19]=3[Cl:33])=[CH:15][CH:14]=2)=[O:12])[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C1COCC1.C(O)C.[OH-].[Na+].Cl>C(OCC)(=O)C>[C:1]([C:5]1[N:6]=[C:7]([NH:10][C:11]([C:13]2[CH:14]=[CH:15][C:16]([O:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]([C:28]([OH:30])=[O:29])[CH2:23][CH2:24][O:25]4)=[CH:20][C:19]=3[Cl:33])=[CH:34][CH:35]=2)=[O:12])[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4nc(C(C)(C)C)cs4)cc3)c(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)c1csc(NC(=O)c2ccc(Oc3cc4c(cc3Cl)C(C(=O)O)CCO4)cc2)n1
Reaction time: 18 h
Yield: 75.5 %

Procedure:
Ethyl 7-(4-(4-tert-butylthiazol-2-ylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate (408 μl, 0.0408 mmol) in 2:1 THF-Ethanol was treated with 1N sodium hydroxide (0.061 ml, 0.061 mmol) at ambient temperature. After 18 hours, the reaction was diluted with ethyl acetate and acidified with hydrogen chloride (81.6 μl, 0.0816 mmol). The reaction was washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo to give the desired product (0.015 g, 76%) as a white solid. MS (APCI)=487.1 (M+1).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[C:12]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:11]=1)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:24][C:25]([O:28][C:29]([NH:31][CH2:32][C:33](ON1C(=O)CCC1=O)=[O:34])=[O:30])([CH3:27])[CH3:26].C(N(CC)CC)C>CN(C=O)C>[C:25]([O:28][C:29]([NH:31][CH2:32][C:33]([NH:2][C@H:3]([C:10]1[CH:11]=[C:12]([C:20]([CH3:22])([CH3:21])[CH3:23])[CH:13]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:15]=1)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:34])=[O:30])([CH3:27])([CH3:26])[CH3:24]
Reactant: CC(C)(C)OC(=O)NCC(=O)ON1C(=O)CCC1=O
Reactant: CCOC(=O)C[C@H](N)c1cc(C(C)(C)C)cc(C(C)(C)C)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C[C@H](NC(=O)CNC(=O)OC(C)(C)C)c1cc(C(C)(C)C)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 107 %

Procedure:
To a solution of a mixture of (S)-ethyl 3-amino-3-(3,5-di-tert-butylphenyl)propionate hydrochloride (112.0 mg, 0.33 mmol) and Boc-Gly-Osu (95.0 mg, 0.35 mmol) in anhydrous DMF was added triethylamine (62 μL, 0.45 mmol) and the reaction mixture was stirred at room temperature under nitrogen atmosphere overnight to give a colorless solution. The solvent was evaporated in-vacuo and the residue was partitioned between ethyl acetate (25 mL), water (25 mL) and saturated NaHCO3 solution (10 mL). The organic layer was removed, washed with water (1×10 mL), dried over anhydrous Na2SO4, filtered and evaporated in vacuo to afford a cream foamy solid (163.4 mg). LC-MS analysis of the solid shows the desired product's mass: m/z 463 (M+H) and m/.z 485 (M+Na); Calcd for C26H42N2O5: 462.62. The above product will be used as such for the Boc-deprotection. (step #5).
Reaction SMILES: [CH3:1][OH:2].[CH2:3]1[CH2:7]O[CH2:5][CH2:4]1>C1C=CC=CC=1>[CH2:3]([C:7]1[CH:5]=[CH:4][CH:3]=[CH:7][C:1]=1[OH:2])[CH:4]=[CH2:5]
Reactant: CO
Reactant: C1CCOC1
Solvent: c1ccccc1
Product: C=CCc1ccccc1O
Temperature: 148.88888888888889 °C

Procedure:
200 g of linear (NPCl2)n in benzene (total volume is about 2400 ml) is added (20 to 30 minutes) the alkyl or aryloxides prepared in a) in 1200 ml of THF and 2500 ml of benzene. The reaction mixture is then stirred at about 300° F. for twenty-four hours. Upon cooling, the polymer is coagulated by pouring into a ten gallon can containing two gallons of methanol with agitation. The solvents are then drawn off. Additional methanol may be added if the polymer does not separate cleanly from the solution. The solid, as free as possible of solvent, is then desalted by washing with water. The resulting chlorine-free polymer is dried at 50° to 60° C. under vacuum.
Reaction SMILES: Br[C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[NH:11]1[CH:15]=[CH:14][CH:13]=[N:12]1.CN[C@H]1CCCC[C@@H]1NC.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.[Cu]I>[CH3:8][C:5]1[N:4]=[C:3]([C:9]#[N:10])[C:2]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)=[CH:7][CH:6]=1
Reactant: Cc1ccc(Br)c(C#N)n1
Reactant: c1cn[nH]c1
Agent: [Cu]I
Agent: CN[C@H]1CCCC[C@@H]1NC
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1ccc(-n2cccn2)c(C#N)n1
Temperature: 120 °C
Yield: 63.9 %

Procedure:
A mixture of 3-bromo-6-methylpicolinonitrile (1 g, 5.1 mmol), 1H-pyrazole (0.52 ml, 7.61 mmol), (1S,2S)—N1,N2-dimethylcyclohexane-1,2-diamine (0.97 ml, 6.09 mmol), Cs2CO3 (2.48 g, 7.61 mmol) and CuI (97 mg, 0.51 mmol) in DMF (10 mL) was degassed and heated at 120° C. for 1 h in a microwave reactor. The solvent was removed in vacuo to obtain the crude which was purified by silica gel chromatography (0˜100% DCM/EtOAc) to yield the title compound as a yellow oil (600 mg, 64%). MS (ESI) 185 (M+H).