Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:12])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29].O>CN(C)C=O>[CH3:12][N:2]([CH3:1])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:16][CH2:17][CH2:18][N:19]2[C:23](=[O:24])[C:22]3[C:21](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:20]2=[O:29])=[CH:7][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: CN(C)CCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCc1ccc(OCCCN2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 4-[2-(dimethylamino)ethyl]phenol (4.13 g) and sodium hydride (0.67 g) in dimethylformamide was stirred at room temperature for 24 h. N-(3-Bromopropyl) phthalimide (6.7 g) was added at 0° and stirring was continued for 24 h. The solution was treated with water and extracted with ether. Evaporation of the solvent gave the title compound as a white solid which was recrystallised from light petroleum (b.p. 60°-80°) 2.3 g) m.p. 81°-82°. TLC silica; ethyl acetate:water:isopropanol:0.88 ammonia 25:8:15:2; Rf 0.45.
Reaction SMILES: [CH3:1][CH:2]1[O:6][C@@H:5]([CH2:7][OH:8])[CH2:4][CH2:3]1.C(OC1C(OC(=O)C)=C(I)C=CC=1)(=[O:11])C.CC1(C)N([O])C(C)(C)CCC1>C(#N)C.O>[CH3:1][CH:2]1[O:6][C@@H:5]([C:7]([OH:11])=[O:8])[CH2:4][CH2:3]1
Reactant: CC1CC[C@H](CO)O1
Reactant: CC(=O)Oc1cccc(I)c1OC(C)=O
Agent: CC1(C)CCCC(C)(C)N1[O]
Solvent: O
Solvent: CC#N
Product: CC1CC[C@H](C(=O)O)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 26 %

Procedure:
Crude (R)-(5-methyltetrahydrofuran-2-yl)methanol was dissolved in 6 mL of 1:1 ACN/water mixture, and bis-acetoxyiodobenzene [BAIB] (0.71 g, 2.20 mmol) was added to the mixture. It was then cooled to 0 C in an ice bath, and TEMPO (0.031 g, 0.2 mmol) was added under argon flow. The mixture was stirred at room temperature for 3 h, and the reaction was quenched by addition of 20 mL of 1 M NaOH. Basic solution was washed 3×15 mL of EtOAc, and re-acidified with 1 M HCl to ca. pH 2. Aqueous layer was then extracted 6×15 mL of EtOAc, organic layers combined, dried over sodium sulfate and evaporated. Resulting oil (0.05 g, 26%) was used in the next step with no purification. 1H NMR (300 MHz, CDCl3) δ 4.48-4.43 (m, 1H), 4.20-4.17 (m, 1H), 2.33-2.21 (m, 3H), 2.08-2.02 (m, 1H), 1.35 (dd, 3H, J1=6.3 Hz, J2=1.8 Hz).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].FC(F)(F)C([O-])=O.C[NH+]1CCCC(C([NH:24][C@H:25]([C:34]2[NH2+:35][C:36]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[CH:37][N:38]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]C(=O)C)=O)C1.FC(F)(F)C([O-])=O.FC(F)(F)C([O-])=O.[NH3+][C@H](C1[NH2+]C(C2C=CC=CC=2)=CN=1)CCCCCC(=O)C.CCN(CC)CC.[CH3:87][O:88][C:89]1[CH:94]=[CH:93][C:92]([S:95](Cl)(=[O:97])=[O:96])=[CH:91][CH:90]=1>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[CH3:87][O:88][C:89]1[CH:90]=[CH:91][C:92]([S:95]([NH:24][C@H:25]([C:34]2[NH2+:35][C:36]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)=[CH:37][N:38]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:3](=[O:5])[CH3:2])(=[O:97])=[O:96])=[CH:93][CH:94]=1
Reactant: CC(=O)CCCCC[C@H](NC(=O)C1CCC[NH+](C)C1)C1=NC=C(c2ccccc2)[NH2+]1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: CC(=O)CCCCC[C@H]([NH3+])C1=NC=C(c2ccccc2)[NH2+]1
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N[C@@H](CCCCCC(C)=O)C2=NC=C(c3ccccc3)[NH2+]2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of Example 1, A3 and Et3N (1.1 eq.) in DCM was added 4-methoxybenzene sulfonyl chloride (1.1 eq.). The reaction mixture was stirred at RT for 3 hr and the mixture was washed with sat. aq. NaHCO3. The organic phase was concentrated under reduced pressure and the crude residue was purified by preparative RP-HPLC, using H2O (0.1% TFA) and MeCN (+0.1% TFA) as eluents (column: C18). The desired fractions were lyophilized to afford the titled compound B1 as a colourless oil. 1H NMR (300 MHz, CD3CN) δ: 8.87 (1H, d, J=9.3 Hz), 7.60-7.52 (4H, m), 7.51-7.40 (3H, m), 7.31 (1H, s), 6.79-6.63 (2H, m), 4.78-4.65 (1H, m), 3.51 (3H, s), 2.37 (2H, t, J=7.3 Hz), 2.04 (3H, s), 1.89-1.78 (2H, m), 1.51-1.32 (3H, m), 1.31-1.14 (3H, m). MS (ES) C24H29N3O4S requires: 455, found: 456 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:7]=[CH:6]2)=[CH2:2].Br[CH:20]([C:25]1[CH:26]=[C:27]([Cl:33])[C:28]([F:32])=[C:29]([Cl:31])[CH:30]=1)[C:21]([F:24])([F:23])[F:22].N1C=CC=CC=1C1C=CC=CN=1>ClC1C=CC=CC=1Cl.Cl[Cu]>[Cl:31][C:29]1[CH:30]=[C:25]([CH:20]([C:21]([F:24])([F:23])[F:22])/[CH:2]=[CH:1]/[C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:7]=[CH:6]3)[CH:26]=[C:27]([Cl:33])[C:28]=1[F:32]
Reactant: Fc1c(Cl)cc(C(Br)C(F)(F)F)cc1Cl
Reactant: C=Cc1ccc2c(ccn2C(=O)OC(C)(C)C)c1
Agent: Cl[Cu]
Agent: c1ccc(-c2ccccn2)nc1
Solvent: Clc1ccccc1Cl
Product: CC(C)(C)OC(=O)n1ccc2cc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc21
Temperature: 150 °C

Procedure:
To a stirred solution of tert-butyl 5-vinyl-1H-indole-1-carboxylate (0.65 g, 2.67 mmol), in 1,2-dichlorobenzene (10.0 mL) was added 5-(1-bromo-2,2,2-trifluoroethyl)-1,3-dichloro-2-fluorobenzene (1.74 g, 5.37 mmol), CuCl (53 mg, 0.537 mmol) and 2,2-bipyridyl (167 mg, 1.07 mmol). The resultant reaction mixture was degassed with argon for 30 min and heated to 150° C. for 2 h. The reaction mixture was cooled to ambient temperature and filtered, and the filtrate concentrated under reduced pressure. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 2% ethyl acetate/petroleum ether) to afford the title compound as a light brown gummy material (0.25 g, 10%): 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J=8.0 Hz, 1H), 7.60 (m, 2H), 7.39 (m, 3H), 6.69 (d, J=16.0 Hz, 1H), 6.55 (d, J=10.5 Hz, 1H), 6.36 (dd, J=16.0, 8.0 Hz, 1H), 4.10 (m, 1H), 1.65 (s, 9H); ESIMS m/z 485.91 ([M−H]−); IR (thin film) 1165, 854 cm−1.
Reaction SMILES: [CH3:1][N:2]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][C:18]([C:21]1[S:22][CH:23]([CH2:26][N:27]3[CH2:32][CH2:31][S:30][CH2:29][CH2:28]3)[CH2:24][N:25]=1)=[CH:17]2)[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)(=[O:5])=[O:4].ClC1C=CC=C(C(OO)=[O:41])C=1>ClCCl.C(OCC)(=O)C>[CH3:1][N:2]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][C:18]([C:21]1[S:22][CH:23]([CH2:26][N:27]3[CH2:32][CH2:31][S:30](=[O:41])[CH2:29][CH2:28]3)[CH2:24][N:25]=1)=[CH:17]2)[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)(=[O:5])=[O:4]
Reactant: CN(c1cccc2cc(C3=NCC(CN4CCSCC4)S3)[nH]c12)S(=O)(=O)c1ccccn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(c1cccc2cc(C3=NCC(CN4CCS(=O)CC4)S3)[nH]c12)S(=O)(=O)c1ccccn1
Reaction time: 3 h
Yield: 21 %

Procedure:
To a solution of N-methyl-N-{2-[5-(thiomorpholinomethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}pyridine-2-sulfonamide (180 mg) in dichloromethane (8 mL) was added m-chloroperbenzoic acid (75 mL) under ice-cooling, and the mixture was stirred for 3 hr under ice-cooling. The reaction solution was diluted with ethyl acetate, washed with aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to basic silica gel column chromatography (ethyl acetate:hexane=6:4-9:1), and the obtained colorless oil was crystallized from ethyl acetate-hexane to give the title compound (39 mg, yield: 21%) as colorless needle crystals. MS: 504 (MH+). melting point 193-194° C.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1.CS(O[CH:21]1[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22]1)(=O)=O.O>CN(C=O)C>[N:3]1([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH:21]3[CH2:22][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24]3)=[CH:13][CH:14]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Reactant: Oc1ccc(CN2CCCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(Oc2ccc(CN3CCCC3)cc2)C1
Temperature: 80 °C
Yield: 64 %

Procedure:
A mixture of NaH (55-65% disp. in oil, 0.62 g, 14.3 mmol) in dry DMF (20 mL) under nitrogen was cooled by an ice-bath. A solution of 4-(pyrrolidin-1-ylmethyl)phenol—see e.g. Bioorganic & Medicinal Chemistry Letters, 15, 3834-3837 (2005)—(2.1 g, 11.9 mmol) in DMF (20 mL) was added drop-wise. The mixture was stirred for one h and then tert-butyl 3-[(methylsulfonyl)oxy]azetidine-1-carboxylate (3.9 g, 15.5 mmol) in DMF (10.0 mL) was added. The mixture was heated to 80° C. overnight and then cooled to RT. Water (150 mL) was added and the mixture was extracted three times with EtOAc (100 mL). The combined organic solutions were washed with brine, dried (MgSO4) and evaporated. The residue was purified twice by column chromatography on SiO2 using 10-100% EtOAc/heptane as eluent. The product was further purified using 0.5% NH3 in MeOH/DCM as eluent. There was obtained 2.5 g (64%) of 1A. 1H NMR (600 MHz, CDCl3): δ 1.43 (s, 9H), 1.77 (s, 4H), 2.47 (s, 4H), 3.54 (s, 2H), 3.95-4.02 (m, 2H), 4.24-4.30 (m, 2H), 4.82-4.88 (m, 1H), 6.67 (d, 2H), 7.23 (d, 2H).
Reaction SMILES: [C:1](=O)([O-])[O-].[Cs+].[Cs+].[F:7][C:8]([F:18])([F:17])[C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].S(C1C=CC(C)=CC=1)(OC)(=O)=O>CN(C)C=O>[CH3:1][O:16][C:9]([C:8]([F:17])([F:18])[F:7])=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: COS(=O)(=O)c1ccc(C)cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C=C(OC)C(F)(F)F
Temperature: 20 °C
Yield: 60.1 %

Procedure:
Cesium carbonate (132.8 g) was added to a mixture of ethyl 4,4,4-trifluoroacetoacetate (75.0 g) and dimethylformamide (400 ml). The reaction mixture was heated to 20° C. for 30 minutes. A mixture of methyl tosylate (83.4 g) and dimethylformamide (150 ml) was added to the resulting reaction mixture within 40 minutes. The mixture was heated for 3 hours and cooled to room temperature. Upon dilution with water (800 ml) the reaction mixture was extracted with diethyl ether three times. The combined organic phases were washed with water and dried. The mixture was concentrated and the residue distilled under reduced pressure to yield the product as a clear liquid (48.5 g, 60%) with a boiling point of 62-70° C. at 12 mm.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[Se](=O)=[O:12].OO>CO>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N+:2]=1[O-:12]
Reactant: O=[Se]=O
Reactant: c1ccc2c(c1)CCNC2
Agent: OO
Solvent: CO
Product: [O-][N+]1=Cc2ccccc2CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 1261.9 %

Procedure:
A mixture of 1.00 g of 1,2,3,4-tetrahydroisoquinoline, 0.042 g of selenium dioxide, 2.30 ml of 30% hydrogen peroxide in 20 ml of methanol is stirred at room temperature for 20 hours. The reaction mixture is concentrated in vacuo to a residue which is diluted with water and extracted with chloroform. The organic layer is dried and evaporated in vacuo to a residue which is purified by column chromatography on silica gel by elution with 99:1 methanol-chloroform to give 0.703 g of the desired product as a solid.
Reaction SMILES: [CH2:1]([C:3]1[C:11]([NH:12][CH2:13][CH2:14][CH2:15][F:16])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2].[C:17]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH2:1]([C:3]1[C:11]([N:12]([CH2:13][CH2:14][CH2:15][F:16])[CH3:17])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCc1nn2ccccc2c1NCCCF
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCc1nn2ccccc2c1N(C)CCCF
Temperature: 25 °C
Reaction time: 22 h
Yield: 59.4 %

Procedure:
A solution of 2-ethyl-N-(3-fluoropropyl)pyrazolo[1,5-a]pyridin-3-amine (0.301 g, 1.36 mmol) in DMF (4 mL) was treated with K2CO3 (0.200 g, 1.45 mmol) and methyl iodide (0.06 mL, 0.96 mmol). The reaction was stirred at room temperature for 22 hours then concentrated in vacuo. The residue was partitioned between CH2Cl2 and water. The aqueous layer was extracted with CH2Cl2 and the combined organics was dried over MgSO4, concentrated in vacuo to give 0.190 g (84%) of a brown oil as the title compound: 1H NMR (400 MHz, DMSO-d6) δ 8.46 (d, J=6.9 Hz, 1H), 7.57 (d, J=8.9 Hz, 1H), 7.08–7.05 (m, 1H), 6.73–6.70 (m, 1H), 4.56 (dt, J=47.5, 5.9 Hz, 2H), 3.09 (t, J=7.0 Hz, 2H), 2.78 (s, 3H), 2.71 (q, J=7.6 Hz, 2H), 1.77–1.64 (m, 2H), 1.24 (t, J=7.6, Hz 3H); 13C NMR (100 MHz, DMSO-d6) δ 152.3, 135.2, 128.7, 122.1, 120.9, 116.4, 110.6, 82.6 (d, J=161.4 Hz), 52.4 (d, J=5.2 Hz), 43.6, 29.0 (d, J=19.3 Hz), 19.0, 13.5; 19F NMR (376 MHz, DMSO-d6) −219.0 (m); HRMS (FAB) calcd for C13H18FN3+H 236.1563. found 236.1573.
Reaction SMILES: [F:1][C:2]1[C:3](Br)=[N:4][C:5]([Br:10])=[C:6]([F:9])[C:7]=1[Br:8].[F:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>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.O1CCCC1>[Br:10][C:5]1[C:6]([F:9])=[C:7]([Br:8])[C:2]([F:1])=[C:3]([C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[F:12])[N:4]=1
Reactant: Fc1c(Br)nc(Br)c(F)c1Br
Reactant: CC1(C)OB(c2cc([N+](=O)[O-])ccc2F)OC1(C)C
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: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)c(-c2nc(Br)c(F)c(Br)c2F)c1
Temperature: 55 °C
Reaction time: 48 h
Yield: 28.2 %

Procedure:
To a degassed mixture of 3,5-difluoro-2,4,6-tribromopyridine (4.26 g, 12.1 mmol), 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (2.80 g, 10.4 mmol), aqueous sodium carbonate (10 ml of a 2M solution) and tetrahydrofuran (40 ml) was added tetrakis(triphenylphosphine)palladium(0) (0.67 g). The mixture was then stirred at 55° C. for 48 h under an atmosphere of nitrogen. The reaction mixture was then partitioned between water and ethyl acetate. The organic layer was separated and evaporated and the residue chromatographed on silica gel eluting with isohexane on a gradient of dichloromethane (20-40%) to afford 2,4-dibromo-3,5-difluoro-6-(2-fluoro-5-nitrophenyl)pyridine as a solid (1.21 g): δH (400 MHz, CDCl3) 7.37 (1H, t, J 9), 8.38 (1H, m), 8.55 (1H, dd, J 6 and 3).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].CN[C@@H:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]1NC.IC1C=CC=CC=1>[Cu]I.C1(C)C=CC=CC=1>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN[C@@H]1CCCC[C@H]1NC
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Ic1ccccc1
Solvent: Cc1ccccc1
Product: O=C1OC[C@@H](Cc2ccccc2)N1c1ccccc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 921.2 %

Procedure:
A 15 mL resealable Schlenk tube was charged with CuI (9.6 mg, 0.0504 mmol, 5.0 mol %), (R)-4-benzyl-2-oxazolidinone (215 mg, 1.21 mmol), K2CO3 (280 mg, 2.03 mmol), evacuated and backfilled with argon. Racemic trans-N,N′-dimethyl-1,2-cyclohexanediamine (16 μL, 0.102 mmol, 10 mol %), iodobenzene (106 μL, 0.947 mmol) and toluene (1.0 mL) were added under argon. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred at 80° C. for 24 h. The resulting pale blue suspension was allowed to reach room temperature and then filtered through a 0.5×1 cm pad of silica gel eluting with 10 mL of ethyl acetate. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (2×15 cm, hexane-ethyl acetate 2:1, 15 mL fractions). Fractions 11-19 provided 238 mg (99% yield) of the desired product as a pale tan solid. HPLC analysis on a Daicel OD column (hexane-isopropanol 85:15, 0.7 mL/min, tr(R)=23.3 min, tr(S)=26.7 min) indicated >99.5% ee.
Reaction SMILES: I[C:2]1[N:7]2[N:8]=[C:9]([S:19][CH3:20])[C:10]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[C:6]2[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.C([O:28][B:29]([O:33]CC)[O:30]CC)C.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[C:14]([O:13][C:12]([NH:11][C:10]1[C:9]([S:19][CH3:20])=[N:8][N:7]2[C:2]([O:28][B:29]([OH:33])[OH:30])=[CH:3][CH:4]=[CH:5][C:6]=12)=[O:18])([CH3:17])([CH3:16])[CH3:15]
Reactant: CSc1nn2c(I)cccc2c1NC(=O)OC(C)(C)C
Reactant: CCOB(OCC)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSc1nn2c(OB(O)O)cccc2c1NC(=O)OC(C)(C)C
Temperature: -78 °C

Procedure:
After dissolving tert-butyl N-(7-iodo-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl)carbamate (200 mg) in tetrahydrofuran (2 mL), the mixture was cooled to −78° C. and n-butyllithium (1.6 M; 0.66 mL) was added dropwise. The mixture was stirred for 1 hour at the same temperature, triethoxyborane (109 μL) was added and the temperature was increased to room temperature. Saturated aqueous ammonium chloride was added to the obtained reaction mixture, and extraction was performed with ethyl acetate. The obtained organic layer washed with brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (106 mg) as grayish white crystals.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC)(C)(C)C.C(Br)(Br)(Br)[Br:41]>CCCCCC>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][Br:41])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCCCCOCc1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COC(C)(C)C
Solvent: CCCCCC
Product: BrCCCCCOCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 59.4 %

Procedure:
7.0 g of 5-hydroxypentyl benzyl ether and 10.6 g of triphenylphosphine were added to 50 ml of methyl tert-butyl ether and then cooled to 0° C. Further, 13.2 g of carbon tetrabromide was added and the mixture was stirred at room temperature for 3 hours. Thereafter, 100 ml of hexane was added and the mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 5.5 g of 5-bromopentyl benzyl ether.
Reaction SMILES: COC1C=CC(B(O)O)=CC=1.Br[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.C(OC([N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32](Br)[CH:33]=2)[CH:28]=[CH:27]1)=O)(C)(C)C>>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:32]2[CH:33]=[C:34]3[C:29]([CH:28]=[CH:27][NH:26]3)=[CH:30][CH:31]=2)[CH:14]=1
Reactant: Brc1cccnc1
Reactant: CC(C)(C)OC(=O)n1ccc2ccc(Br)cc21
Agent: COc1ccc(B(O)O)cc1
Product: c1cncc(-c2ccc3cc[nH]c3c2)c1

Procedure:
The desired compound was prepared according to the method of Example 25, step 1, except substituting 6-indolylboronic acid, prepared as in step 1 for 4-methoxyphenylboronic acid, and 3-bromopyridine for 1-tert-butoxycarbonyl-6-bromoindole.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH2:6][CH2:7]Br)[CH3:2].[OH:10][N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21].CCN(C(C)C)C(C)C.[Cl-].[NH4+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH2:6][CH2:7][O:10][N:11]1[C:15](=[O:16])[C:14]2[C:13](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]1=[O:21])[CH3:2]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CCOC(=O)CCCBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCON1C(=O)c2ccccc2C1=O
Temperature: 80 °C
Yield: 86.5 %

Procedure:
To a solution of 4-bromo-n-butyric acid ethyl ester (1.2 g, 6.13 mmol) in dimethylformamide (9 ml) were added N-hydroxyphthalimide (1.5 g, 9.19 mmol) and Hunig base (N,N-diisopropylethylamine, 2.13 mL) at room temperature, and the mixture was stirred at 80° C. over night. The reaction mixture was poured into saturated aqueous ammonium chloride, and the resultant mixture was extracted with ethyl acetate (3×40 ml). The combined organic layers were washed with saturated brine (2×30 ml), dried over Na2SO4, and concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (100 g, n-hexane/ethyl acetate (2:1)) to give 4-(1,3-dioxo-1,3-dihydro-isoindol-2-yloxy)-butyric acid ethyl ester (1.47 g, 100%).
Reaction SMILES: [Br-].[C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:7][CH:6]=1)([OH:4])=[O:3].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:42]([O:49][C:50]1[C:51]([CH:56]=O)=[N:52][CH:53]=[CH:54][CH:55]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C1COCC1>[CH2:42]([O:49][C:50]1[C:51]([CH:56]=[CH:12][CH2:11][C:8]2[CH:7]=[CH:6][C:5]([C:2]([OH:4])=[O:3])=[CH:10][CH:9]=2)=[N:52][CH:53]=[CH:54][CH:55]=1)[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: O=Cc1ncccc1OCc1ccccc1
Reactant: O=C(O)c1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CC=Cc2ncccc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(2-(4-Carboxyphenyl)ethyl)triphenylphosphonium bromide (0.58 g, 1.17 mmol) was suspended in THF (7 ml) and lithium bis(trimethylsilyl)amide was added (1M in THF, 2.46 ml). The reaction mixture turned orange and was allowed to stir for 1 hour at ambient temperature. A solution of 3-benzyloxy-2-pyridinecarbaldehyde (0.25 g, 1.17 mmol) in THF (3.5 ml) was added slowly. The reaction was stirred at ambient temperature for 1 hour. The reaction was quenched by the addition of water (8 ml) and ether (8 ml). The layers were separated, the ether layer was washed with water and the as aqueous layers were combined, acidified with 1N HCl and extracted with EtOAc (2×). The organic extracts were dried (MgSO4) and evaporated to give the title product as a mixture of isomers (2.7 g 66%).
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[CH3:7][N:8]1[C:17]2[C:12](=[CH:13][C:14]([S:18]([OH:21])(=O)=[O:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1>ClCCl.CN(C=O)C>[CH3:7][N:8]1[C:17]2[C:12](=[CH:13][C:14]([S:18]([Cl:4])(=[O:21])=[O:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN1CCCc2cc(S(=O)(=O)O)ccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1CCCc2cc(S(=O)(=O)Cl)ccc21
Reaction time: 2 h
Yield: 20.3 %

Procedure:
Oxalyl chloride (20 g, 157.60 mmol) was added dropwise at room temperature to a solution of 1-methyl-1,2,3,4-tetrahydroquinoline-6-sulfonic acid (5 g, 22.00 mmol) in dichloromethane (100 mL) and DMF (10 mL). The resulting solution was stirred for 2 hours, then quenched by adding 200 mL of iced water. The resulting solution was extracted using dichloromethane (2×100 mL), and the combined organics were dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography using a 1:4 ethyl acetate/petroleum ether solvent system to afford 1.1 g (20.1%) of 1-methyl-1,2,3,4-tetrahydroquinoline-6-sulfonyl chloride as a yellow solid. 1H NMR (CDCl3) δ 7.69 (d, 1H), 7.51 (s, 1H), 6.54 (d, 1H), 3.57 (t, 2H), 3.02 (s, 3H), 2.78 (d, 2H), 1.98 (m, 2H).
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2N=NN(CC)C=2N=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:42][C:38]3([CH2:41][O:40][CH2:39]3)[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].Cl[CH2:44][C:45]1[O:49][N:48]=[C:47]([CH3:50])[N:46]=1>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:37][C:38]3([CH2:39][O:40][CH2:41]3)[CH2:42]2)[C:30]2[N:35]=[N:34][N:33]([CH2:44][C:45]3[O:49][N:48]=[C:47]([CH3:50])[N:46]=3)[C:31]=2[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1nc(N2CC3(COC3)C2)c2nn[nH]c2n1
Reactant: Cc1noc(CCl)n1
Agent: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Product: Cc1noc(Cn2nnc3c(N4CC5(COC5)C4)nc(C(C)(C)C)nc32)n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-Butyl-7-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 5-(chloromethyl)-3-methyl-1,2,4-oxadiazole and isolated as light-red solid. MS (m/e): 371.2 (MH+).