Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[O:12]=[P:13](Cl)([Cl:15])[Cl:14].C(N(CC)CC)C>CC(OC)(C)C>[P:13]([Cl:15])([Cl:14])(=[O:12])[O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Oc1cccc2ccccc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Product: O=P(Cl)(Cl)Oc1cccc2ccccc12
Reaction time: 3 h
Yield: 86.3 %

Procedure:
In a 22 L 3-neck flask equipped with a mechanical stirrer, an internal thermocouple, a cooling bath of dry/acetone, an additional funnel and a nitrogen inlet was placed 1-naphthol (780 g, 5.41 mol, 491 g used from Aldrich, ≧99% grade, Product No N1000 and 289 g used from Alfa Aesar 99% grade, Product No A11862) in 10 L of MTBE at room temperature. POCl3 (495 mL, 5.41 mol, ReagentPlus® 99%, Product No 201170, Aldrich) in an additional funnel was dropwise added in 5 min (note: no exothermic observed) under nitrogen pressure. To this solution at −25° C. (an internal temperature) was slowly added by triethylamine (754 mL, 5.41 mol, ≧99.5% grade, Product No 471283, Aldrich) for one h (note: exotherm observed) and then the cooling bath was removed after the addition was completed. The reaction mixture was aged for 3 h at room temperature under nitrogen pressure. The triethylamine hydrochloride salt was filtered off using a 3 L sintered funnel (Medium size) and the filtrate was concentrated to dryness under reduced pressure at <20° C. of water bath to give desired product as clear dark yellow oil (1219 g, 86.3%) which was used without further purification.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3](=O)[CH:4]=[CH:5][NH:6][CH:7]=[CH:8][C:9]([O:11][CH3:12])=[O:10].Cl>CO>[F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[CH:5][N:6]=[CH:7][C:8]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C=CNC=CC(=O)C(F)(F)F
Agent: Cl
Solvent: CO
Product: COC(=O)c1cnccc1C(F)(F)F
Temperature: 30 °C
Reaction time: 1 h

Procedure:
19 g (0.1 mol) of methyl 3-(4,4,4-trifluoro-3-oxo-1-butenylamino)acrylate were dissolved in 200 ml of methanol in a three-neck flask and 1 g of Li2CO3 was added. The reaction mixture was heated for 6-8 h under reflux, cooled to 30° C. and 10 ml of aqueous HCl were added. The reaction mixture was stirred for 1 h, the methanol removed under reduced pressure and the product extracted with diethyl ether. The solvent was removed and methyl 4-trifluoronicotinate purified by vacuum distillation. 14 g (81%) of the product having a boiling point of 80° C./18 mbar were obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)N.N(OC(C)(C)C)=O.[S:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1>[Cu]>[Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([C:18]2[S:17][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: c1ccsc1
Reactant: Cc1c(N)cccc1Cl
Agent: [Cu]
Agent: CC(C)(C)ON=O
Product: Cc1c(Cl)cccc1-c1cccs1
Yield: 62.2 %

Procedure:
During a 30 minute period a solution of 3-chloro-2-methylaniline (8.3 g, 0.2 mole) in thiophene (100 ml) was added dropwise to a stirred mixture of t-butyl nitrite (30.9 g, 0.3 mole) and copper powder (10.0 g, 0.16 mole) in thiophene (1.9 l). After complete addition, the mixture was heated at 60° for two hours, then at reflux for approximately 18 hours. The reaction mixture was cooled, filtered, and the filtrate evaporated under reduced pressure to leave a residue. The residue was subjected to column chromatography on silica gel, elution with toluene. The toluene was evaporated under reduced pressure to leave a residue which was rechromatographed on silica gel, elution with n-heptane. The fractions which contained the desired product was combined and evaporated under reduced pressure to leave an oil. The oil was purified by distillation under reduced pressure to yield 2-(3-chloro-2-methylphenyl)thiophene (25.9 g, 62.2% yield, bp 93°/0.1 mm). This experiment is designated Run 5/1 in the following tabulation of several experiments conducted with and without copper, but under otherwise similar conditions.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8]>CCOC(C)=O.[Pd]>[NH2:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][N:4]([CH2:3][CH2:2][OH:1])[C:5](=[O:11])[O:6][C:7]([CH3:9])([CH3:10])[CH3:8])=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N(CCO)Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(CCO)Cc1ccc(N)cc1
Reaction time: 18 h

Procedure:
A suspension of tert-butyl (2-hydroxyethyl)(4-nitrobenzyl)carbamate (A69) (2.40 g, 8.09 mmol) and 10% Pd/C (0.240 g) in EtOAc (12 mL) was stirred under a hydrogen atmosphere for 18 hours. The resulting mixture was filtered through a pad of Celite, washing with EtOAc and the filtrate concentrated in vacuo. The residue was purified using silica gel column chromatography (CombiFlash Rf, 40 g SiO2 cartridge, 20-50% EtOAc in cyclohexane) to give the title compound A70 as a viscous light yellow oil (1.99 g, 92%); 1H NMR (300 MHz, CDCl3) δ 7.05 (d, J=7.5 Hz, 2H), 6.66 (d, J=8.0 Hz, 2H), 4.37 (s, 2H), 3.67 (m, 4H), 3.37 (s, 2H), 3.10 (s, 1H), 1.50 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[C:7]([I:8])=[CH:6][C:5]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[I:19].Cl[S:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[C:26]([OH:33])[CH:25]=1)(=[O:23])=[O:22]>C1COCC1>[I:19][C:3]1[CH:4]=[C:5]([C:9](=[O:10])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:6]=[C:7]([I:8])[C:2]=1[O:1][S:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[C:26]([OH:33])[CH:25]=1)(=[O:23])=[O:22]
Reactant: COc1ccc(C(=O)c2cc(I)c(O)c(I)c2)cc1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2cc(I)c(OS(=O)(=O)c3ccc(C(=O)O)c(O)c3)c(I)c2)cc1
Yield: 15.7 %

Procedure:
The title compound was prepared according to the procedure in Example 4 using (4-hydroxy-3,5-diiodo-phenyl)-(4-methoxy-phenyl)-methanone (0.202 g, 0.421 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.398 g, 1.68 mmol) in THF (5 mL). Purification by preparative HPLC (C18, eluting with 70% CH3CN/H2O containing 0.1% TFA) gave 0.045 g (16%) of the title compound as a white solid, mp 214-215° C. 1H NMR (DMSO-d6) δ 3.86 (s, 3H), 7.11 (d, 2H), 7.44-7.48 (m, 2H), 7.73 (d, 2 H), 8.04-8.07 (m, 3H). IR (KBr) 3400, 3050, 1690, 1600, 1260 and 1175 cm-1. mass spectrum (-ESI) m/z 679 (M-H). Anal. Calcd. for C21H14I2O8S: C,37.08; H,2.07; N,0.00. Found: C,37.43; H,2.24; N,0.00.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]2[C:12]([C:17]([OH:19])=[O:18])=[N:13][CH:14]=[CH:15][CH:16]=2)[N:7]([C:20]2[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:27])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.ClCCl.[I:35]N1C(=O)CCC1=O.[OH-].[K+]>O>[C:1]([C:5]1[C:9]([I:35])=[C:8]([NH:10][C:11]2[C:12]([C:17]([OH:19])=[O:18])=[N:13][CH:14]=[CH:15][CH:16]=2)[N:7]([C:20]2[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:27])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cccc(C)c1-n1nc(C(C)(C)C)cc1Nc1cccnc1C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: Cc1cccc(C)c1-n1nc(C(C)(C)C)c(I)c1Nc1cccnc1C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 74.3 %

Procedure:
To a solution of 3-{[3-tert-butyl-1-(2,6-dimethylphenyl)-1H-pyrazol-5-yl]amino}pyridine-2-carboxylic acid (Example 10, 50 mg, 0.14 mmol) in an acetic acid/dichloromethane mixture (1 mL of each) was added N-iodosuccinimide (31 mg, 0.14 mmol). The solution was stirred at rt for 12 h, and then water (10 mL) was added. The reaction mixture was basified to pH 9 using KOH (1.0 M ice cold solution). The water layer was extracted with dichloromethane (50 mL), and the organic phase was subsequently washed with saturated sodium sulfite, brine, and concentrated to dryness. The crude material was subjected to HPLC purification to give the desired product (51 mg, 75%). 1H NMR (300 MHz, CD2Cl2) δ 9.70 (s, 1H), 9.20 (s, 1H), 8.04 (m, 1H), 7.45 (m, 1H), 7.20 (m, 2H), 7.10 (m, 2H), 2.12 (s, 6H), 1.50 (s, 9H). ES-MS m/z 490.9 (MH+); HPLC RT (min) 3.40.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:16])[N:7]2[CH2:13][CH:14]=O.[NH:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH2:18]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)(Cl)Cl.CO>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:16])[N:7]2[CH2:13][CH2:14][N:17]1[CH2:18][CH2:19][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:21][CH2:22]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=CCn1c(=O)ccc2c(F)cc(F)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.2 %

Procedure:
(5,7-Difluoro-2-oxo-1(2H)-quinolinyl)acetaldehyde (2.1 g; 9.4 mmol) and 1,1-dimethylethyl 4-piperidinylcarbamate (2.82 g; 14.1 mmol) were dissolved in a 1:1 mixture of chloroform and MeOH (60 ml:60 ml) and stirred at rt for 1 h. This was then treated with NaBH(OAc)3 (8.92 g; 42.3 mmol) and stirred for a further 1 h. More 1,1-dimethylethyl 4-piperidinylcarbamate (470 mg; 2.35 mmol) was added and the reaction stirred under the same conditions for 20 mins, this was then treated with NaBH(OAc)3 (1.98 g; 9.4 mmol) and stirred for 25 mins. More 1,1-dimethylethyl 4-piperidinylcarbamate (470 mg; 2.35 mmol) was then added and the reaction stirred for 20 mins. More NaBH(OAc)3 (500 mg; 2.38 mmol) was then added to the reaction and it was stirred overnight at rt. The solvents were then removed and the crude residue purified by column chromatography on silica gel using a 0-15% MeOH/DCM gradient to give the desired product (2 g; 52%).
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:15]=[C:14]([SH:16])[CH:13]=[CH:12][C:6]=1[NH:7][S:8]([CH3:11])(=[O:10])=[O:9].Cl[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:15]=[C:14]([S:16][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)[CH:13]=[CH:12][C:6]=1[NH:7][S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: CS(=O)(=O)Nc1ccc(S)cc1Oc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: CS(=O)(=O)Nc1ccc(Sc2ccc([N+](=O)[O-])cc2)cc1Oc1ccc(F)cc1F
Yield: 73.2 %

Procedure:
A mixture of 2'-(2,4-difluorophenoxy)-4'-mercaptomethanesulfonanilide (1.5 g), p-chloronitrobenzene (0.75 g) and potassium carbonate (0.66 g) in xylene (30 ml) was stirred and refluxed for 5 hours. The reaction mixture was acidified, washed with water, dried, and concentrated to dryness. The residual oil was crystallized from ethanol to give crystals of 2'-(2,4-difluorophenoxy)-4'-(4-nitrophenylthio)methanesulfonanilide (1.5 g).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[C:19]([O:25][CH3:26])=[CH:20][C:21]([C:23]#N)=[CH:22][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[PH2]([O-])=[O:28].[Na+].C(O)(=O)C>[Ni].N1C=CC=CC=1>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[C:19]([O:25][CH3:26])=[CH:20][C:21]([CH:23]=[O:28])=[CH:22][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: O=[PH2][O-]
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(C#N)cc(OC)c21
Agent: [Ni]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(C=O)cc(OC)c21
Temperature: 60 °C
Reaction time: 6 h
Yield: 68.3 %

Procedure:
A mixture of 480 mg (1.37 mmol) 2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carbonitrile (example 32), 15 mg Raney-Nickel (in water), 967 mg (11.0 mmol) sodium hypophosphite (in 10 ml water), 10 ml acetic acid and 20 ml pyridine is stirred for 6 h at 60° C. The catalyst is filtered off and the filtrate is poured on water and extracted (3×) with ethyl acetate. The combined organic layers are washed with water (2×) and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=1:1) to afford 330 mg of the title compound as a white crystalline solid.
Reaction SMILES: [OH:1]/[N:2]=[C:3](\Cl)/[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.CN([CH:15]=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])C.C(N(CC)CC)C>C(OCC)C>[CH2:20]([O:19][C:17]([C:16]1[C:3]([C:4]2[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=2)=[N:2][O:1][CH:15]=1)=[O:18])[CH3:21]
Reactant: CCOC(=O)C=CN(C)C
Reactant: O/N=C(\Cl)c1ccc(Cl)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)c1conc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 90.5 %

Procedure:
To a solution of (E)- and/or (Z)—N-hydroxy-4-chloro-benzenecarboximidoyl chloride (58.0 g, 250.3 mmol) in diethylether (1.04 L) was added a solution of ethyl 3-(N,N-dimethylamino)acrylate (90.4 mL, 624 mmol) and triethylamine (50.1 mL, 362 mmol) in diethylether (1.04 L). The resulting mixture was then stirred for 14 h at room temperature and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 4:1) afforded the title product (57 g, 91%) which was obtained as a white solid. MS: m/e=252.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:25])(=[O:24])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9]([OH:11])=O)[CH:7]=1.[CH:26]1([NH2:30])[CH2:29][CH2:28][CH2:27]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.O.CO>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:24])(=[O:25])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9]([NH:30][CH:26]2[CH2:29][CH2:28][CH2:27]2)=[O:11])[CH:7]=1
Reactant: NC1CCC1
Reactant: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)O)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)NC2CCC2)c1
Reaction time: 16 h
Yield: 50.2 %

Procedure:
To a stirred solution of 2-(5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetic acid (400 mg, 1.2 mmol) and cyclobutylamine (0.8 mL, 6 mmol) in 20 mL of DMF was added PyBOP (850 mg, 1.7 mmol) and TEA (1 mL, 7 mmol). The reaction mixture was stirred for 16 hours. After water was added, the reaction mixture was extracted with ethyl acetate and washed with water, 1N HCl and brine. The organic layer was dried over Na2SO4 and concentrated. The crude residue was purified by ISCO CombiFlash Rf silica chromatography eluted with 88:10:2 chloroform:MeOH:H2O to give the desired product as a yellow solid (250 mg, yield 54%). MS calcd for (C19H22BN3O5S): 415.1. MS found (ESI negative): (M−H)−=414.2. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.85 (s, 1H), 9.17 (s, 1H), 8.28 (d, J=7.6 Hz, 1H), 7.42 (m, 2H), 7.22 (d, J=8.4 Hz, 1H), 7.10 (dd, J=8, 2 Hz, 1H), 6.44 (d, J=2.4 Hz, 1H), 6.34 (dd, J=8, 2 Hz, 1H), 5.93 (bs, 2H), 4.87 (s, 2H), 4.20 (m, 1H), 3.75 (s, 2H), 2.18 (m, 2H), 1.89 (m, 2H), 1.64 (m, 2H).
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[CH:10]=[C:11]([CH:21]=[CH:22][CH:23]=2)[CH2:12][N:13]2[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[N:14]2)[O:8][CH2:7][CH2:6][O:5]1.[NH4+].[Cl-]>CCO.O.[Fe]>[CH3:3][C:4]1([C:9]2[CH:10]=[C:11]([CH:21]=[CH:22][CH:23]=2)[CH2:12][N:13]2[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]2)[O:8][CH2:7][CH2:6][O:5]1
Reactant: CC1(c2cccc(Cn3cc([N+](=O)[O-])cn3)c2)OCCO1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CC1(c2cccc(Cn3cc(N)cn3)c2)OCCO1
Temperature: 75 °C
Reaction time: 2 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-[3-(2-methyl-[1,3]dioxolan-2-yl)-benzyl]-4-nitro-1H-pyrazole (148 mg, 0.51 mmol), iron powder (87 mg, 1.54 mmol) and NH4Cl (138 mg, 2.56 mmol) in a mixture of EtOH (2.0 mL) and water (1.0 mL) was stirred at 75° C. for 2 h. The reaction mixture was filtered while hot and concentrated under reduced pressure. CH2Cl2 (20 mL) was added followed by 1N NaOH (20 mL). The aq. layer was extracted with CH2Cl2 (2×20 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a deep red oil. LC-MS-conditions 02: tR=0.65 min; [M+H]+=260.25.
Reaction SMILES: [CH3:1][C:2](O)([CH2:5][CH2:6][CH2:7][CH:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH:3]=[CH2:4].P(Br)(Br)[Br:18].O>CCCCCC.N1C=CC=CC=1>[Br:18][CH2:4][CH:3]=[C:2]([CH3:1])[CH2:5][CH2:6][CH2:7][CH:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13]
Reactant: C=CC(C)(O)CCCC(C)CCCC(C)C
Reactant: BrP(Br)Br
Solvent: c1ccncc1
Solvent: CCCCCC
Solvent: O
Product: CC(=CCBr)CCCC(C)CCCC(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 189.9 %

Procedure:
In 300 ml of hexane were dissolved 50 g of 3,7,11-trimethyl-1-dodecen-3-ol and 0.87 g of pyridine, and 30.8 g of phosphorus tribromide was added dropwise to the solution at 0° to -10° C. After 2 hours of stirring at 0° C., the reaction mixture was poured into water and extracted with hexane. The hexane layer was successively washed with aqueous sodium hydrogen carbonate and aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled off to give 62.5 g of crude 1-bromo-3,7,11-trimethyl-2-dodecene. To a suspension of 14.2 g of zinc in 26 ml of acetic acid was added dropwise 62.5 g of the crude 1-bromo-3,7,11 -trimethyl-2-dodecene and the mixture was stirred at room temperature for 1 hour. Thereafter, the zinc was filtered off and the filtrate was poured into water and extracted with hexane. The hexane layer was washed with aqueous sodium hydrogen carbonate and aqueous sodium chloride in that order and dried over anhydrous sodium sulfate. The solvent was then distilled off and the residue was further distilled under reduced pressure to give 10.6 g (yield 25%) of 3,7,11-trimethyl-1-dodecene. The physical constants of the compound are as follows.
Reaction SMILES: N#N.[Si:3]([O:10][CH2:11][C:12]1[N:13]=[C:14]([CH:17]=[O:18])[O:15][CH:16]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[CH3:19][Al](C)C.[NH4+].[Cl-]>C(Cl)Cl.C1(C)C=CC=CC=1>[Si:3]([O:10][CH2:11][C:12]1[N:13]=[C:14]([CH:17]([OH:18])[CH3:19])[O:15][CH:16]=1)([C:6]([CH3:9])([CH3:7])[CH3:8])([CH3:5])[CH3:4]
Reactant: C[Al](C)C
Reactant: CC(C)(C)[Si](C)(C)OCc1coc(C=O)n1
Agent: N#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(O)c1nc(CO[Si](C)(C)C(C)(C)C)co1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 4-(((tert-butyldimethylsilyl)oxy)methyl)oxazole-2-carbaldehyde (268 mg, 1.11 mmol) in CH2Cl2 (9.2 mL) was treated dropwise at 0° C. with trimethylaluminium (1.11 mL of a 2.0 M solution in toluene, 2.22 mmol) and the resulting yellow solution was stirred for 45 min at 0° C. Sat. aq. NH4Cl was added to the reaction mixture which was extracted with CH2Cl2 (3×25 mL) and the combined org. layers were dried over Na2SO4, filtered and the solvent was removed under reduced pressure. Purification of the residue by FC (1:1 hept-EA) gave the title compound as a yellow oil: TLC: rf (1:1 hept-EA)=0.40. LC-MS-conditions 07: tR=0.85 min, [M]+=257.81.
Reaction SMILES: [CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]([CH:14]2[CH2:23][CH2:22][C:17]3(OCC[O:18]3)[CH2:16][CH2:15]2)[C:7](=[O:24])[C:6]=1[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]2[NH:42][C:41](=[O:43])[O:40][N:39]=2)=[CH:28][CH:27]=1)[CH2:2][CH2:3][CH3:4].Cl.O1CCCC1>C(OCC)(=O)C>[CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]([CH:14]2[CH2:23][CH2:22][C:17](=[O:18])[CH2:16][CH2:15]2)[C:7](=[O:24])[C:6]=1[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]2[NH:42][C:41](=[O:43])[O:40][N:39]=2)=[CH:28][CH:27]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC3(CC2)OCCO3)c2ncnn12
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 3 h
Yield: 84.1 %

Procedure:
A mixture of 7-butyl-4-(1,4-dioxaspiro[4.5]dec-8-yl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.27 g), 6N hydrochloric acid (2 mL) and tetrahydrofuran (10 mL) was stirred at 40° C. for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.21 g, 83%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([OH:15])[CH2:11][C:12](O)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH:10]([OH:15])[CH2:11][CH2:12][OH:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC(O)CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(O)CCO
Temperature: 0 °C
Reaction time: 3 h
Yield: 59.1 %

Procedure:
To a borane tetrahydrofuran complex solution 1M in tetrahydrofuran (15 ml) was added at 0° C. under an atmosphere of argon a solution of 4-tert-butoxycarbonylamino-3-hydroxy-butyric acid (1.5 g) in tetrahydrofuran (35 ml). The reaction mixture was stirred at 0° C. for 3 hours. The reaction was quenched by drop wise addition of 10% acetic acid in methanol (30 ml). Ethyl acetate was added (250 ml) and the mixture was washed with 1M hydrochloric acid (60 ml) and 1M sodium hydrogenocarbonate (80 ml). The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified over silica gel (ethyl acetate/methanol 9:1) to give (2,4-dihydroxy-butyl)-carbamic acid tert-butyl ester (0.83 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=3)[S:10][C:3]=12.[CH2:17]([C:19]1[N:20]([CH3:33])[C:21]2[C:26]([C:27]=1[C:28]([NH:30][CH3:31])=[O:29])=[CH:25][CH:24]=[C:23]([OH:32])[CH:22]=2)[CH3:18].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:31][NH:30][C:28]([C:27]1[C:26]2[C:21](=[CH:22][C:23]([O:32][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]5[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=5)[S:10][C:3]=34)=[CH:24][CH:25]=2)[N:20]([CH3:33])[C:19]=1[CH2:17][CH3:18])=[O:29]
Reactant: CCc1c(C(=O)NC)c2ccc(O)cc2n1C
Reactant: Cn1ccnc1-c1cc2nccc(Cl)c2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCc1c(C(=O)NC)c2ccc(Oc3ccnc4cc(-c5nccn5C)sc34)cc2n1C
Yield: 39.4 %

Procedure:
This material was prepared by the reaction 7-chloro-2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridine 1e (0.084 g, 0.34 mmole) with 2-ethyl-6-hydroxy-N,1-dimethyl-1H-indole-3-carboxamide 73 g (0.078 g, 0.33 mmole) and Cs2CO3 (0.111 g, 0.34 mmole) in a manner as previously described for example 1 to give an off-white solid (0.058 g, 40%). 1H NMR (300 MHz, CD3OD 67 8.27 (1H, d, J=5.4 Hz), 7.68 (1H, d, J=8.6 Hz), 7.59 (1H, s), 7.24 (1H, d, J=1.9 Hz), 7.17 (1H, s), 6.96 (1H, s), 6.90 (1H, dd, J=1.9, 8.6 Hz), 6.50 (1H, d, J=5.4 Hz), 3.87 (3H, s), 3.58 (3H, s), 3.01 (2H, m), 2.85 (3H, s), 1.14 (3H, m). HRMS (MH+): Calcd: 446.1655; Found: 446.1651.