Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:16](Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(Cl)n1
Reactant: CC(C)(C)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1cccc(Cl)n1
Temperature: 25 °C

Procedure:
To 6-chloropyridin-2-amine (20.0 g, 156 mmol) and triethylamine (23.7 mL, 171 mmol) in 100 mL toluene at 50° C. was added pivaloyl chloride (19.6 mL, 163 mmol) dropwise via syringe. The reaction mixture was allowed to stir, and eventually became a solid mass. 50 mL toluene was added. The reaction mixture was heated overnight, and cooled to ambient temperature. The reaction mixture was quenched with 400 mL 2N aq. HCl, and diluted with 300 mL EtOAc. The organic layer was washed with water, brine, dried over sodium sulfate, filtered, and concentrated to a solid. The solid was dissolved in a min. volume of hot MTBE (50° C.), and approx. 300 mL hexanes was added with swirling. On standing, crystals form, which were collected by filtration, rinsing with hexanes to give a total of N-(6-chloropyridin-2-yl)pivalamide. MS (ESI) m/z: calculated: 212.1; Observed: 213.2 (M++1).
Reaction SMILES: [C:1]1([CH3:28])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([N:17]1[CH:21]=[C:20]([C:22]([O:24]CC)=[O:23])[CH:19]=[N:18]1)[NH:11][C:10]2=O.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[O:32]1[CH2:33][CH2:34][N:29]([C:10]2[C:9]3[C:14](=[CH:15][CH:16]=[C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=4[CH3:28])[CH:8]=3)[N:13]=[C:12]([N:17]3[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[N:18]3)[N:11]=2)[CH2:30][CH2:31]1
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(-c4ccccc4C)cc3c(=O)[nH]2)c1
Reactant: C1COCCN1
Product: Cc1ccccc1-c1ccc2nc(-n3cc(C(=O)O)cn3)nc(N3CCOCC3)c2c1

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-(o-tolyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and morpholine in step E. MS (ESI/CI): predicted mass C23H21N5O3, 415.2.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.C(N(CC)C(C)C)(C)C.[CH2:30]([NH:34][CH2:35][C:36]1[CH:48]=[CH:47][C:39]([O:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[C:38]([CH3:49])[CH:37]=1)[CH2:31][CH2:32][CH3:33]>C(Cl)Cl>[CH2:30]([N:34]([CH2:35][C:36]1[CH:48]=[CH:47][C:39]([O:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[C:38]([CH3:49])[CH:37]=1)[C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CS(=O)(=O)c1nccc(-c2ccc(C(F)(F)F)cc2)n1
Reactant: CCCCNCc1ccc(OCC(=O)OCC)c(C)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1nccc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 100 °C
Yield: 21.9 %

Procedure:
A mixture of 2-(methylsulfonyl)-4-[4-(trifluoromethyl)phenyl]pyrimidine (0.3 g, 1 mmol), N,N-diisopropylethylamine (0.18 mL, 1 mmol) and ethyl {4-[(butylamino)methyl]-2-methylphenoxy}acetate (0.424 g, 1.53 mmol) was heated at 100° C. in a sealed reactivial for 18 h. The residue was dissolved in CH2Cl2 and purified by Biotage™ chromatography (Silica, 40 g) eluting 3:97 EtOAc:cyclohexane to afford the title compound as a pale yellow oil (110 mg).
Reaction SMILES: [CH2:1]([Si:3]([CH2:17][CH3:18])([CH2:15][CH3:16])[N:4]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:5][CH:6]=[CH2:7])[CH3:2].[CH3:19][SiH:20]([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23]>[Pt].C([Si](C)(C)O[Si](C=C)(C)C)=C.C1(C)C=CC=CC=1>[CH2:17]([Si:3]([CH2:15][CH3:16])([CH2:1][CH3:2])[N:4]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:5][CH2:6][CH2:7][Si:20]([CH3:19])([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23])[CH3:18]
Reactant: C=CCN(Cc1ccccc1)[Si](CC)(CC)CC
Reactant: CCO[SiH](C)OCC
Agent: [Pt]
Agent: C=C[Si](C)(C)O[Si](C)(C)C=C
Solvent: Cc1ccccc1
Product: CCO[Si](C)(CCCN(Cc1ccccc1)[Si](CC)(CC)CC)OCC
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A flask equipped with a stirrer, reflux condenser, dropping funnel and thermometer was charged with 26.2 g (0.1 mol) of N-triethylsilyl-N-benzyl-N-allylamine and 0.07 g of a toluene solution of platinum/1,3-divinyl-1,1,3,3-tetramethyldisiloxane complex (Pt concentration 3 wt %) and heated at 50° C. Once the internal temperature became steady, 13.4 g (0.1 mol) of methyldiethoxysilane was added dropwise over 1 hour. Stirring was continued at the temperature for a further 1 hour. The reaction solution was distilled, collecting 31.0 g of a fraction having a boiling point of 151-152° C./0.1 kPa.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:19]([OH:21])=[O:20])[CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:19]([OH:21])=[O:20])[CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCOCCOCC(NC(=O)OC(C)(C)C)C(=O)O
Solvent: ClC(Cl)Cl
Product: COCCOCCOC[C@H](NC(=O)OC(C)(C)C)C(=O)O

Procedure:
Nα-tert-butyloxycarbonyl-L-serine (4.59 g, 22.3 mmol) was dissolved in N,N-dimethylformamide (100 mL), the solution was then cooled to 0° C. and treated with sodium hydride (1.97 g, 49.2 mmol). 1-Bromo-2-(2-methoxyethoxy)ethane (10.0 g, 49.2 mmol) was added to the solution and the reaction mixture was stirred at ambient temperature for 3 h. The solvent was then removed under a reduced pressure at 40° C. bath temperature. The residue was dissolved in water (75 mL) and washed twice with diethyl ether (30 mL each time). The aqueous layer was then acidified to pH 3 with 1M HCl and then extracted with ethyl acetate. The organic layer was dried over anhydrous MgSO4 and the solvent was removed in vacuo to yield the compound as a yellow oil (4.1 g, 63%). The compound has the following characteristics: FTIR (CHCl3): 1735 (vCO, s), 1712 (vCO, s). 1H NMR (CDCl3): δ 5.63 (d, (CH3)3COC(O)NHCH(CH2OCH2CH2OCH2CH2OCH3)C(O)OH, 1H), 4.38 (s, (CH3)3COC(O)NHCH(CH2OCH2CH2O—CH2CH2OCH3)C(O)OH, 1H), 4.14-3.53 (m, (CH3)3COC(O)NHCH(CH2OCH2CH2O—CH2CH2OCH3)C(O)OH, 10H), 3.47 (s, (CH3)3COC(O)NHCH(CH2OCH2CH2OCH2—CH2OCH3)C(O)OH, 3H), 1.52 (s, (CH3)3COC(O)NHCH(CH2O—CH2CH2OCH2CH2—OCH3)C(O)OH, 9H). MALDITOF-MS: MH+: 307.34 calcd, 309.19 found.
Reaction SMILES: [CH2:1]([N:8]([CH2:14][C:15](O)([CH2:21][CH3:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(S(F)(F)[F:30])CC>ClCCl>[CH2:1]([N:8]([CH2:14][C:15]([F:30])([CH2:21][CH3:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(O)(CC)CN(Cc1ccccc1)C1CCCC1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(F)(CC)CN(Cc1ccccc1)C1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.2 %

Procedure:
To ethyl 2-((benzyl(cyclopentyl)amino)methyl)-2-hydroxybutanoate (2.9 g, 9.1 mmol) in 30 ml of dichlormethane at −78° C., was added DAST (2.4 ml, 18 mmol) dropwise. The reaction mixture was gradually warmed up to room temperature and stirred for 1 h. It was then diluted to dichloromethane, washed by NaHCO3, brine and water. Organic extract dried and concentrated to a residue, which was purified on silica gel column chromatographically (Hex/EtOAc=40:1 to 20:1) to give 2.2 g product (75%) as light yellow liquid. [M+H] calc'd for C19H28FNO2, 322; found 322.
Reaction SMILES: [CH2:1]([C:3]1[S:15][C:6]2=[N:7][CH:8]=[C:9]([C:12]([OH:14])=[O:13])[C:10]([OH:11])=[C:5]2[CH:4]=1)[CH3:2].B(F)(F)F.CCOCC.[CH2:25](O)[CH:26]([CH3:28])[CH3:27]>>[CH2:1]([C:3]1[S:15][C:6]2=[N:7][CH:8]=[C:9]([C:12]([O:14][CH2:25][CH:26]([CH3:28])[CH3:27])=[O:13])[C:10]([OH:11])=[C:5]2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(O)c(C(=O)O)cnc2s1
Reactant: CC(C)CO
Agent: FB(F)F
Solvent: CCOCC
Product: CCc1cc2c(O)c(C(=O)OCC(C)C)cnc2s1
Yield: 31 %

Procedure:
A mixture of 2-ethyl-4-hydroxythieno[2,3-b]pyridine-5-carboxylic acid (200 mg, 0.9 mmol) and boron trifluoride-ethyl ether (47%, 0.5 ml) in isobutyl alcohol (10 ml) was heated under reflux for 5 hours. The reaction mixture was allowed to cool and concentrated to dryness. The resulting residue was purified by flash column chromatography on silica gel. The column was eluted with chloroform/ethyl acetate (3:1) to give 80 mg (31%) of the title compound as colorless crystals.
Reaction SMILES: [N:1]#N.[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8](Cl)=[O:9].Cl.N[C:13]1[CH:18]=[C:17]([CH:19]([CH3:21])[CH3:20])[C:16]([OH:22])=[C:15]([CH:23]([CH3:25])[CH3:24])[CH:14]=1.C(=O)([O-])O.[Na+]>C(Cl)Cl.O.C(OCC)(=O)C>[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]([C:13]1[CH:18]=[C:17]([CH:19]([CH3:21])[CH3:20])[C:16]([OH:22])=[C:15]([CH:23]([CH3:25])[CH3:24])[C:14]=1[NH2:1])=[O:9]
Reactant: N#N
Reactant: O=C(Cl)c1cccs1
Reactant: CC(C)c1cc(N)cc(C(C)C)c1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: CC(C)c1cc(C(=O)c2cccs2)c(N)c(C(C)C)c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under ice-cooling and N2 atmosphere, a solution of 1.47 g of 2-thiophenecarbonyl chloride in 10 ml of methylene chloride is added to a mixture of 2.91 g of 4-amino-2,6-diisopropylphenol hydrochloride, 90 ml of ethyl acetate, 80 ml of water, and 8.0 g of sodium hydrogen carbonate during a period of 30 minutes. After stirring at room temperature for one hour, organic layer is separated, washed with water, 10 % HCl, water, dried, and concentrated. The obtained solid is recrystallized from chloroform-hexane to give 1.7 g of 4-(2-thienylcarbonyl)-amino-2,6-diisopropylphenol.
Reaction SMILES: COC(=O)[NH:4][C:5]12[CH2:12][CH2:11][C:8]([C:13]3[NH:21][C:20]4[C:19](=[O:22])[N:18]([CH2:23][CH2:24][CH3:25])[C:17](=[O:26])[N:16]([CH2:27][CH2:28][CH3:29])[C:15]=4[N:14]=3)([CH2:9][CH2:10]1)[CH2:7][CH2:6]2>Cl>[NH2:4][C:5]12[CH2:12][CH2:11][C:8]([C:13]3[NH:21][C:20]4[C:19](=[O:22])[N:18]([CH2:23][CH2:24][CH3:25])[C:17](=[O:26])[N:16]([CH2:27][CH2:28][CH3:29])[C:15]=4[N:14]=3)([CH2:9][CH2:10]1)[CH2:7][CH2:6]2
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(NC(=O)OC)(CC3)CC4)nc2n(CCC)c1=O
Agent: Cl
Product: CCCn1c(=O)c2[nH]c(C34CCC(N)(CC3)CC4)nc2n(CCC)c1=O

Procedure:
[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-carbamic acid methyl ester (Example 13d) (8.3 gm, 20 mmol) was refluxed in 40 ml of conc. HCl for 3 h. The reaction mixture was concentrated in vacuo to a solid residue which was triturated in acetonitrile to afford 5.8 gm (77%) as a white solid (MH+=360.02)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH3:20])[C:14]([F:16])([F:15])[C:13]([CH3:18])([CH3:17])[O:12][CH2:11][C:10](=[O:19])[NH:9]2)[CH:7]=1.CN[C@@H]1CCCC[C@H]1NC.[I-:32].[Na+]>O1CCOCC1.[Cu]I>[F:15][C:14]1([F:16])[C:13]([CH3:18])([CH3:17])[O:12][CH2:11][C:10](=[O:19])[NH:9][C@@:8]1([C:6]1[CH:7]=[C:2]([I:32])[CH:3]=[CH:4][C:5]=1[F:21])[CH3:20]
Reactant: CC1(C)OCC(=O)N[C@](C)(c2cc(Br)ccc2F)C1(F)F
Reactant: [I-]
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(C)OCC(=O)N[C@](C)(c2cc(I)ccc2F)C1(F)F
Temperature: 110 °C
Reaction time: 15 h
Yield: 96.2 %

Procedure:
A solution of (R)-5-(5-bromo-2-fluorophenyl)-6,6-difluoro-5,7,7-trimethyl-1,4-oxazepan-3-one (intermediate B6.1) (200 mg, 546 μmol) in dioxane (2 ml) was treated consecutively with trans-N,N′-dimethyl-1,2-cyclohexanediamine (16.0 mg, 109 μmol), copper(I)iodide (10.6 mg, 54.6 μmol), and sodium iodide (165 mg, 1.09 mmol). The reaction mixture was stirred at 110° C. for 15 hours. Following TLC the reaction was incomplete. Another amount of copper(I)iodide (10.6 mg, 54.6 μmol), trans-N,N′-dimethyl-1,2-cyclohexanediamine (16.0 mg, 109 μmol), and sodium iodide (165 mg, 1.09 mmol) was added. Stirring was continued at 110° C. during the weekend. For the workup, the reaction mixture was evaporated at reduced pressure and the residue was purified by chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 90:60 as the eluent. The (R)-6,6-difluoro-5-(2-fluoro-5-iodo-phenyl)-5,7,7-trimethyl-[1,4]oxazepan-3-one (217 mg, 96% yield) was obtained as light yellow viscous oil. MS (ISP): m/z=414.1 [M+H]+.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:22]=[CH:21][C:10]3[N:11]([OH:20])[C:12]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[N:13][C:9]=3[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[H][H].Cl[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C)C=O>[N:1]1([CH2:6][C:7]2[CH:22]=[CH:21][C:10]3[N:11]([O:20][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:12]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[N:13][C:9]=3[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: ClCc1ccccc1
Reactant: On1c(-c2ccccc2)nc2cc(Cn3ccnc3)ccc21
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(COn2c(-c3ccccc3)nc3cc(Cn4ccnc4)ccc32)cc1
Yield: 66.7 %

Procedure:
A mixture of 3 parts of 5-(1H-imidazol-1-ylmethyl)-2-phenyl-1H-benzimidazol-1-ol and 47 parts of N,N-dimethylformamide was stirred till a clear solution was obtained. 0.5 Parts of a sodium hydride dispersion 50% were added portionwise and stirring was continued till hydrogen evolution had ceased. Upon complete addition, 1.2 parts of (chloromethyl)benzene were added at once at room temperature. Upon complete reaction, the N,N-dimethylformamide layer was evaporated. The residue was taken up in water and the product was extracted with methylbenzene and a mixture of trichloromethane and methanol (90:10 by volume). The combined extracts were dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from ethyl acetate. The product was filtered off, washed with a small amount of ethyl acetate and 2,2'-oxybispropane and dried in vacuo at 50° C., yielding 2.64 parts (66.7%) of 5-(1H-imidazol-1-ylmethyl)-2-phenyl-1-(phenylmethoxy)-1H-benzimidazole; (compound 253).
Reaction SMILES: [N:1]([N:3]([CH3:7])C(N)=O)=O.C(OC(C)C)(C)C.[OH-].[K+].[Br:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][C:19]=1[S:27](=[O:30])(=[O:29])[NH2:28]>C(OCC)(=O)C.C(OCC)C>[Br:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](=[O:23])[CH:7]=[N+:3]=[N-:1])=[CH:20][C:19]=1[S:27](=[O:29])(=[O:30])[NH2:28]
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Br
Reactant: CN(N=O)C(N)=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)OC(C)C
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: [N-]=[N+]=CC(=O)c1ccc(Br)c(S(N)(=O)=O)c1
Reaction time: 0.17 h

Procedure:
26 g of freshly prepared N-nitroso-N-methyl urea were introduced portionwise at 0° to -5° C. into a stirred two-phase mixture of 200 ml of diethyl ether (or diisopropyl ether) and 80 ml of 40% aqueous potassium hydroxide solution, the ice-cold etheral diazomethane solution was separated in the separating funnel and dried over a small amount of solid potassium hydroxide at -10° C. during 3 hours. The dry solution of the diazomethane in diethyl ether (or diisopropyl ether) was cooled to -5° C. to -10° C. in a 500 ml three-neck flask provided with stirrer, inner thermometer and KOH drying tube. A suspension of 16.8 g of 4-bromo-3-sulfamoylbenzoyl chloride was added in small portions into 40 ml of anhydrous ethyl acetate, the temperature of the reaction mixture not being allowed to exceed +5° C. After the addition of 4-bromo-3-sulfamoylbenzoyl chloride stirring was continued for another 10 minutes at +5° C. and the fair yellow crystalline precipitate of 4'-bromo-3'-sulfamoyl-diazoacetophenone was filtered off. The 4'-bromo-3'-sulfamoyl-diazoacetophenone so obtained was introduced without further purification in small portions into a stirred mixture cooled to 0° C. of 30 ml of diethylene glycol dimethyl ether and 20 ml of concentrated HCl (37%). After nitrogen development had finished, stirring was continued for another 10 minutes at 0° C., 150 ml of water were added and after dwelling for 1 hour at 0° C. the crystalline precipitate of 4'-bromo-3'-sulfamoyl-2-chloroacetophenone was filtered off. Colorless crystals, melting point: 152° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[CH:6]=[CH:5]2.C[Si]([C:22]#[CH:23])(C)C.C(N(CC)CC)C.C(#N)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[C:22]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[CH:6]=[CH:5]2)#[CH:23]
Reactant: Fc1ccc(-n2ccc3cc(Br)ccc32)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C#Cc1ccc2c(ccn2-c2ccc(F)cc2)c1
Temperature: 25 °C
Yield: 35.1 %

Procedure:
A mixture of 5-bromo-1-(4-fluorphenyl)-1H-indole (40 g) (prepared as described by Perregaard et al. J. Med. Chem. 1992 35, 1092-1101), (trimethylsilyl)acetylen (21.4 g), bis(triphenylphospine)palladium(II) dichloride (2.9 g) copper(I) iodide (1.3 g), triethylamine (40 mL) and acetonitrile (150 mL) was boiled under reflux for 8 hours. After cooling to room temperature, water was added and the resulting mixture was extracted with ethyl acetate (4×300 mL). The combined organic phases were washed with brine (2×800 mL), dried (Na2SO4) and the solvents evaporated in vacuo. A solution of the remaining oil and potassium hydroxide (12.1 g) in a mixture of methanol (500 mL) and water (200 mL) was boiled at reflux for 3 h. The volatile solvents were evaporated in vacuo and a mixture of water (200 mL) and ethyl acetate (1000 mL) was added. The phases were separated and the aqueous phase extracted with ethyl acetate (250 mL). The combined organic phases were dried (Na2SO4) and the volatile solvents evaporated in vacuo. Purification of the remaining oil by column chromatography on silica gel (dichloromethane/heptane 1:6) afforded crystalline pure title compound 18a (11.4 g): Sp 99-100° C.; 1H NMR (CDCl3) δ 3.00 (s, 1H), 6.55 (d, 1H), 7.20 (t, 2H), 7.25 (d, 1H), 7.35 (m, 2H), 7.40 (dd, 2H), 7.85 (broad s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:22]([CH:24]1[C:32]2[C:27](=[N:28][CH:29]=[CH:30][CH:31]=2)[C:26](=O)[O:25]1)[CH3:23].Cl>C1COCC1>[CH2:22]([CH:24]1[C:32]2[C:27](=[N:28][CH:29]=[CH:30][CH:31]=2)[C:26](=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][C:6]2=[O:11])[O:25]1)[CH3:23]
Reactant: CCC1OC(=O)c2ncccc21
Reactant: O=C1Cc2cc(F)ccc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC1OC(=C2C(=O)Nc3ccc(F)cc32)c2ncccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 16.2 %

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one (966 mg, 6.4 mmol.) in THF (6 mL) is cooled to 0° C. under an Argon atmosphere and treated with a solution of lithium bis(trimethylsilyl)amide (12.8 mL of a 1 M solution in THF, 12.8 mmol) dropwise. The resulting solution is stirred at 0° C. for 10 min and warmed to room temperature. A solution of 5-ethyl-5H-furo[3,4-b]pyridin-7-one, (697 mg, 4.27 mmol) in THF (7 mL) is added dropwise to the reaction mixture. The resulting solution is stirred for 4 h. The reaction mixture is poured into aqueous 10% HCl solution (160 mL). The resulting mixture is heated to 90° C. for 45 min and stirred at room temperature for 36 h. The precipitate which formed is collected by filtration washed with small volumes of ethyl acetate (10×3 mL) and dried to give the title compound as a yellow solid (205 mg, 16%).
Reaction SMILES: N([O-])=O.[Na+].[N+:5]([C:8]1[CH:13]=[CH:12][C:11](N)=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:9]=1)([O-:7])=[O:6].[S:19](=[O:21])=[O:20].O.[ClH:23]>C(O)(=O)C.[Cu](Cl)Cl>[N+:5]([C:8]1[CH:13]=[CH:12][C:11]([S:19]([Cl:23])(=[O:21])=[O:20])=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:9]=1)([O-:7])=[O:6]
Reactant: O=S=O
Reactant: Nc1ccc([N+](=O)[O-])cc1C(F)(F)F
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71 %

Procedure:
Sodium nitrite (1.8 g, 26 mmol) was added portion wise to a stirred solution of 4-nitro-2-trifluoromethyl-phenylamine (5.0 g, 24 mmol) in acetic acid (37 ml) and HCl (concentrated, 7.5 ml) while maintaining the temperature below 15° C. This solution was then added drop wise to a stirred solution of saturated sulfur dioxide, copper (II) chloride (0.6 g, 4.5 mmol) and water (7.5 ml) in acetic acid (24 ml) at 5° C. The reaction mixture was allowed to warm to room temperature and poured over ice water and stirred for a further 15 minutes. The resulting precipitate was collected by filtration, washed with water and dried overnight in a vacuum oven to give the title compound (3.5 g, 71% yield) as a yellow solid which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10](O)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].[B-](F)(F)(F)F.CN(C(ON1C(=O)C=CC=C1)=[N+](C)C)C.CN1CCOCC1.Cl.[C:41]([N:45]1[N:49]=[N:48][C:47]([C:50]2[CH:55]=[CH:54][C:53]([CH2:56][N:57]([NH:70][C:71](=[O:82])[C@H:72]([C:78]([CH3:81])([CH3:80])[CH3:79])[NH:73][C:74]([O:76][CH3:77])=[O:75])[CH2:58][C@H:59]([OH:69])[C@@H:60]([NH2:68])[CH2:61][C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)=[CH:52][CH:51]=2)=[N:46]1)([CH3:44])([CH3:43])[CH3:42]>CN(C=O)C.C(Cl)Cl>[C:41]([N:45]1[N:49]=[N:48][C:47]([C:50]2[CH:55]=[CH:54][C:53]([CH2:56][N:57]([NH:70][C:71](=[O:82])[C@H:72]([C:78]([CH3:81])([CH3:80])[CH3:79])[NH:73][C:74]([O:76][CH3:77])=[O:75])[CH2:58][C@H:59]([OH:69])[C@@H:60]([NH:68][C:10](=[O:11])[C@H:6]([CH:7]([CH3:8])[CH3:9])[NH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:61][C:62]3[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=3)=[CH:52][CH:51]=2)=[N:46]1)([CH3:43])([CH3:42])[CH3:44]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: COC(=O)N[C@H](C(=O)NN(Cc1ccc(-c2nnn(C(C)(C)C)n2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(-c2nnn(C(C)(C)C)n2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere, 54 mg (0.308 mmol) of N-methoxycarbonyl-(L)-valine and 92 mg (0.308 mmol) of TPTU in 1 ml of DMF and 101 μl (0.91 mmol) of NMM are stirred at room temperature for 10 min. 190 mg (0.308 mmol) of 1-[4-(2-tert-butyl-2H-tetrazol-5-yl)-phenyl]-4(S)-hydroxy-5(S)-amino-2-N-[N-methoxycarbonyl-(L)-tert-leucyl]amino-6-phenyl-2-azahexane hydrochloride (Example 34g) in 2 ml of DMF are added thereto and the mixture is stirred at room temperature overnight to complete the reaction. The reaction mixture is diluted with methylene chloride and washed with brine. The aqueous phases are extracted 2× with methylene chloride; the organic phases are filtered through cotton wadding, concentrated by evaporation and chromatographed (SiO2; methylene chloride/methanol 30:1): TLC: Rf=0.21 (methylene chloride/methanol 19:1); FAB MS (M+H)+=738.