Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:32])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH:23][C:24]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:25])=[N:13][CH:14]=1.[C:33]1(=O)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:32])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH:23][C:24]([CH:26]2[CH2:31][CH2:30][N:29]([CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[CH2:28][CH2:27]2)=[O:25])=[N:13][CH:14]=1
Reactant: O=C1CCCCC1
Reactant: O=C(Nc1ccc(Cl)cn1)c1ccccc1NC(=O)C1CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(Cl)cn1)c1ccccc1NC(=O)C1CCN(C2CCCCC2)CC1

Procedure:
Using procedures substantially equivalent to those described in example 27, N-(5-chloropyridin-2-yl)-2-[(1-cyclohexlpiperidin-4-ylcarbonyl)amino]benzamide (34 mg, 72%, 97% pure by HPLC analysis) was prepared from N-(5-chloropyridin-2-yl)-2-[(piperidin-4-ylcarbonyl)amino]-benzamide trifluoroacetate and cyclohexanone.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=2)[N:5]=[C:4]([NH2:16])[N:3]=1.C1C(=O)N([I:24])C(=O)C1>C(Cl)Cl.CO>[I:24][C:7]1[C:2]([CH3:1])=[N:3][C:4]([NH2:16])=[N:5][C:6]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cc(-c2cccc(C#N)c2)nc(N)n1
Solvent: ClCCl
Solvent: CO
Product: Cc1nc(N)nc(-c2cccc(C#N)c2)c1I

Procedure:
The title compound is synthesized according to general procedure GP1 starting from 3.2 g (12 mmol) 4-methyl-6-(3-cyano-phenyl)-pyrimidin-2-ylamine and 2.8 g (13 mmol) NIS. Yield after chromatography on silica gel with DCM/MeOH: 3.5 g (78%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([CH2:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][OH:18])[CH2:13][CH2:12]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:21].[Na+]>C(Cl)(Cl)(Cl)Cl.O.C(#N)C.O.[Ru](Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:7]([CH3:8])[CH2:9][CH2:10][C@H:11]1[CH2:12][CH2:13][C@H:14]([C:17]([OH:21])=[O:18])[CH2:15][CH2:16]1)=[O:19])([CH3:3])([CH3:2])[CH3:4]
Reactant: CN(CC[C@H]1CC[C@H](CO)CC1)C(=O)OC(C)(C)C
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: CN(CC[C@H]1CC[C@H](C(=O)O)CC1)C(=O)OC(C)(C)C

Procedure:
A solution of 17.1 g (63.1 mmol) of trans-[2-(4-hydroxymethyl-cyclohexyl)-ethyl]-methyl-carbamic acid tert-butyl ester in 60 mL of CCl4, 60 mL of water and 90 mL of acetonitrile were treated with 0.075 g (0.33 mmol, 0.05 eq) of ruthenium (III) chloride-hydrate and 55.4 g (259 mmol, 4.1 eq) of sodium metaperiodate within 30 min. After 6 h the reaction was decanted and washed with CH2Cl2 (×3). The decanted phase was partitioned between CH2Cl2 (×3)/H2O, the organic phase was dried over Na2SO4 and evaporated to yield 17.24 g (96%) of trans-4-[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-cyclohexanecarboxylic acid, MS: 284 (M−H−).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:17][CH2:18][CH3:19])[C:5]1[O:6][C:7]2[CH:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:8]=2[CH:9]=1)[CH3:2].[ClH:20].Cl.[NH2:22][C@@H:23]1[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1>>[ClH:20].[N:25]12[CH2:30][CH2:29][CH:28]([CH2:27][CH2:26]1)[C@@H:23]([NH:22][C:14]([C:12]1[CH:11]=[CH:10][C:8]3[CH:9]=[C:5]([CH:4]([O:3][CH2:1][CH3:2])[O:17][CH2:18][CH3:19])[O:6][C:7]=3[CH:13]=1)=[O:16])[CH2:24]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: CCOC(OCC)c1cc2ccc(C(=O)O)cc2o1
Agent: Cl
Product: CCOC(OCC)c1cc2ccc(C(=O)N[C@H]3CN4CCC3CC4)cc2o1
Yield: 69.9 %

Procedure:
2-(Diethoxymethyl)-1-benzofuran-6-carboxylic acid (264 mg, 1.0 mmol) is coupled with (R)-3-aminoquinuclidine dihydrochloride (219 mg, 1.1 mmol) and salt made according to Method A with non-critical changes to afford 286 mg (70%) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-(diethoxymethyl)-1-benzofuran-6-carboxamide hydrochloride as a white solid. HRMS (FAB) calcd for C21H28N2O4+H: 373.2127, found 373.2121 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Cl-].[Na+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.CN(C)C=O>[CH2:16]([O:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[Br:1])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(F)cc1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Fc1ccc(OCc2ccccc2)c(Br)c1
Reaction time: 1.5 h
Yield: 91 %

Procedure:
To a mixture of 2-bromo-4-fluorophenol (24.7 g, 129 mmol), tetrabutylammonium iodide (4.8 g, 13.0 mmol), potassium carbonate (35.9 g, 260 mmol) and N,N-dimethylformamide (390 mL), benzyl bromide (23.5 g, 137 mmol) was added at room temperature and stirred for 1.5 hours. The reaction mixture was poured into a mixture of ethyl acetate and saturated aqueous sodium chloride, and then extracted with ethyl acetate. The organic phase was washed twice with saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=90:10–80:20) to give 1-benzyloxy-2-bromo-4-fluorobenzene (33.0 g, 90%).
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH2:16][OH:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:18]>CO>[OH:17][CH2:16][CH2:15][N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:18])[C:11]=2[N:12]=[CH:13]1
Reactant: OCCn1cnc2c(Cl)nc3ccccc3c21
Reactant: N
Solvent: CO
Product: Nc1nc2ccccc2c2c1ncn2CCO

Procedure:
A mixture of 4.0 g (0.016 mole) of 4-chloro-1-(2-hydroxyethyl)-1H-imidazo[4,5-c]quinoline (from Example 118) and 30 ml of 10% ammonia in methanol was heated in a steel bomb for 12 hours at 150° C. The resulting solid was separated from the cooled mixture by filtration, and was washed sequentially with water and methanol. The air-dried solid was recrystallized from N,N-dimethylformamide to provide white solid 1-(2-hydroxyethyl)-1H-imidazo[4,5-c]-quinolin-4-amine, m.p. 260°-262° C. Analysis: Calculated for C12H12N4O: % C, 63.1; % H, 5.3; % N, 24.5; Found: % C, 63.0; % H, 5.2; % N, 24.3.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]12[CH2:19][CH2:18][C:15]([C:20]([O:22]C)=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]12[CH2:19][CH2:18][C:15]([C:20]([OH:22])=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C12CCC(NC(=O)OCc3ccccc3)(CC1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(NC12CCC(C(=O)O)(CC1)CC2)OCc1ccccc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
Methyl 4-benzyloxycarbonylaminobicyclo[2.2.2]octane-1-carboxylate (64.3 g) was dissolved in ethanol (1100 mL). To this solution, a 1 mol/L aqueous solution of sodium hydroxide (1000 mL) was added and the mixture was stirred at 50° C. for 1 hour. Ethanol in the mixture was evaporated under reduced pressure and the residue was washed with diethylether (500 mL), followed by addition of concentrated hydrochloric acid to adjust the pH to acidic (pH 1). The resulting crystals were filtrated, washed with water, and dried under reduced pressure to give 4-benzyloxycarbonylaminobicyclo[2.2.2]octane-1-carboxylic acid (56.1 g).
Reaction SMILES: [CH2:1]([N:3]([CH3:23])[C:4]([N:6]1[CH2:11][CH:10]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][CH:13]=2)[CH2:9][CH:8]([C:20]([OH:22])=O)[CH2:7]1)=[O:5])[CH3:2].[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:31](=[N:33]O)[NH2:32])=[CH:27][CH:26]=1>>[CH2:1]([N:3]([CH3:23])[C:4]([N:6]1[CH2:7][CH:8]([C:20]2[O:22][N:33]=[C:31]([C:28]3[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=3)[N:32]=2)[CH2:9][CH:10]([C:12]2[CH:13]=[CH:14][C:15]([CH2:18][CH3:19])=[CH:16][CH:17]=2)[CH2:11]1)=[O:5])[CH3:2]
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N(C)CC)C2)cc1
Reactant: NC(=NO)c1ccc(F)cc1
Product: CCc1ccc(C2CC(c3nc(-c4ccc(F)cc4)no3)CN(C(=O)N(C)CC)C2)cc1

Procedure:
64 mg (0.20 mmol) of 1-[ethyl(methyl)carbamoyl]-5-(4-ethylphenyl)piperidine-3-carboxylic acid (Example 45A) and 34 mg (0.22 mmol, 1.1 eq.) of 4-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 46 mg (52% of theory)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[CH2:17][N:16]([CH3:21])[CH2:15][CH2:14][C:13]=3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:22]([O:25][CH2:26][C:27]1[C:32]([N:33]2[CH2:45][CH2:44][N:36]3[C:37]4[CH2:38][CH2:39][CH2:40][CH2:41][C:42]=4[CH:43]=[C:35]3[C:34]2=[O:46])=[CH:31][C:30]([F:47])=[CH:29][C:28]=1N1CCN2C3CCCCC=3C=C2C1=O)(=[O:24])[CH3:23].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>ClCCl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O.C(#N)C>[C:22]([O:25][CH2:26][C:27]1[C:32]([N:33]2[CH2:45][CH2:44][N:36]3[C:37]4[CH2:38][CH2:39][CH2:40][CH2:41][C:42]=4[CH:43]=[C:35]3[C:34]2=[O:46])=[CH:31][C:30]([F:47])=[CH:29][C:28]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[CH2:17][N:16]([CH3:21])[CH2:15][CH2:14][C:13]=3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)OCc1c(N2CCn3c(cc4c3CCCC4)C2=O)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: CN1CCc2nc(Nc3cc(Br)cn(C)c3=O)ccc2C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: CC(=O)OCc1c(-c2cc(Nc3ccc4c(n3)CCN(C)C4)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 110 °C
Yield: 35.2 %

Procedure:
A 15 mL microwave reaction vial with a magnetic stirrer was charged with 205b (0.35 g, 1 mmol), 4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 210d (0.48 g, 1 mmol), potassium phosphate (0.54 g, 2 mmol), sodium acetate (0.17 g, 2 mmol), acetonitrile (10 mL), water (1 mL), and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane (0.08 g, 0.1 mmol). The mixture was heated at 110° C. for 2 hours under argon atmosphere. After this time, the mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column-chromatography eluting with 40:1 DMC/methanol to give 205c (0.22 g, 36%). LC/MS: m/z 625 (M+H)+
Reaction SMILES: ClC1C=C(C=C(Cl)C=1)C(NN)=O.[Cl:13][C:14]1[CH:15]=[C:16]([CH:25]=[C:26]([Cl:28])[CH:27]=1)[C:17]([NH:19][NH:20][C:21](=[O:24])[CH2:22][Cl:23])=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:23][CH2:22][C:21]1[O:24][C:17]([C:16]2[CH:15]=[C:14]([Cl:13])[CH:27]=[C:26]([Cl:28])[CH:25]=2)=[N:19][N:20]=1
Reactant: O=C(CCl)NNC(=O)c1cc(Cl)cc(Cl)c1
Agent: NNC(=O)c1cc(Cl)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClCc1nnc(-c2cc(Cl)cc(Cl)c2)o1
Temperature: 100 °C
Yield: 69.4 %

Procedure:
A mixture of compound 5 (700 mg, 2.14 mmol), compound 6 (222 mg, 1.86 mmol) and K2CO3 (772 mg, 5.59 mmol, 2 eq.) in 10 ml of DMF was heated to 100° C. for 3 hours. The reaction mixture was brought to ambient temperature, filtered and the filtrate was evaporated to obtain a crude residue which was purified by column chromatography using EtOAc/hexane (50:50) as an eluent to obtain compound 7 as a colorless liquid (340 mg). Yield: 50%.
Reaction SMILES: [OH-].[K+].O.NN.[CH3:6][CH:7]([CH3:15])[C:8]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)=O>C(O)COCCO.O>[CH2:8]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[CH:7]([CH3:15])[CH3:6]
Reactant: CC(C)C(=O)c1cccs1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: CC(C)Cc1cccs1
Temperature: 180 °C
Reaction time: 2 h

Procedure:
To a mixture of potassium hydroxide (2.24 g, 40 mmol) and hydrazine monohydrate (3.0 g, 60 mmol) in diethylene glycol (25 ml) was added 2-methyl-1-thiophen-2-yl-propan-1-one (1.54 g, 10 mmol). The combined mixture was heated at 180° C. for 1 h and then at 210° C. for a further 2 h. The mixture was cooled to rt and diluted with water (100 ml) and extracted with diethyl ether (3×). The combined organic extracts were washed with water, brine, dried (Na2SO4), filtered and concentrated under reduced pressure to yield a yellow oil: 0.9 g (61%) GC-MS: M=140.0.
Reaction SMILES: C[N:2](C)[CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=2)[NH:7][CH:6]=1.IC.[C-]#N.[K+].C1OCCOCCOCCOCCOCCOC1>CS(C)=O>[N+:14]([C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:4][C:3]#[N:2])([O-:16])=[O:15]
Reactant: CN(C)CCc1c[nH]c2ccc([N+](=O)[O-])cc12
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [C-]#N
Agent: [K+]
Solvent: CI
Solvent: CS(C)=O
Product: N#CCc1c[nH]c2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dissolve the N,N-dimethyl-5-nitrotryptamine obtained above in 200 mL dry DMSO, treat with iodomethane (7.7 mL, 17.5 g, 124 mmol), and stir for 1 hour at ambient temperature. Add KCN (40 g, 621 mmol) and 18-crown-6 (0.5 g). Warm the reaction to 110° C. for 45 minutes, cool, poured onto ice then saturate with NaCl. Extract the quenched reaction mixture with EtOAc, combine the extracts, and wash 3 times with brine. Dry over MgSO4 and concentrate under vacuum chromatograph on silica gel eluting with 1% MeOH in CHCl3 to give (5-nitro-1H-indol-3-yl)acetonitrile as a solid: FDMS 201 (M+); Analysis for C10H7N3O2: calcd: C, 59.70; H, 3.51; N, 20.89. found: C, 59.32; H, 3.52; N, 20.56.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[C@H:12]([C:13]([OH:15])=[O:14])[CH2:11][CH:10]([OH:16])[CH2:9]1)=[O:7])([CH3:4])[CH3:3].[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27](F)[N:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CC(C)([O-])C.[K+].S(=O)(=O)(O)[O-].[K+]>CS(C)=O>[CH2:17]([O:24][C:25]1[N:26]=[C:27]([O:16][C@H:10]2[CH2:9][N:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[C@H:12]([C:13]([OH:15])=[O:14])[CH2:11]2)[CH:28]=[CH:29][CH:30]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Fc1cccc(OCc2ccccc2)n1
Reactant: CC(C)(C)OC(=O)N1CC(O)C[C@H]1C(=O)O
Agent: CC(C)(C)[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1C[C@H](Oc2cccc(OCc3ccccc3)n2)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 100 %

Procedure:
A 500 mL 3-neck round bottom flask under nitrogen was charged with Boc-L-4-hydroxyproline (Chem Impex) (2.00 g, 8.65 mmol) and DMSO (80 ml). Attached an addition funnel containing a solution of the product of Step 1 (1.758 g, 8.65 mmol) in DMSO (10 ml). Cooled reaction in an ice bath to +18° C. Added potassium-t-butoxide (2.91 g, 25.9 mmol) slowly keeping the internal temperature<20° C. Stirred 45 minutes at room temperature. Cooled to 15° C. Added contents of addition funnel dropwise. Warmed to room temperature. Stirred 1.5 hours. Poured into 2.5% potassium bisulfate. Extracted three times with ethyl acetate, washed combined organic portions with water then brine, dried with anhydrous magnesium sulfate, filtered and rotary evaporated filtrate to give the title compound as a white foam. (3.58 g, 8.65 mmol, 100% yield). LCMS (ES+) m/z 415.3 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:14]([OH:16])=O)[CH2:10][CH2:11][CH2:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:18][O:19][C:20](=[O:23])[CH2:21][NH2:22].C(OCC)C>CCCCCC>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:14]([NH:22][CH2:21][C:20]([O:19][CH3:18])=[O:23])=[O:16])[CH2:10][CH2:11][CH2:12][CH3:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)CN
Agent: Cl
Solvent: CCOCC
Solvent: CCCCCC
Product: CCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)OC
Yield: 92.6 %

Procedure:
The title compound was prepared by the general method of Example 1 using 15.0 g (65 mmol) of t-butoxycarbonyl-D-norleucine (Boc-D-Nle) and 8.1 g (65 mmol) of glycine methyl ester hydrochloride. Trituration of the product oil with diethyl ether and (Skellysolve B) produced 18.2 g of the title compound as a pale yellow solid. Structure assignment was supported by elemental analysis.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:9]=2)[C:4](=O)[CH2:3]1.[CH3:17][C:18]1([C:24](=[O:28])[CH2:25][C:26]#[N:27])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH3:1][C:2]1([CH3:16])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:9]=2)[C:4](=[C:25]([C:24]([C:18]2([CH3:17])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:28])[C:26]#[N:27])[CH2:3]1
Reactant: CC(C)(C)c1ccc2c(c1)C(C)(C)CC2=O
Reactant: CC1(C(=O)CC#N)CCCCC1
Product: CC1(C(=O)C(C#N)=C2CC(C)(C)c3cc(C(C)(C)C)ccc32)CCCCC1

Procedure:
3,3-Dimethyl-5-tert-butyl-1-indanone are reacted with 3-(1′-methylcyclohexyl)-3-oxo-propiononitrile analogously to Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][C:6]([C:12](OCC)=[O:13])=[CH:5]2.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.C(Cl)Cl.O=[Mn]=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][C:6]([CH:12]=[O:13])=[CH:5]2
Reactant: CCOC(=O)c1cc2cc(Cl)c(Cl)cc2[nH]1
Agent: O=[Mn]=O
Agent: [Al+3]
Agent: [H-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=Cc1cc2cc(Cl)c(Cl)cc2[nH]1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 65.4 %

Procedure:
Ethyl 5,6-dichloro-1H-indole-2-carboxylate (77.5 g, 301 mmol) dissolved in dry THF (70 ml) was added dropwise to an ice cold solution of LiAlH4 (19.17 g, 505 mmol) in anhydrous THF (1000 ml) under nitrogen. The mixture was stirred for 45 min at 0° C. and then quenched by the sequential addition of water (20 ml), 15% aqueous NaOH (20 ml) and water (60 ml). The mixture was filtered through-a Celite pad and then washed with THF (2×500 ml). The filtrate dried over Na2SO4 and evaporated at reduced pressure yielded an orange raw solid. This was dissolved in CH2Cl2 (1500 ml) and activated MnO2 (150 g, 1.73 mol) was added. The mixture was stirred at RT for 12 hours and then filtered through a Celite pad which was washed with warm acetone (4×750 ml), and the combined filtrates were evaporated to dryness, yielding pure title compound (42.1 g, 197 mmol, yield 65.4%), mp=207-208° C.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([Br:14])=[CH:9][N:8]=1.C(N(CC)CC)C>C(Cl)Cl>[Br:14][C:10]1[CH:11]=[C:12]([CH3:13])[C:7]([NH:6][C:3](=[O:4])[CH2:2][Cl:1])=[N:8][CH:9]=1
Reactant: O=C(Cl)CCl
Reactant: Cc1cc(Br)cnc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(Br)cnc1NC(=O)CCl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.75 mL (22 mmol) chloroacetyl chloride are added to a solution, cooled to 0° C., of 3.74 g (20 mmol) 2-amino-5-bromo-3-methylpyridine in 50 mL DCM and then 6.1 mL (44 mmol) triethylamine are slowly added dropwise. After the addition has ended the ice bath is removed and the reaction mixture is stirred for 4 h at RT. It is poured onto water, extracted exhaustively with DCM, the combined organic phases are washed with water and saturated NaCl solution and dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, cyc/EtOAc 2:1).
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9]([Si:13]([O:16][CH2:17][CH2:18][C:19]#[CH:20])([CH3:15])[CH3:14])([CH3:12])([CH3:11])[CH3:10]>C(N(CC)CC)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.[Cu]I>[Si:13]([O:16][CH2:17][CH2:18][C:19]#[C:20][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4])([C:9]([CH3:10])([CH3:11])[CH3:12])([CH3:15])[CH3:14]
Reactant: Nc1ccccc1I
Reactant: C#CCCO[Si](C)(C)C(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCC#Cc1ccccc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Iodoaniline (1.76 g, 8 mmol) was dissolved in triethylamine (50 mL) and placed under N2. tert-Butylbut-3-ynyloxydimethylsilane (2.58 g, 14 mmol) was added, followed by bis(triphenylphosphine)palladium(II) chloride (30 mg, 0.042 mmol) and copper(I) iodide (7 mg, 0.036 mmol), and the reaction was stirred overnight at room temperature. Triethylamine was evaporated, and the residue was diluted with ether and filtered through Celite. The filtrate was concentrated, and the residue was purified by SiO2 chromatography (5-20% ethyl acetate/hexanes) to give the desired product. The reaction was assumed to be quantitative.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])=[CH:13][CH:12]=1
Reactant: N#Cc1ccccc1F
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccccc1Oc1ccc(Br)cc1
Temperature: 120 °C
Reaction time: 5 h

Procedure:
A mixture of 2-fluorobenzonitrile (28.8 g), 4-bromophenol (36.9 g), potassium carbonate (58.9 g) and dimethylformamide (30 ml) was heated with stirring under nitrogen at 120° C. for 5 hours. The mixture was allowed to stand overnight at ambient temperature and then partitioned between ethyl acetate and water. The organic layer was separated, washed, dried and evaporated to give an oil which solidified on standing. The solid was triturated with petroleum ether b.p. 40-60° C. and filtered to give 2-(4-bromophenoxy)benzonitrile.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]([N+:14]([O-:16])=[O:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:18])([CH3:17])[O:7]2.[C:19]([O-])([O-])=O.[K+].[K+].CI>>[CH3:19][O:1][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]([N+:14]([O-:16])=[O:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:18])([CH3:17])[O:7]2
Reactant: O=C([O-])[O-]
Reactant: CC1(C)C=Cc2c(O)c(C=O)cc([N+](=O)[O-])c2O1
Agent: [K+]
Solvent: CI
Product: COc1c(C=O)cc([N+](=O)[O-])c2c1C=CC(C)(C)O2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-hydroxy-2,2-dimethyl-8-nitro-2H-chromene-6-carbaldehyde (2.34 g, 10 mmol), K2CO3 (4.12 g, 29.8 mmol) and MeI (2.13 g, 0.94 mL, 15 mmol in Me2CO (40 mL) is refluxed for 4 h and stirred at room temperature overnight. The mixture is concentrated, treated with water (15 mL) and extracted with dichloromethane. The combined organic layers are washed with water, dried over Na2SO4, and the solvent is removed in vacuo to afford an oil, which is chromatographed with 3% Me2CO in hexane to afford 5-methoxy-2,2-dimethyl-8-nitro-2H-chromene-6-carbaldehyde.