Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:23][S:24][CH2:25][C@H:26]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:20]([OH:22])=O)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:54][CH2:55][CH2:56][O:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][P:66](=[O:73])([O:70][CH2:71][CH3:72])[O:67][CH2:68][CH3:69].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:23][S:24][CH2:25][C@H:26]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:20](=[O:22])[NH:54][CH2:55][CH2:56][O:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][P:66](=[O:73])([O:67][CH2:68][CH3:69])[O:70][CH2:71][CH3:72])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OCCCCCCCCCCCC
Reactant: CCOP(=O)(CCOCCOCCOCCN)OCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCOCCOCCOCCP(=O)(OCC)OCC)OCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(((R)-2,3-bis(dodecyloxy)propyl)thio)propanoic acid (1 eq) in DCM (0.1 M) was added diethyl 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethylphosphonate (1.3 eq, from example 18, step 4), DIEA (2.5 eq) and HBTU (1.2 eq). The reaction mixture was then stirred at room temperature for 2 hours. The mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-10% MeOH/DCM to give the product.
Reaction SMILES: [N:1]1([C:5]2[C:10]3=[C:11]([C:15]4[CH:16]=[N:17][N:18]([CH3:21])[C:19]=4Br)[N:12]=[C:13]([CH3:14])[N:9]3[N:8]=[CH:7][N:6]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[C:26]([CH3:33])[CH:25]=1.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C)C=O>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.O>[N:1]1([C:5]2[C:10]3=[C:11]([C:15]4[CH:16]=[N:17][N:18]([CH3:21])[C:19]=4[C:27]4[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][C:26]=4[CH3:33])[N:12]=[C:13]([CH3:14])[N:9]3[N:8]=[CH:7][N:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nc(-c2cnn(C)c2Br)c2c(N3CCC3)ncnn12
Reactant: COc1ccc(B(O)O)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2c(-c3nc(C)n4ncnc(N5CCC5)c34)cnn2C)c(C)c1
Temperature: 150 °C

Procedure:
4-(Azetidin-1-yl)-5-(5-bromo-1-methyl-1H-pyrazol-4-yl)-7-methylimidazo[5,1-f][1,2,4]triazine (200 mg, 0.574 mmol) was combined with (4-methoxy-2-methylphenyl)boronic acid (180 mg, 1.08 mmol), potassium phosphate dihydrate (98%, 571 mg, 2.25 mmol), tetrakis(triphenylphosphine)palladium(0) (99.9%, 65.9 mg, 0.057 mmol) and N,N-dimethylformamide (12 mL) and heated in a microwave reactor at 150° C. for 60 minutes. This reaction mixture was combined with crude reaction products from three other identical reactions, and poured into water. The mixture was extracted with ethyl acetate, and the combined organic layers were washed with water, then with saturated aqueous sodium chloride solution. After drying over sodium sulfate, the organic extracts were filtered and concentrated in vacuo. Purification via silica gel chromatography (Eluants: heptane/ethyl acetate/methanol mixtures, 90:15:10 followed by 60:30:10, 45:55:10, 30:70:10 ratios) provided the product as a solid. Combined yield: 508 mg, 1.30 mmol, 56%. LCMS m/z 390.2 (M+1). 1H NMR (400 MHz, CDCl3) δ 2.08 (s, 3H), 2.26-2.35 (m, 2H), 2.60 (s, 3H), 3.69 (s, 3H), 3.79 (s, 3H), 3.8-4.2 (v br m, 4H), 6.72-6.76 (m, 2H), 7.17-7.24 (br m, 1H), 7.67 (s, 1H), 7.78 (s, 1H).
Reaction SMILES: [CH2:1]([N:4]([CH3:33])[CH2:5]/[CH:6]=[CH:7]/[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:31])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27]C(=O)C)=[CH:12][C:11]=1[F:32])[CH:2]=[CH2:3].Cl>C(O)C>[CH2:1]([N:4]([CH3:33])[CH2:5]/[CH:6]=[CH:7]/[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:31])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH2:27])=[CH:12][C:11]=1[F:32])[CH:2]=[CH2:3]
Reactant: C=CCN(C)C/C=C/COc1ccc(C(=O)CCCCCCCCCCNC(C)=O)cc1F
Agent: Cl
Solvent: CCO
Product: C=CCN(C)C/C=C/COc1ccc(C(=O)CCCCCCCCCCN)cc1F
Reaction time: 24 h
Yield: 88.5 %

Procedure:
A solution of 1.84 g of (E)-N-[11-[4-[4-(allyl-methyl-amino)-but-2-enyloxy]-3-fluoro-phenyl]-11-oxo-undecyl]-acetamide (Ex. 4c) in 30 ml of ethanol/5 ml of 18% aqueous hydrochloric acid is boiled for 7 hrs. and, after the addition of 4 ml of concentrated hydrochloric acid, boiled for 24 hrs. and, after the addition of a further 4 ml of concentrated hydrochloric acid, boiled for 30 hrs. After concentration the residue is taken up in 10% potassium hydrogen sulphate solution/methylene chloride and the aqueous phase is made basic with 10% sodium hydroxide solution and extracted with methylene chloride. The organic phase is dried and concentrated. There are obtained 1.48 g of (E)-1-[4-[4-(allyl-methyl-amino)-but-2-enyloxy]-3-fluoro-phenyl]-11-amino-undecan-1-one which is converted into the fumarate, MS: m/e 419 (M+H+).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[N:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][CH:9]=2)[N:6]=[N:5][N:4]=1.[OH-].[Li+].Cl>C1COCC1.CO.O>[F:19][C:2]([F:1])([F:18])[C:3]1[N:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[N:6]=[N:5][N:4]=1
Reactant: COC(=O)c1ccc(-n2nnnc2C(F)(F)F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(-n2nnnc2C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.2 %

Procedure:
To a solution of the compound (5.2 g) obtained in step 1 in THF/methanol/water (6.0/18/9.5 mL) was added 4N aqueous lithium hydroxide solution (9.5 mL), and the mixture was stirred at room temperature for 4 hr. The mixture was acidified with 1N hydrochloric acid, concentrated under reduced pressure, diluted with water, and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried, filtered through silica gel (eluted with ethyl acetate). The filtrate was concentrated under reduced pressure, and crystallized from ethyl acetate/hexane to give the title compound (4.3 g, 86%) as a pale-yellow powder.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:18]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:19][N:20]=2)[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[C:7]=1[C:8]#[N:9].[N-:27]=[N+:28]=[N-:29].[Na+].CCOC(C)=O>CN(C=O)C>[N:27]([C:2]1[C:3]2[N:4]([C:18]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)=[CH:19][N:20]=2)[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[C:7]=1[C:8]#[N:9])=[N+:28]=[N-:29]
Reactant: N#Cc1c(-c2ccc(Cl)cc2Cl)cn2c(N3CCOCC3)cnc2c1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1c(-c2ccc(Cl)cc2Cl)cn2c(N3CCOCC3)cnc2c1N=[N+]=[N-]
Temperature: 60 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
A mixture of 8-chloro-6-(2,4-dichloro-phenyl)-3-morpholin-4-yl-imidazo[1,2-a]pyridine-7-carbonitrile (135 mg, 0.33 mmol, prepared according to Example 30, Step 16.1) and sodium azide (108 mg, 1.66 mmol) in DMF (1 mL) was heated at 60° C. and stirred for 4 h. The reaction mixture was cooled to RT, poured into AcOEt and washed successively with water and brine. The organic layer was dried over Na2SO4, filtered and evaporated to dryness to yield the crude title compound (144 mg, 0.33 mmol, quant.) as a brownish solid, which was used in the next step without further purification. HPLC: AtRet=2.77.
Reaction SMILES: [Cl:1][CH:2]([C:7]1([C:16]([F:19])([F:18])[F:17])[O:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8]1)[C:3]([F:6])([F:5])[F:4].[N+:20]([O-])([OH:22])=[O:21].S(=O)(=O)(O)O>C(Cl)Cl>[N+:20]([C:13]1[CH:14]=[CH:15][C:9]2[O:8][C:7]([CH:2]([Cl:1])[C:3]([F:6])([F:5])[F:4])([C:16]([F:19])([F:18])[F:17])[O:11][C:10]=2[CH:12]=1)([O-:22])=[O:21]
Reactant: FC(F)(F)C(Cl)C1(C(F)(F)F)Oc2ccccc2O1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2c(c1)OC(C(Cl)C(F)(F)F)(C(F)(F)F)O2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
613 g of 2-(1-chloro-2,2,2-trifluoroethyl)-2-trifluoromethyl-1,3-benzodioxole of Example 2a were dissolved in 1.2 l of methylene chloride and the solution was added dropwise at 0° to 10° C. to a mixture of 400 ml of 65% strength nitric acid and 400 ml of concentrated sulphuric acid. Stirring was continued for 2 hours at room temperature. Then, the mixture was poured carefully into 2 l of ice-water and extracted using methylene chloride. The combined organic phases were washed twice using water, dried and concentrated. The yield was 652 g (93% of theory). The NMR spectra showed the following characteristic absorptions: 19F-NMR: -66.4 and -79.2 ppm. 1H-NMR: 4.81 ppm.
Reaction SMILES: [CH2:1]([C:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[S:16][CH3:17])[N:7]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[C:26]([C:31]([O:33]C)=[O:32])=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:21][CH:20]=2)[CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].C(O)C.P([O-])([O-])(O)=O.[Na+].[Na+]>O>[CH2:1]([C:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[S:16][CH3:17])[N:7]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[C:26]([C:31]([OH:33])=[O:32])=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:23][CH:24]=2)[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cn(Cc2ccc(-c3ccccc3C(=O)OC)cc2)c2cccc(SC)c2c1=O
Agent: O=P([O-])([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCc1cn(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2cccc(SC)c2c1=O
Reaction time: 2 h
Yield: 34.4 %

Procedure:
A mixture of 270 mg of the product of Example 7, 5 ml of a 5N sodium hydroxide solution and 5 ml of ethanol was stirred for 2 hours at reflux and the mixture was poured into water and acidified with sodium hydrogen phosphate. Extraction was carried out with ethyl acetate and the extracts were washed with water, dried and evaporated to dryness. The residue was chromatographed on silica (eluant: methylene chloride-methanol (9-1)) and the product was impasted in a mixture of 5 ml of ethyl acetate and 5 ml of isopropyl ether to obtain 90 mg of the desired compound melting at 155° C.
Reaction SMILES: C(N(CC)CC)C.ClC([O:11][CH2:12][CH3:13])=O.[OH:14][CH:15]([C:21]1[CH:26]=[CH:25][C:24]([N:27]2[C:31](=[O:32])[CH2:30][CH2:29][C@@H:28]2[CH2:33][CH2:34][CH2:35][C:36]2[S:40][C:39]([C:41]([OH:43])=[O:42])=[CH:38][CH:37]=2)=[CH:23][CH:22]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(O)CO>>[OH:11][CH2:12][CH2:13][O:42][C:41]([C:39]1[S:40][C:36]([CH2:35][CH2:34][CH2:33][C@H:28]2[CH2:29][CH2:30][C:31](=[O:32])[N:27]2[C:24]2[CH:23]=[CH:22][C:21]([CH:15]([OH:14])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:26][CH:25]=2)=[CH:37][CH:38]=1)=[O:43]
Reactant: CCOC(=O)Cl
Reactant: CCCCCC(O)c1ccc(N2C(=O)CC[C@@H]2CCCc2ccc(C(=O)O)s2)cc1
Solvent: OCCO
Solvent: CCN(CC)CC
Product: CCCCCC(O)c1ccc(N2C(=O)CC[C@@H]2CCCc2ccc(C(=O)OCCO)s2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
Triethylamine (17.5 μL, 0.13 mmol) and ethyl chloroformate (6 μL, 0.063 mmol) were added sequentially to a solution 5-(3-{(S)-1-[4-(1-hydroxyhexyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic acid (derived from the faster eluting [HPLC] ester diastereomer, see U.S. Ser. No. 10/599,046 or U.S. Provisional Patent Application No. 60/777,506, filed on Feb. 28, 2006, incorporated by reference herein, 18 mg, 0.042 mmol) in CH2Cl2 (0.6 mL) at 0° C. The mixture was allowed to warm to room temperature. After 30 min at room temperature, ethylene glycol (25 μL, 0.45 mmol) was added. After stirring overnight at room temperature, the reaction mixture was concentrated under a stream of nitrogen. The residue was diluted with EtOAc (20 mL) and washed with H2O (2×5 mL) and brine (5 mL). The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→10% MeOH/CH2Cl2, gradient) afforded 8.5 mg (43%) of the title compound (1).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[N:7][C:8]([O:11][CH2:12][C:13]2[C:14]([CH2:19][CH2:20][CH2:21][CH3:22])=[N:15][O:16][C:17]=2[CH3:18])=[CH:9][CH:10]=1)=[O:4].[NH2:23][CH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[O:27]1[CH2:28][CH2:29][CH:24]([NH:23][C:3]([C:5]2[N:6]=[N:7][C:8]([O:11][CH2:12][C:13]3[C:14]([CH2:19][CH2:20][CH2:21][CH3:22])=[N:15][O:16][C:17]=3[CH3:18])=[CH:9][CH:10]=2)=[O:4])[CH2:25][CH2:26]1
Reactant: CCCCc1noc(C)c1COc1ccc(C(=O)OC)nn1
Reactant: NC1CCOCC1
Product: CCCCc1noc(C)c1COc1ccc(C(=O)NC2CCOCC2)nn1
Yield: 74 %

Procedure:
As described for example 1e, 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid methyl ester (110 mg, 0.36 mmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (100 mg, 74%) which was obtained as a colourless oil after purification by chromatography (silica, 0 to 5% methanol in dichloromethane). MS: m/e=375.4 [M+H]+.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:12]1[S:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1](=[O:10])[N:13]=1
Reactant: COC(=O)c1ccccc1S
Reactant: N#Cc1ccccn1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=c1nc(-c2ccccn2)sc2ccccc12
Yield: 43.8 %

Procedure:
Methyl thiosalicylate (1.6 g, 9.51 mM) and 2-cyanopyridine (1.0 g, 9.60 mM) were dissolved in toluene (2 ml), and then triethylamine (2 ml, 14.4 mM) was added thereto. After heating the mixture under reflux for 8 hours, and the toluene was distilled away. Ethanol was added to the residues, and the resulting precipitates were collected by filtration to give crude crystals (1.7 g). The product was purified by silica gel column chromatography (hexane:chloroform=5:1→chloroform) to give the title compound as crystals (1.0 g, 43.4%).
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:9][C:10]([O-:12])=[O:11].[Na+]>C1COCC1.CS(C)=O>[CH:1]1([O:7][CH2:9][C:10]([OH:12])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C([O-])CCl
Reactant: OC1CCCCC1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: O=C(O)COC1CCCCC1
Temperature: 25 °C
Yield: 83.1 %

Procedure:
A solution of cyclohexanol (1.75 g, 17.5 mmol) in THF was added, and the mixture was warmed to 25° C. for 1 hour. The THF was removed by distillation under vacuum, and a solution of sodium chloroacetate (2.5 g, 22 mmol) in DMSO (50 ml) was added. The reaction mixture was treated as in Example 3 and 2.3 g of product (83% yield) was obtained as a colorless oil.
Reaction SMILES: [C:1]([OH:13])(=O)[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:47][CH2:48][CH2:49][NH:50][C:51]1[N:56]=[C:55]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[N:54]=[C:53]([NH:63][CH2:64][CH2:65][NH:66][C:67](=[O:69])[CH3:68])[C:52]=1[CH3:70]>CN1C(=O)CCC1>[C:67]([NH:66][CH2:65][CH2:64][NH:63][C:53]1[N:54]=[C:55]([C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)[N:56]=[C:51]([NH:50][CH2:49][CH2:48][NH:47][C:1]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[O:13])[C:52]=1[CH3:70])(=[O:69])[CH3:68]
Reactant: O=C(O)c1ccc2ccccc2n1
Reactant: CC(=O)NCCNc1nc(-c2ccccc2)nc(NCCN)c1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCCNc1nc(-c2ccccc2)nc(NCCNC(=O)c2ccc3ccccc3n2)c1C
Reaction time: 12 h

Procedure:
A solution of quinaldic acid (30 μl of a 0.3M solution in NMP), HATU (30 μl of a 0.3M solution in NMP) and diisopropylethylamine (30 μl of a 0.3M solution in NMP) was shaken at ambient temperature in a well of a 96 position microtitre plate for 45 min. N-[2-({6-[(2-aminoethyl)amino]-5-methyl-2-phenylpyrimidin-4-yl}amino)ethyl]acetamide (30 μl of a 0.3M solution in NMP) was then added and the mixture shaken for a further 12 hrs. Purification via ion exchange silica (SCX) yields the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([C:10]#[N:11])[CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[NH2:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]2[CH:3]=[CH:2][O:1][C:5]=2[CH:6]=1
Reactant: N#Cc1ccc2ccoc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1ccc2ccoc2c1
Temperature: 50 °C
Yield: 82.9 %

Procedure:
Dissolve benzofuran-6-carbonitrile (0.5 g, 3.28 mmol) in anhydrous THF (10 mL) and add slowly to 1M lithium aluminum hydride in THF (6.56 mL, 6.56 mmol) at ambient temperature. Heat the reaction mixture at 50° C. for 17 h and cool to ambient temperature. Quench the reaction mixture with water until a granular precipitate starts to form and filter through a pad of Celite®g. Evaporate the solvent and purify by SCX chromatography to obtain the title compound as a yellow oil (0.4 g, 79%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18].N1CCC[C@H]1C(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C.[Cu]I>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:10][N:11]([C:14]2[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cccc(I)c1
Reactant: CC(C)(C)OC(=O)NC1CNC1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc(N2CC(NC(=O)OC(C)(C)C)C2)c1
Temperature: 120 °C
Reaction time: 2 h
Yield: 57.2 %

Procedure:
A suspension of 3-tert-butoxycarbonylaminoazetidine (300 mg, 1.74 mmol), ethyl 3-iodobenzoate (721 mg, 2.61 mmol) and copper (I) iodide (66 mg, 0.35 mmol), proline (80 mg, 0.70 mmol) and potassium carbonate (721 mg, 5.22 mmol) in DMSO was stirred at 120° C. for two hours. The reaction solution was diluted with ethyl acetate and then filtered. The filtrate was washed with brine and then dried over anhydrous magnesium sulfate. Following filtration, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=4/1) to obtain 319 mg of the title compound as a milk white solid (57%).
Reaction SMILES: C(OCC)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:12][CH:13]([CH2:18][CH2:19]/[CH:20]=[C:21](\[CH3:28])/[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[CH2:14][C:15](O)=[O:16].C(OCC)(=O)C>O>[CH3:12][CH:13]([CH2:18][CH2:19]/[CH:20]=[C:21](\[CH3:28])/[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[CH2:14][CH2:15][OH:16]
Reactant: CC(C)=CCC/C(C)=C/CCC(C)CC(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)=CCC/C(C)=C/CCC(C)CCO
Temperature: 10 °C

Procedure:
To 150 ml. of anhydrous diethyl ether there was added 1.9 g. of lithium aluminum hydride. To the mixture was dropwise added, under stirring and at 10° C., 11.9 g. of the carboxylic acid compound obtained in Example 3. The resulting mixture was then stirred at room temperature for 1 hour, and then 1 ml. of ethyl acetate and 1 ml. of water were added thereto. The mixture was subsequently washed with water and dried. The solvent was removed by evaporation and the resulting residual oil was purified by silica gel column chromatography to obtain 10.3 g. of the desired oily product.
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16].[C:24](Cl)(=O)C(Cl)=O.CN(C=O)C.CCN(CC)CC>C(Cl)Cl.CO>[F:1][C:2]1[C:10]([C:11]([O:13][CH3:24])=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[Si:14]([CH:18]([CH3:20])[CH3:19])([CH:21]([CH3:23])[CH3:22])[CH:15]([CH3:16])[CH3:17]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(F)c(C(=O)O)ccc21
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(ccn2[Si](C(C)C)(C(C)C)C(C)C)c1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-fluoro-1-triisopropylsilanyl-1H-indole-5-carboxylic acid 22d (prepared using the procedure described in Eur. J. Org. Chem. 2006, 2956) (2.71 g, 8.08 mmol) in dry CH2Cl2 (20 mL) was added oxalyl chloride (0.82 mL, 9.69 mmol) followed by DMF (0.063 mL, 0.81 mmol). The reaction was stirred at rt for 30 min and then concentrated. The residue was dissolved in CH2Cl2 (20 mL) and cooled to 0° C. Et3N (5.6 mL, 40.4 mmol) was added, followed by slow addition of MeOH. The reaction mixture was stirred at 0° C. for 30 min and concentrated. The residue was partitioned between EtOAc and water. The organic layer was concentrated and purified by flash column chromatography (silica gel, 5% EtOAc/hexanes) to give compound 22e.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][N+:7]([O-])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Si]([C:15]#[N:16])(C)(C)C.CN(C)C(Cl)=O>C(Cl)Cl.C(Cl)(Cl)Cl>[CH:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:15]#[N:16])[CH:5]=1)([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)C#N
Reactant: CC(C)c1cc[n+]([O-])cc1
Agent: CN(C)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)c1ccnc(C#N)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirring solution of 139 mg (1.01 mmol) of 4-isopropylpyridine N-oxide in 10 mL of CH2Cl2 at r.t. was added 160 μL (1.20 mmol) of TMSCN. After 5 min., 100 μL (1.09 mmol) of dimethylcarbamyl chloride was added, and the solution was stirred at r.t. for 16 h. The solution was diluted with chloroform and washed with 20 mL of 10% aqueous K2CO3. The layers were separated, and the aqueous layer was extracted 3 times with CHCl3. The combined extracts were dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (30% EtOAc/hexanes) provided 4-isopropylpicolinonitrile with some impurity as a liquid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([NH2:11])=[N:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].CC1C=CC(S(O[CH2:23][C@H:24]2[CH2:28][CH2:27][CH2:26][O:25]2)(=O)=O)=CC=1>[I-].C([N+](CC)(CC)CC)C.CN(C)C=O>[C:1]([C:5]1[CH:6]=[CH:7][C:8](=[NH:11])[N:9]([CH2:23][C@H:24]2[CH2:28][CH2:27][CH2:26][O:25]2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(N)nc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Agent: CC[N+](CC)(CC)CC
Agent: [I-]
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(=N)n(C[C@H]2CCCO2)c1
Temperature: 25 °C

Procedure:
A mixture of Example 59B (0.5 g, 3.3 mmol), (R)-(tetrahydrofuran-2-yl)methyl 4-methyl-benzenesulfonate (0.9 g, 3.6 mmol), and tetraethylammonium iodide (0.4 g, 1.6 mmol) in N,N-dimethylformamide (1.0 mL) was heated at 95° C. for 16 hours. After cooling to ambient temperature, the mixture was quenched with saturated NaHCO3 (10 mL) and extracted with dichloromethane (3×30 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide the title compound. LCMS (APCI+) m/z 235 (M+H)+.