Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1C2C=CC=C(C=O)C=2OCC1.O1C2C=CC=C(C=N)C=2OCC1.C[Mg]Br.[O:28]1[C:33]2[CH:34]=[CH:35][CH:36]=[C:37]([CH:38]([NH2:40])[CH3:39])[C:32]=2[O:31][CH2:30][CH2:29]1.FC(F)(F)C(O)=O.[CH3:48][NH:49][C:50]([C:52]1[CH:57]=[C:56]([O:58][C:59]2[CH:70]=[CH:69][C:62]3[N:63]=[C:64](S(C)=O)[O:65][C:61]=3[CH:60]=2)[CH:55]=[CH:54][N:53]=1)=[O:51]>>[CH3:48][NH:49][C:50]([C:52]1[CH:57]=[C:56]([O:58][C:59]2[CH:70]=[CH:69][C:62]3[N:63]=[C:64]([NH:40][CH:38]([C:37]4[C:32]5[O:31][CH2:30][CH2:29][O:28][C:33]=5[CH:34]=[CH:35][CH:36]=4)[CH3:39])[O:65][C:61]=3[CH:60]=2)[CH:55]=[CH:54][N:53]=1)=[O:51]
Reactant: CNC(=O)c1cc(Oc2ccc3nc(S(C)=O)oc3c2)ccn1
Reactant: CC(N)c1cccc2c1OCCO2
Agent: C[Mg]Br
Agent: N=Cc1cccc2c1OCCO2
Agent: O=Cc1cccc2c1OCCO2
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1cc(Oc2ccc3nc(NC(C)c4cccc5c4OCCO5)oc3c2)ccn1

Procedure:
An amine linked to a resin is reacted with 2,3-dihydro-benzo[1,4]dioxine-5-carbaldehyde, thus giving C-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-methyleneamine. C-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-methyleneamine is derivatized with alkylation at the imino site, such as with methyl magnesium bromide. Other alkylating agents can be used according to the desired molecule. The resulting 1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-ethylamine is cleaved from the resin. An example of a resin-cleaving agent is trifluoroacetic acid (TFA). The resulting 1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-ethylamine can be used for synthesis of a compound of the embodiments. For instance, 1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-ethylamine can be used to react with 4-(2-methanesulfinyl-benzooxazol-6-yloxy)-pyridine-2-carboxylic acid methylamide to form 4-{2-[1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-ethylamino]-benzooxazol-6-yloxy}-pyridine-2-carboxylic acid methylamide.
Reaction SMILES: [H-].[Na+].[Cl-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)C=CC=CC=1.[C:30]1(=[O:42])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]([CH:40]=O)=[N:32][NH:31]1>CCCCCC.CS(C)=O>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12](/[CH:11]=[CH:40]\[C:33]2[C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:30](=[O:42])[NH:31][N:32]=2)[CH:13]=1
Reactant: c1ccc([P+](Cc2cccnc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1n[nH]c(=O)c2ccccc12
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCCCCC
Product: O=c1[nH]nc(/C=C\c2cccnc2)c2ccccc12
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
Under N2 atmosphere, 723 mg NaH (60% in oil; 18.1 mmol) is washed twice with hexane, 21 ml DMSO is added, and the mixture heated for 20 min to 70° C. (gas evolution). After cooling to RT, the mixture is diluted with 15 ml DMSO, 6.71 g (17.2 mmol) triphenyl(pyridin-3-yl-methyl)phosphonium chloride (for preparation, see 1a) is added in portions, and the blackish-yellow solution is stirred for 10 min (Wittig reagent). A second flask is prepared with 3.0 g (17.2 mmol) phthalazin-1(2H)-one-4-carbaldehyde in 39 ml DMSO under an inert gas. The above Wittig reagent is added and a little DMSO is then rinsed in. After stirring for 75 min at RT, the mixture is poured onto water/EtOAc, the aqueous phase separated off and extracted again twice with EtOAc. The organic phases are washed with water and brine, combined and extracted twice with 1 N HCl and then discarded. The acidic aqueous phases are immediately adjusted to alkaline pH with sat. Na2CO3 solution and extracted three times with EtOAc. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated by evaporation. This yields the title compound as an E/Z mixture: TLC (EtOAc) Rf=0.18/0.22; HPLC5-40 tR=9.2/9.6; FAB-MS (M+H)+=250.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:48])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:44]([CH3:47])[CH2:45][CH3:46])[C@H:25]([O:42][CH3:43])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:40][CH3:41])[C@H:35]([C:37](O)=[O:38])[CH3:36])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.[CH3:56][O:57][C:58](=[O:76])[C:59]1[CH:64]=[CH:63][C:62](/[CH:65]=[CH:66]/[C@@H:67]([NH2:75])[CH2:68][C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)=[CH:61][CH:60]=1>>[C:1]([O:5][C:6]([N:8]([CH3:48])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:44]([CH3:47])[CH2:45][CH3:46])[C@H:25]([O:42][CH3:43])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:40][CH3:41])[C@@H:35]([CH3:36])[C:37]([NH:75][C@H:67](/[CH:66]=[CH:65]/[C:62]1[CH:61]=[CH:60][C:59]([C:58]([O:57][CH3:56])=[O:76])=[CH:64][CH:63]=1)[CH2:68][C:69]1[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=1)=[O:38])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:11])[CH3:12])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OC(C)(C)C)C(C)C
Reactant: COC(=O)c1ccc(/C=C/[C@@H](N)Cc2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](/C=C/c1ccc(C(=O)OC)cc1)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OC(C)(C)C)C(C)C

Procedure:
First, N-(tert-butoxycarbonyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-3-{[(2S,3E)-4-[4-(methoxycarbonyl)phenyl]-1-phenylbut-3-en-2-yl}amino)-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide was synthesized by analogy with the synthesis of intermediate 17 by reacting 20 mg (29 μmol) N-(tert-butoxycarbonyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-2-carboxy-1-methoxypropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (intermediate 7) with 12.7 mg (32 μmol) methyl-4-[(1E,3S)-3-amino-4-phenylbut-1-en-1-yl]benzoate trifluoroacetic acid salt (intermediate 16).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([NH2:15])[N:12]=[N:13][CH:14]=1.[Br:16]N1C(=O)CCC1=O>>[Br:16][C:14]1[N:13]=[N:12][C:11]([NH2:15])=[N:10][C:9]=1[C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1nncc(-c2ccc(F)cc2F)n1
Product: Nc1nnc(Br)c(-c2ccc(F)cc2F)n1
Yield: 21.6 %

Procedure:
6-Bromo-5-(2,4-difluorophenyl)-1,2,4-triazin-3-amine (0.13 g, 21%) was prepared from 5-(2,4-difluorophenyl)-1,2,4-triazin-3-amine (0.45 g, 2.1 mmol) and N-bromosuccinimide (0.49 g, 2.80 mmol) according to the general procedure of Preparation 3.
Reaction SMILES: [CH2:1]([S:8][CH2:9][C:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[S:12][C:11]=1[C:25](OCC)=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.Cl>O1CCCC1.CCOCC>[CH2:1]([S:8][CH2:9][C:10]1[CH:14]=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:19][CH:20]=2)[S:12][C:11]=1[CH2:25][OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)cc1CSCc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: OCc1sc(-c2ccc(C(F)(F)F)cc2)cc1CSCc1ccccc1

Procedure:
A solution of ethyl 3-[(benzylthio)methyl]-5-[4-(trifluoromethyl)phenyl]thiophene-2-carboxylate (intermediate 45, 0.87 g) in dry tetrahydrofuran (5 ml) was cooled to 0° C. and 1M lithium aluminium hydride solution in diethyl, ether (0.299 ml) added. The reaction mixture as stirred with cooling for 3 hours. Water (0.5 ml) was added drop-wise followed by 2M hydrochloric acid (0.5 ml), the further water (50 ml), the resulting mixture was extracted twice with ethyl acetate, the extracts were combined, dried over magnesium sulfate and concentrated. The residue was purified by SPE (Si cartridge) eluting initially with cyclohexane:chloroform (1:1) and then chloroform to give the title compound as a white solid.
Reaction SMILES: [C-:1]#[N:2].[K+].Br[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([F:17])([F:16])[F:15])=[O:7].ClCCl.C(O)(=O)C>O.C(O)C>[O:7]=[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([F:17])([F:16])[F:15])[CH2:5][C:1]#[N:2]
Reactant: [C-]#N
Reactant: O=C(CBr)c1ccccc1C(F)(F)F
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Solvent: CC(=O)O
Product: N#CCC(=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
A solution of 26.04 g (0.40 mole) of potassium cyanide in 30 mL of water was added to a stirring solution of 27.00 g (0.10 mole) of 2-bromo-1-(2-trifluoromethyl-phenyl)-ethanone in 500 mL of ethanol. The mixture was stirred at room temperature overnight. Water and dichloromethane were added to the mixture. The mixture was then acidified with acetic acid (pH=5-6). The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Recrystallization of the residue with ether and hexane gave 14.97 g of 3-oxo-3(2-trifluoromethyl-phenyl)-propionitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[N:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22]C(=O)C)=[O:15])=[CH:9][CH:8]=2)=[C:4]([CH3:28])[CH:3]=1>O1CCCC1>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[N:12]=[CH:11][C:10]([NH:13][C:14](=[O:15])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[OH:22])=[CH:9][CH:8]=2)=[C:4]([CH3:28])[CH:3]=1
Reactant: CC(=O)Oc1ccccc1C(=O)Nc1ccc(Oc2ccc(Cl)cc2C)nc1
Solvent: C1CCOC1
Product: Cc1cc(Cl)ccc1Oc1ccc(NC(=O)c2ccccc2O)cn1
Temperature: 22 °C
Reaction time: 0.5 h

Procedure:
Acetic acid 2-(6-(4-chloro-2-methyl-phenoxy)-pyridin-3-ylcarbamoyl)-phenyl ester (304 mg, 0.77 mmol) dissolved in tetrahydrofuran (3.8 mL) was treated with an aqueous lithium hydrozide solution (1.0 M, 3.8 mL, 3.8 mmol). The solution was stirred for 30 minutes at 22° C. then quenched with aqueous saturated NH4Cl. The mixture was diluted with ethyl acetate then the organics were washed with water, 2× saturated NaHCO3, saturated NaCl, dried over Na2SO4 and concentrated in vacuo. MS (m/z): 354/356 (M+H)+; C19H15N2O3Cl requires 354.8.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:7]([F:16])=[CH:8][C:9]([C:12]([O:14]C)=[O:13])=[N:10][CH:11]=2)[CH2:3][CH2:2]1.C1COCC1.[OH-].[Li+].Cl>CO>[CH:1]1([CH2:4][O:5][C:6]2[C:7]([F:16])=[CH:8][C:9]([C:12]([OH:14])=[O:13])=[N:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1cc(F)c(OCC2CC2)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc(F)c(OCC2CC2)cn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 94.7 %

Procedure:
To a solution of methyl 5-(cyclopropylmethoxy)-4-fluoropyridine-2-carboxylate (1.07 g) in a mixed solvent of THF (10 mL) and methanol (1.1 mL) was added 2 M lithium hydroxide aqueous solution (4.75 mL), and the mixture was stirred at room temperature for 20 min. The reaction mixture was allowed to cool to room temperature, and neutralized with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained solid was washed with diethyl ether/hexane to give the title compound (0.950 g).
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[CH3:12][O:13][CH2:14][CH2:15][C:16]1[N:17]([CH2:42][CH2:43][CH3:44])[C:18]2[C:27]3[CH:26]=[CH:25][C:24]([O:28][CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:23][C:22]=3[N+:21]([O-])=[CH:20][C:19]=2[N:41]=1.[OH-].[NH4+:46]>ClCCl>[NH2:46][C:20]1[C:19]2[N:41]=[C:16]([CH2:15][CH2:14][O:13][CH3:12])[N:17]([CH2:42][CH2:43][CH3:44])[C:18]=2[C:27]2[CH:26]=[CH:25][C:24]([O:28][CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:23][C:22]=2[N:21]=1
Reactant: [NH4+]
Reactant: CCCn1c(CCOC)nc2c[n+]([O-])c3cc(OCCCNC(=O)OC(C)(C)C)ccc3c21
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Product: CCCn1c(CCOC)nc2c(N)nc3cc(OCCCNC(=O)OC(C)(C)C)ccc3c21
Reaction time: 0.33 h

Procedure:
p-Toluenesulfonyl chloride (8.0 g, 42 mmol) was added over ten minutes to a stirred mixture of tert-butyl 3-{[2-(2-methoxyethyl)-5-oxido-1-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}propylcarbamate (19.3 g, 42.0 mmol) in dichloromethane (300 mL) and concentrated ammonium hydroxide (300 mL) at 7° C. The mixture was allowed to stir for 20 minutes, then the cooling bath was removed and the mixture was allowed to stir at ambient temperature for 2 hours. The layers were separated and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure. Recrystallization from acetonitrile afforded 12.0 g of tert-butyl 3-{[4-amino-2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}propylcarbamate as flocculent white crystals, mp 133.5-135° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=1)C1C=CC=CC=1>O1CCCC1.CO.[Pd]>[CH2:21]([O:20][CH:15]([C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=1)[C:16]([F:17])([F:18])[F:19])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCOC(c1ccc(OCc2ccccc2)cc1)C(F)(F)F
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCOC(c1ccc(O)cc1)C(F)(F)F
Reaction time: 8 h
Yield: 98.9 %

Procedure:
1.1 g (3 mmol) of the product (9-1) of Preparation Example 2 was dissolved in a mixture of 80 ml of tetrahydrofuran and 20 ml of methanol, and the solution was added with 0.2 g of 10% Pd/C and stirred vigorously under hydrogen pressure of 1-1.2 atm. for 8 hours. After the reaction, Pd/C was filtered out and the filtrate was concentrated to obtain 0.82 g of (+)-4-(1-hexyloxy-2,2,2-trifluoroethyl)phenol (3-1). Yield: 99%; [α]D20 =+44.0° (c=1, CHCl3).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[O:12][C:7]1([CH2:11][CH2:10][O:9][CH2:8]1)[CH2:6][C:5]2=O.[C:17](=[N:23][Si](C)(C)C)=[N:18][Si](C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[O:12][C:7]1([CH2:11][CH2:10][O:9][CH2:8]1)[CH2:6]/[C:5]/2=[N:23]\[C:17]#[N:18]
Reactant: O=C1CC2(CCOC2)Oc2ccc(Br)cc21
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#C/N=C1\CC2(CCOC2)Oc2ccc(Br)cc21
Reaction time: 1 h
Yield: 100.2 %

Procedure:
To a solution of 6-bromo-4′,5′-dihydro-2′H-spiro[chroman-2,3′-furan]-4-one (206 mg, 0.731 mmol) in anhydrous DCM (6 mL) was added TiCl4 (281 mg, 1.48 mmol) dropwise within 15 minutes at room temperature and resulting mixture was stirred for 1 h. To this mixture was added N,N′-methanediylidenebis(1,1,1-trimethylsilanamine) (300 mg, 1.61 mmol). The resulting mixture was stirred for another 18 hours after addition. The reaction mixture was poured into water-ice and extracted with DCM. The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated to give crude product (225 mg, 100%), which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[C:5]([N+:10]([O-])=O)[C:3]=1[NH2:4].[H][H]>[Ni].C(O)C>[Cl:1][C:2]1[C:3]([NH2:4])=[C:5]([NH2:10])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: Nc1c([N+](=O)[O-])ccc(Cl)c1Cl
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: Nc1ccc(Cl)c(Cl)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
2,3-Dichloro-6-nitroaniline (20.11 g, 97.14 mmol), Raney nickel (Aldrich, Milwaukee, slurry in water, 4.78 g wet), and ethanol (250 mL) were combined in an autoclave which was presssurized to 150 psig with hydrogen. The resulting reaction mixture was allowed to stir at rt overnight. The mixture was then filtered through a pad of Celite, which was subsequently washed with several portions of methanol, and the solvents were removed by rotary evaporation to leave a dark brown solid. The solid was slurried in hexanes and was collected on a Büchner funnel to afford 16.31 g (95%) of a brown solid. MS (EI): m/z 177.0 (M+H); 1H NMR (DMSO-d6) δ: 6.60 (d, J=8.3 Hz, 1H, ArH), 6.49 (d, J=8.4 Hz, 1H, ArH), 4.98 (br s, 4H, overlapping NH2).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[NH:14][CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.[H-].[Na+].[C:21]([O:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35]Br)=[CH:30][CH:29]=1)(=[O:23])[CH3:22]>CN(C=O)C>[C:21]([O:24][CH2:25][CH2:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:34][CH2:35][N:14]2[CH2:13][C@@H:12]([C:10]3[CH:9]=[CH:8][C:6]4[O:7][C:2]([CH3:18])([CH3:1])[O:3][CH2:4][C:5]=4[CH:11]=3)[O:16][C:15]2=[O:17])=[CH:32][CH:33]=1)(=[O:23])[CH3:22]
Reactant: CC1(C)OCc2cc([C@@H]3CNC(=O)O3)ccc2O1
Reactant: CC(=O)OCCOc1ccc(CCBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCCOc1ccc(CCN2C[C@@H](c3ccc4c(c3)COC(C)(C)O4)OC2=O)cc1
Reaction time: 1 h
Yield: 44.8 %

Procedure:
(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (651 mg) in DMF (15 mL) was treated with sodium hydride (84 mg) under nitrogen and stirred for 1 h. A solution of 2-[4-(2-bromoethyl)phenoxy]ethyl acetate (500 mg) in DMF (5 mL) was added and the reaction mixture was stirred for a further 2 h. This was then concentrated in vacuo and the residue was taken up in EtOAc, washed with water, brine and dried (MgSO4). The solution was concentrated in vacuo and the residue was purified by chromatography (Biotage, 90 g) eluting with cyclohexane-EtOAc (2:1) to give the title compound (355 mg). LCMS RT=3.26 min.
Reaction SMILES: [ClH:1].O1CCOCC1.[CH3:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[N:15]1[CH2:19][CH2:18][N:17]([C:20]2[CH:36]=[CH:35][C:23]3[N:24](COCC[Si](C)(C)C)[N:25]=[N:26][C:22]=3[CH:21]=2)[C:16]1=[O:37].CO>C(Cl)Cl>[ClH:1].[NH:24]1[C:23]2[CH:35]=[CH:36][C:20]([N:17]3[CH2:18][CH2:19][N:15]([C:10]4[CH:11]=[N:12][CH:13]=[CH:14][C:9]=4[CH3:8])[C:16]3=[O:37])=[CH:21][C:22]=2[N:26]=[N:25]1
Reactant: Cc1ccncc1N1CCN(c2ccc3c(c2)nnn3COCC[Si](C)(C)C)C1=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1ccncc1N1CCN(c2ccc3[nH]nnc3c2)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.4 %

Procedure:
Dioxane HCl (10 ml) was added to 1-(4-methyl-pyridin-3-yl)-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzotriazol-5-yl]-imidazolidin-2-one (I-141a: 350 mg, 0.78125 mmol) and the resulting mixture was stirred room temperature for 12 hours. The reaction was monitored by TLC (10% MeOH in DCM). The reaction mixture was concentrated and washed with ether. The solid formed was collected and dried under reduced pressure to afford 230 mg of the product (89.4% yield).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]#[C:11][CH2:12][OH:13].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.[OH-].[K+]>CCOCC>[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20]([O:13][CH2:12][C:11]#[C:10][CH2:9][CH2:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: OCC#CCCOC1CCCCO1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)OCC#CCCOC2CCCCO2)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 99.1 %

Procedure:
A solution of alcohol 8 (6.16 g, 33.5 mmol) and p-toluenesulphonyl chloride (7.36 g, 38.5 mmol) in dry ether (80 mL) was cooled to -10°. Powdered KOH (25 g, 446 mmol) was added in 5 g portions over 20 min. The resulting suspension was stirred at 0° for 45 min, poured into ice-water (200 mL) and extracted with ether (3×100 mL). The combined ether solutions were washed with brine, dried (MgSO4), and concentrated in vacuo. Final traces of solvent were removed by pumping for 6 hr at 0.1 mmHg, yielding 11.23 g of 9 (99%). This was used without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH2:8][C:9]([C:12]([OH:14])=O)=[N:10][N:11]=2)[CH:2]=1.[NH2:15][CH2:16][CH2:17][N:18]1[CH:22]=[CH:21][C:20]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([CH3:31])[CH:24]=2)=[N:19]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>>[C:27]([C:26]1[CH:29]=[CH:30][C:23]([C:20]2[CH:21]=[CH:22][N:18]([CH2:17][CH2:16][NH:15][C:12]([C:9]3[NH:10][N:11]=[C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH:8]=3)=[O:14])[N:19]=2)=[CH:24][C:25]=1[CH3:31])#[N:28]
Reactant: Cc1cc(-c2ccn(CCN)n2)ccc1C#N
Reactant: O=C(O)C1=NN=C(c2cccnc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2ccn(CCNC(=O)c3cc(-c4cccnc4)n[nH]3)n2)ccc1C#N
Yield: 63.8 %

Procedure:
The title compound was prepared using the method of Example 31 using 5-pyridin-3-yl-4H-pyrazole-3-carboxylic acid (0.46 g; 2.43 mmol), 4-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-2-methylbenzonitrile (0.50 g; 2.21 mmol), HOBt (0.45 g; 3.31 mmol), EDCI (0.64 g; 3.31 mmol) and 0.58 ml (3.31 mmol) of DIPEA as starting materials. After workup the product was precipitated out from DCM to give 0.56 g (64%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 3.67-3.76 (m, 2H), 4.33-4.41 (m, 2H), 6.85 (d, 1H), 7.22 (s, 1H), 7.49 (dd, 1H), 7.74-7.82 (m, 2H), 7.83 (d, 1H), 7.88 (broad s, 1H), 8.10-8.18 (m, 1H), 8.44-8.58 (m, 2H), 9.00 (broad s, 1H), 13.82 (s, 1H).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[O:21][CH2:20][CH2:19][CH2:18]3)O1.Br[C:27]1[C:28]2[C:45]([CH3:46])=[CH:44][CH:43]=[CH:42][C:29]=2[S:30][C:31]=1[CH:32]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:33]([O:35][CH3:36])=[O:34].CN(C)C=O>O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[C:38]([O:37][CH:32]([C:31]1[S:30][C:29]2[CH:42]=[CH:43][CH:44]=[C:45]([CH3:46])[C:28]=2[C:27]=1[C:15]1[CH:24]=[CH:23][C:22]2[O:21][CH2:20][CH2:19][CH2:18][C:17]=2[CH:16]=1)[C:33]([O:35][CH3:36])=[O:34])([CH3:41])([CH3:40])[CH3:39]
Reactant: COC(=O)C(OC(C)(C)C)c1sc2cccc(C)c2c1Br
Reactant: CC1(C)OB(c2ccc3c(c2)CCCO3)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(OC(C)(C)C)c1sc2cccc(C)c2c1-c1ccc2c(c1)CCCO2
Temperature: 100 °C
Yield: 53.6 %

Procedure:
Under a nitrogen atmosphere, sodium carbonate (33 mg, 0.3 mmol), palladium tetrakis(triphenylphosphine) (35 mg, 0.03 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman (78 mg, 0.3 mmol) were added to a solution of methyl (3-bromo-4-methyl-benzo[b]thiophen-2-yl)-tert-butoxy-acetate (23i) (100 mg, 0.28 mmol) in a mixture of water (1 mL) and N,N(-dimethylformamide (3 mL). The mixture was heated at 100° C. for 1 hour. The mixture was then cooled at room temperature, concentrated in vacuo and water (30 mL) was added. The aqueous layer was extracted with ethyl acetate (2×30 mL). The organic layer was washed with brine (30 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 90/10) to afford the desired product (23j) as a white solid (65 mg, 0.15 mmol, 57%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O-:8])=[O:7].[Na+].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CC(C)=O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7]
Reactant: O=C([O-])CCCCO
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(CCCCO)OCc1ccccc1
Temperature: 45 °C
Yield: 176.2 %

Procedure:
To a suspension of 569 mg (4.06 mmol) of sodium 5-hydroxypentanoate 69 in 3 mL of acetone was added 1.39 g (0.97 mL, 8.11 mmol, 2.0 equiv) of benzyl bromide and 65 mg (0.203 mmol, 0.05 equiv) of tetrabutylammonium bromide. The mixture was heated at 45° C. for 24 hours, cooled, and concentrated. The residue was dissolved in 200 mL of ethyl acetate, washed with 50 mL portions of 1N aqueous sodium bisulfate, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated to give 1.49 g of a pale yellow oil. Purification by MPLC (Lobar C-column, 45% ethyl acetate/hexane) have 641 mg (76%) of the title compound as an oil: 1H NMR (300 MHz, CDCl3) δ7.38-7.26 (m, 5H), 5.12 (s, 2H), 3.64 (t, 2H, J=6.3 Hz), 2.41 (t, 2H, J=7.2 Hz), 1.80-1.71 (m, 2H), 1.64-1.54 (m, 3H).