Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6]=1[CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:24][CH2:23]1)=[O:4].[ClH:34]>>[ClH:34].[ClH:34].[N:28]1([CH:25]2[CH2:26][CH2:27][N:22]([CH2:21][C:6]3[C:7]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)=[N:8][C:9]4[C:14]([C:5]=3[C:3]([OH:4])=[O:2])=[CH:13][CH:12]=[CH:11][CH:10]=4)[CH2:23][CH2:24]2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: COC(=O)c1c(CN2CCC(N3CCCCC3)CC2)c(-c2ccccc2)nc2ccccc12
Agent: Cl
Product: O=C(O)c1c(CN2CCC(N3CCCCC3)CC2)c(-c2ccccc2)nc2ccccc12

Procedure:
3.5 g (7.9 mmol) of 3-[1,4′]bipiperidinyl-1′-ylmethyl-2-phenyl-quinoline-4-carboxylic acid methyl ester (compound of Description 5) and 50 ml of 6N HCl are refluxed for 1.5 h and then concentrated to dryness. The residue was triturated in acetone. This process was re-applied twice to the solid thus obtained affording, after drying in vacuo, 4.5 g of the title compound as a crude dihydrochloride used without further purification in the next step.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH:12]1[CH2:17][CH2:16][CH:15]([C:18]([O:20]CC)=[O:19])[CH2:14][CH2:13]1.C(N(CC)CC)C>C(Cl)Cl>[CH2:5]([O:4][C:2]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=[O:19])[CH2:14][CH2:13]1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)C1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 5 °C
Reaction time: 18 h
Yield: 77 %

Procedure:
Benzyl chloroformate (8.5 g) was added dropwise to a stirred mixture of ethyl piperidine-4-carboxylate (7.85 g), triethylamine (6.95 ml) and methylene chloride (50 ml) which had been cooled to 5° C. The mixture was stirred at ambient temperature for 18 hours. The mixture was partitioned between ethyl acetate and 2N aqueous hydrochloric acid. The organic phase was washed with water and with brine, dried (MgSO4) and evaporated. The residue was dissolved in methanol (100 ml) and 2N aqueous sodium hydroxide (125 ml) was added. The mixture was stirred at ambient temperature for 1 hour. The mixture was concentrated by evaporation and the residue was partitioned between diethyl ether and water. The aqueous phase was acidified to pH 3 by the addition of concentrated hydrochloric acid and the mixture was extracted with ethyl acetate. The organic extract was washed with water, dried (HgSO4) and evaporated to give 1-benzyloxycarbonylpiperidine-4-carboxylic acid (10.1 g).
Reaction SMILES: BrCCBr.C[Si](Cl)(C)C.[CH3:10][O:11][C:12](=[O:21])/[C:13](/I)=[CH:14]\[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:41][C:42]1[CH:47]=[C:46](I)[CH:45]=[CH:44][C:43]=1[N:49]1[C:53]([CH3:54])=[N:52][N:51]=[N:50]1.[Cl-].[NH4+]>O1CCCC1.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH3:10][O:11][C:12](=[O:21])/[C:13](/[C:46]1[CH:45]=[CH:44][C:43]([N:49]2[C:53]([CH3:54])=[N:52][N:51]=[N:50]2)=[C:42]([F:41])[CH:47]=1)=[CH:14]/[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Cc1nnnn1-c1ccc(I)cc1F
Reactant: COC(=O)/C(I)=C\C1CCCC1
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: BrCCBr
Solvent: C1CCOC1
Product: COC(=O)/C(=C/C1CCCC1)c1ccc(-n2nnnc2C)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 69 %

Procedure:
A mixture of zinc dust (650 mg, 10 mmol, Aldrich, −325 mesh) and dry tetrahydrofuran (1 mL) under argon was treated with 1,2-dibromoethane (187 mg, 1 mmol). The zinc suspension was then heated with a heat gun to ebullition, allowed to cool, and heated again. This process was repeated three times to make sure the zinc dust was activated. The activated zinc dust suspension was then treated with trimethylsilyl chloride (108 mg, 1 mmol), and the suspension was stirred for 15 min at 25° C. The reaction mixture was then treated dropwise with a solution of (E)-3-cyclopentyl-2-iodo-acrylic acid methyl ester (2.21 g, 7.5 mmol) in dry tetrahydrofuran (3 mL) over 3 min. The resulting reaction mixture was then stirred at 40-45° C. for 1 h and then stirred overnight at 25° C. The reaction mixture was then diluted with dry tetrahydrofuran (5 mL), and the stirring was stopped to allow the excess zinc dust to settle down (2 h). In a separate reaction flask, bis(dibenzylideneacetone)palladium(0) (90 mg, 0.16 mmol) and triphenylphosphine (160 mg, 0.6 mmol) in dry tetrahydrofuran (10 mL) was stirred at 25° C. under argon for 10 min and then treated with 1-(2-fluoro-4-iodo-phenyl)-5-methyl-1H-tetrazole (1.52 g, 5 mmol) and the freshly prepared zinc compound in tetrahydrofuran. The resulting brick red solution was stirred at 25° C. over the weekend and then heated at 40-45° C. for 4 h. The reaction mixture was cooled to 25° C. and then poured into a saturated aqueous ammonium chloride solution (50 mL), and the organic compound was extracted into ethyl acetate (3×50 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 4/1 to 1/1 hexanes/ethyl acetate) afforded (E)-3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-acrylic acid methyl ester (1.14 g, 68%) as a light yellow solid: mp 111-114° C.; EI-HRMS m/e calcd for C17H19FN4O2 (M+) 330.1492, found 330.1493.
Reaction SMILES: [S:1]1[C:5]2[C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.C1(C)C=CC=CC=1.S(Cl)([Cl:22])=O>CN(C)C=O>[S:1]1[C:5]2[C:6]([C:10]([Cl:22])=[O:12])=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: O=C(O)c1cccc2nnsc12
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccc2nnsc12
Temperature: 85 °C

Procedure:
290 g of benzo-1,2,3-thiadiazole-7-carboxylic acid are suspended in 1.6 I of toluene, 3.5 ml of dimethylformamide and 129 ml of thionyl chloride are added and the mixture is stirred at 80-90° C., the suspension turning into a solution as the release of gas progresses. When the reaction has ended, the solution is cooled and filtered over a little Hyflo, the residue is rinsed with toluene and the filtrate is evaporated. 297 g (93%) of crude acid chloride, which can be further reacted directly, result.
Reaction SMILES: [N+](=[CH2:3])=[N-].[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH:17]([S:19]([CH2:21][C:22]([OH:24])=[O:23])=[O:20])[CH3:18])=[CH:13][CH:12]=1>CCOCC>[CH3:3][O:23][C:22](=[O:24])[CH2:21][S:19]([CH:17]([C:14]1[CH:15]=[CH:16][C:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[F:4])=[CH:12][CH:13]=1)[CH3:18])=[O:20]
Reactant: CC(c1ccc(-c2ccccc2F)cc1)S(=O)CC(=O)O
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)CS(=O)C(C)c1ccc(-c2ccccc2F)cc1

Procedure:
A solution of 320 mgm (7.6 millimols) of diazomethane (prepared from 2.14 gm of p-toluenesulfonyl-methylnitrosoamide in 30 ml of ether and 0.4 gm of potassium hydroxide in 10 ml of 96% ethanol and subsequent distillation) was added, while stirring, to a suspension of 2.3 gm (7.5 millimols) of [1-(2'-fluoro-4-biphenylyl)-ethylsulfinyl]-acetic acid (m.p.: 164° - 165° C) in 20 ml of ether. The acid dissolved, accompanied by nitrogen evaluation. After the reaction was finished, the mixture was evaporated, and the residue was recrystallized from benzene cyclohexane (1/5). Yield: 2.0 gm (83.5% of theory); m.p.: 75° - 77° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27].ClCCl>>[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27].[C:18]1([C:11]2([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)C1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1(c2ccccc2)CCNCC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Methyl 1-t-butoxycarbonyl-4-phenylpiperidine-4-carboxylate (5.0 g) was dissolved in trifluoroacetic acid-dichloromethane (10%, 100 mL) and the mixture was stirred at room temperature for 6 h. The solvent was evaporated under reduced pressure to give the title compound as a yellow gum (5.2 g), δH (CDCl3) 2.11-2.20 (2H, m), 2.64-2.68 (2H, m), 3.03-3.13 (2H, m), 3.38-3.44 (2H, m), 3.63 (3H, s), 7.18-7.33 (5H, m), and 7.98 (1H, br s).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Br:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4](O)=[O:5].[CH:13]([NH2:15])=O>>[Br:11][C:10]1[CH:9]=[C:8]([Cl:12])[CH:7]=[C:3]2[C:2]=1[N:1]=[CH:13][NH:15][C:4]2=[O:5]
Reactant: NC=O
Reactant: Nc1c(Br)cc(Cl)cc1C(=O)O
Product: O=c1[nH]cnc2c(Br)cc(Cl)cc12

Procedure:
8-Bromo-6-chloro-4(3H) quinazolinone was prepared from 2-amino-3-bromo-5-chlorobenzoic acid (10 g, 40 mmol). The acid was heated in excess formamide (50 mL) at reflux overnight. The mixture was cooled and quenched with water. The solid that formed was washed with acetonitrile, 6.7 g crude (65%); MS: 260.8 (M+H)+
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:10][CH2:9][C@@H:8]([CH2:11][C:12]3[N:13]([C:18]4[CH:23]=[CH:22][C:21](B5OC(C)(C)C(C)(C)O5)=[CH:20][CH:19]=4)[C:14](=[O:17])[NH:15][N:16]=3)[CH2:7]2)=[O:5])[CH2:3][CH2:2]1.Br[C:34]1[CH:35]=[C:36]([F:43])[C:37]2[O:41][CH:40]=[CH:39][C:38]=2[CH:42]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[CH:1]1([C:4]([N:6]2[CH2:10][CH2:9][C@@H:8]([CH2:11][C:12]3[N:13]([C:18]4[CH:23]=[CH:22][C:21]([C:34]5[CH:35]=[C:36]([F:43])[C:37]6[O:41][CH:40]=[CH:39][C:38]=6[CH:42]=5)=[CH:20][CH:19]=4)[C:14](=[O:17])[NH:15][N:16]=3)[CH2:7]2)=[O:5])[CH2:3][CH2:2]1
Reactant: Fc1cc(Br)cc2ccoc12
Reactant: CC1(C)OB(c2ccc(-n3c(C[C@@H]4CCN(C(=O)C5CC5)C4)n[nH]c3=O)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3cc(F)c4occc4c3)cc2)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
A solution of 5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (0.297 mmol) in dioxane (1.5 mL) was treated with 5-bromo-7-fluoro-1-benzofuran (0.297 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane adduct (17 mg), and 2M aq potassium carbonate (0.89 mmol). The reaction mixture was purged with nitrogen, sealed, and stirred at 100° C. overnight. The reaction mixture was cooled to room temperature and was diluted with water (50 mL). The aqueous layer was acidified to pH˜4 using 1N aq HCl and was extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by reverse phase HPLC (20-50% acetonitrile/water+0.1% NH4OH) to afford the title compound as a beige solid (47%). MS(ES)+ m/e 447.1 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([C:7]1[CH:8]=[C:9]([CH:22]=[C:23]([CH2:25]Br)[CH:24]=1)[C:10]([NH:12][C@@H:13]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[CH3:14])=[O:11])[S:3]([CH3:6])(=[O:5])=[O:4].[NH2:27][C:28]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:29][OH:30].NC(CC1C=CC=CC=1)(CCCC)COCC1C=C(C=C(N(C)S(C)(=O)=O)C=1)C(N[C@@H](C1C=CC(F)=CC=1)C)=O>>[NH2:27][C:28]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:29][O:30][CH2:25][C:23]1[CH:22]=[C:9]([CH:8]=[C:7]([N:2]([CH3:1])[S:3]([CH3:6])(=[O:5])=[O:4])[CH:24]=1)[C:10]([NH:12][C@@H:13]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[CH3:14])=[O:11]
Reactant: C[C@@H](NC(=O)c1cc(CBr)cc(N(C)S(C)(=O)=O)c1)c1ccc(F)cc1
Reactant: NC(CO)(Cc1ccccc1)Cc1ccccc1
Agent: CCCCC(N)(COCc1cc(C(=O)N[C@H](C)c2ccc(F)cc2)cc(N(C)S(C)(=O)=O)c1)Cc1ccccc1
Product: C[C@@H](NC(=O)c1cc(COCC(N)(Cc2ccccc2)Cc2ccccc2)cc(N(C)S(C)(=O)=O)c1)c1ccc(F)cc1

Procedure:
Prepared from 3-(N-methyl-N-(methylsulfonyl)amino)-5-(bromomethyl)-N-((R)-1-(4-fluorophenyl)ethyl)benzamide and 2-amino-2-benzyl-3-phenylpropan-1-ol using a similar procedure as described for the preparation of 3-{[(2-amino-2-benzylhexyl)oxy]methyl}-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[methyl(methyl sulfonyl)amino]benzamide (Example 4). HRMS ES calculated for C34H38FN3O4S: 604.2640, found: 604.2641.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1([C:23](=[O:37])[NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32](=[O:36])[N:33]([CH3:35])[CH3:34])[CH:26]=2)[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([O-])(O)=O.[Na+]>C(O)(C)C>[CH3:34][N:33]([CH3:35])[C:32](=[O:36])[O:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([NH:24][C:23]([C:10]2([CH2:9][O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)=[O:37])[CH:26]=1
Reactant: CN(C)C(=O)Oc1cccc(NC(=O)C2(COCc3ccccc3)CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CN(C)C(=O)Oc1cccc(NC(=O)C2(COCc3ccccc3)CCNCC2)c1
Reaction time: 2 h
Yield: 99.2 %

Procedure:
tert-Butyl 4-(benzyloxymethyl)-4-(3-(dimethylcarbamoyloxy)phenylcarbamoyl)piperidine-1-carboxylate from step C (0.25 g, 0.49 mmol) was dissolved in isopropanol, treated with 4 N HCl, and stirred for two hours. The reaction mixture was adjusted to pH 7-8 with NaHCO3, and then extracted with Et2O. The organic extracts were concentrated under vacuum to give the title compound (0.2 g, 100%). MS (ES+) [M+H]+=412.
Reaction SMILES: C([O:5][C:6](=[O:17])/[CH:7]=[CH:8]/[C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][N:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:15]([C:12]1[CH:13]=[CH:14][C:9](/[CH:8]=[CH:7]/[C:6]([OH:17])=[O:5])=[N:10][CH:11]=1)=[O:16]
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C=O)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=Cc1ccc(/C=C/C(=O)O)nc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 143.5 %

Procedure:
A mixture of (E)-3-(5-formyl-pyridin-2-yl)-acrylic acid tert-butyl ester (described in Example 11 STEP A-D, 250 mg, 1.07 mmol) and TFA (1 ml) in DCM (4 ml) was stirred at room temperature for 6 h. The solvent was then removed in vacuo and the solid was triturated with Et2O to give 272 mg of (E)-3-(5-formyl-pyridin-2-yl)-acrylic acid as its trifluoroacetate salt.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[C:5]([OH:7])=O.[CH:17]1([C:23]2([CH2:29][N:30]3[CH:34]=[N:33][CH:32]=[N:31]3)[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.CN(C)CCCN=C=NCC.[Cl-].[NH4+]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:16])[CH:4]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[C:5]([N:26]1[CH2:25][CH2:24][C:23]([CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)([CH2:29][N:30]2[CH:34]=[N:33][CH:32]=[N:31]2)[CH2:28][CH2:27]1)=[O:7]
Reactant: c1ncn(CC2(C3CCCCC3)CCNCC2)n1
Reactant: COC(=O)C(Cc1ccc(F)cc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc(F)cc1)C(=O)N1CCC(Cn2cncn2)(C2CCCCC2)CC1
Reaction time: 8 h

Procedure:
To a solution of 2-(4-fluoro-benzyl)-malonic acid monomethyl ester, 56, (47.5 mg, 0.21 mmol), 4-cyclohexyl-4-[1,2,4]triazol-1-ylmethyl-piperidine, 18, (50 mg, 0.20 mmol), 1-hydroxybenzotriazole (54 mg, 0.40 mmol), 4-methylmorpholine (88 □l, 0.80 mmol) in N,N-dimethylformamide (7 mL) is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (50 mg, 0.26 mmol). The reaction mixture is stirred overnight and then aqueous ammonium chloride is added. The reaction is extracted with ethyl acetate, and the organics are separated dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product is purified by preparative HPLC to afford the desired compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([C:25]4[CH:26]=[CH:27][C:28]([O:34][CH3:35])=[C:29]([CH:33]=4)[C:30]([OH:32])=O)=[CH:18][C:11]=3[C:12]=2[C:13]2[NH:14][CH:15]=[CH:16][N:17]=2)=[CH:4][CH:3]=1.Cl.[N:37]1[CH:42]=[CH:41][CH:40]=[N:39][C:38]=1[C:43]1([NH2:46])[CH2:45][CH2:44]1.C(N(CC)CC)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([C:25]4[CH:26]=[CH:27][C:28]([O:34][CH3:35])=[C:29]([CH:33]=4)[C:30]([NH:46][C:43]4([C:38]5[N:39]=[CH:40][CH:41]=[CH:42][N:37]=5)[CH2:45][CH2:44]4)=[O:32])=[CH:18][C:11]=3[C:12]=2[C:13]2[NH:14][CH:15]=[CH:16][N:17]=2)=[CH:6][CH:7]=1
Reactant: NC1(c2ncccn2)CC1
Reactant: COc1ccc(-c2cc3c(-c4ncc[nH]4)c(-c4ccc(F)cc4)oc3cc2[N+](=O)[O-])cc1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2cc3c(-c4ncc[nH]4)c(-c4ccc(F)cc4)oc3cc2[N+](=O)[O-])cc1C(=O)NC1(c2ncccn2)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-(2-(4-fluorophenyl)-3-(1H-imidazol-2-yl)-6-nitrobenzofuran-5-yl)-2-methoxybenzoic acid (300 mg, 0.634 mmol) and 1-(pyrimidin-2-yl)cyclopropanamine hydrochloride (131 mg, 0.760 mmol) in DMF (15 mL) at room temperature under a nitrogen atmosphere was added triethylamine (TEA) (0.442 mL, 3.17 mmol). The mixture was cooled to 0° C. and added with BOP reagent (420 mg, 0.951 mmol). The reaction mixture was then stirred at rt overnight, and then diluted with water. The solid was filtered and dried under suction to obtain the title compound as a light yellow solid. Yield: 350 mg (94%). 1H NMR (400 MHz, DMSO-d6) δ ppm: 12.52 (br. s, 1H) 8.93 (s, 1H) 8.70 (s, 2 H) 8.49 (s, 1H) 8.00-8.14 (m, 2H) 7.88 (d, J=2.51 Hz, 1H) 7.74 (s, 1H) 7.52 (dd, J=8.53, 2.51 Hz, 1H) 7.34-7.43 (m, 4H) 7.20 (s, 1H) 3.89 (s, 3H) 1.54-1.68 (m, 2H) 1.36-1.49 (m, 2H). LCMS: (ES+) m/z=591.39 (M+H)+; Column—ACQUITY UPLC BEH C8 (50×2.1 mm; 1.7 μm); Mphase A: 5 mM Ammonium Acetate:MeCN (95:5); Mphase B: 5 mM Ammonium Acetate: MeCN (5:95)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].OS(O)(=O)=O.[CH3:18]O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:18])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CO
Reactant: O=C(O)Cc1ccc(O)c(Cl)c1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(O)c(Cl)c1
Yield: 96 %

Procedure:
2-(3-Chloro-4-hydroxyphenyl)acetic acid (5.0 g, 26.8 mmol) was dissolved in 30 mL of MeOH and H2SO4 (0.744 ml, 13.4 mmol) was added dropwise at ambient temperature. The reaction was refluxed for four hours and then concentrated in vacuo. The residue was diluted with 150 mL of EtOAc and washed sequentially with saturated NaHCO3, water, and brine, dried over H2SO4, and concentrated in vacuo to provide methyl 2-(3-chloro-4-hydroxyphenyl)acetate (5.16 g, 96.0% yield) as a semi-opaque thick oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:23])=[C:4]([C:13]([NH:15][C:16]([CH2:21][OH:22])([CH2:19][OH:20])[CH2:17][OH:18])=[O:14])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.C(O[C:33](=[O:35])[CH3:34])(=O)C>>[C:7]([NH:1][C:2]1[C:3]([I:23])=[C:4]([C:13]([NH:15][C:16]([CH2:17][O:18][C:33](=[O:35])[CH3:34])([CH2:19][O:20][C:17](=[O:18])[CH3:16])[CH2:21][O:22][C:13](=[O:14])[CH3:4])=[O:14])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([OH:9])=[O:8])(=[O:8])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1c(I)c(C(=O)O)c(I)c(C(=O)NC(CO)(CO)CO)c1I
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1c(I)c(C(=O)O)c(I)c(C(=O)NC(COC(C)=O)(COC(C)=O)COC(C)=O)c1I
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Amino-2,4,6-triiodo-N-[tris(hydroxymethyl)methyl]isophthalamic acid (50.0 g., 0.076 mol.) was added in one portion to a stirred solution of sulfuric acid (0.36 ml.) in acetic anhydride (136.0 ml.). The temperature of the reaction mixture rose briefly to 82° and dissolution was effected. As the reaction mixture cooled to room temperature, the product began to precipitate at 47° and the mixture was diluted with toluene (100 ml.). The mixture was stirred at room temperature for 1 hr., and filtered. The filter cake was washed with toluene (50 ml.), dried, dissolved in hot methanol (300 ml.), and treated with charcoal (6 g.). After removal of the charcoal, the product precipitated from the cold station and was collected and dried (70° ) to give white crystalline 5-acetamido-2,4,6-triiodo-N-[tris(acetoxymethyl)methyl]-isophthalamic acid (38.8 g.) m.p. 248-251 (dec., uncorr.). (Yield, 62%). This material was pure by TLC analysis (benzene, 2-butanone, 88% formic acid; 60:25:20) and its structure was confirmed by IR and NMR. Anal. Calcd. for C20H21I3N2O10 : C, 28.94; H, 2.55; N.E., 830.12. Found: C, 29.02; H, 2.70; N.E., 825.6.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[CH2:5]([C:7]1[N:12]=[C:11](Cl)[C:10]([N+:14]([O-:16])=[O:15])=[C:9]([Cl:17])[N:8]=1)[CH3:6]>C(O)C>[CH2:5]([C:7]1[N:8]=[C:9]([Cl:17])[C:10]([N+:14]([O-:16])=[O:15])=[C:11]([NH:4][CH:1]2[CH2:3][CH2:2]2)[N:12]=1)[CH3:6]
Reactant: CCc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Reactant: NC1CC1
Solvent: CCO
Product: CCc1nc(Cl)c([N+](=O)[O-])c(NC2CC2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.3 %

Procedure:
28.6 g (0.5 mole) of cyclopropylamine are added dropwise ar -50° C to 55.5 g (0.25 mole) of 2-ethyl-4,6-dichloro-5-nitro-pyrimidine in 1 liter of ethanol. The reaction mixture is stirred for 3 hours at room temperature and then cooled to -40° C. The crystalline precipitate that has formed is filtered off and dried. Yield: 21 g of 2-ethyl-4-chloro-5-nitro-6-cyclopropylamino-pyrimidine of m.p. 61°-62° C. A Further 22 g of 2-ethyl-4-chloro-5-nitro-6-cyclopropylamino-pyrimidine of m.p. 61°-62° C are obtained by evaporating the filtrate, suspending the residue in water, extracting with ether, drying the ethereal extracts over MgSO4 and evaporating them.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:11][O:12][CH3:13])[CH:7]=[CH:8][CH:9]=1.[Cl:22][C:23]1[N:28]=[C:27](Cl)[C:26](=[O:30])[N:25]([CH2:31][C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[C:24]=1[CH3:42].C(N(CC)CC)C>C(OCC)(=O)C>[C:17]([O:16][C:15]([NH:14][CH:10]([C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[CH2:3][CH2:2][NH:1][C:27]1[C:26](=[O:30])[N:25]([CH2:31][C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[C:24]([CH3:42])=[C:23]([Cl:22])[N:28]=1)[CH2:11][O:12][CH3:13])=[O:21])([CH3:18])([CH3:20])[CH3:19]
Reactant: Cc1c(Cl)nc(Cl)c(=O)n1CC(=O)OCc1ccccc1
Reactant: COCC(NC(=O)OC(C)(C)C)c1cccc(CCN)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COCC(NC(=O)OC(C)(C)C)c1cccc(CCNc2nc(Cl)c(C)n(CC(=O)OCc3ccccc3)c2=O)c1
Yield: 75.7 %

Procedure:
A mixture of tert-butyl (1R/S)-1-[3-(2-aminoethyl)phenyl]-2-methoxyethylcarbamate (preparation 121) (196 mg, 0.67 mmol), benzyl 2-[3,5-dichloro-2-methyl-6-oxo-1(6H)-pyrazinyl]acetate (preparation 17) (182 mg, 0.56 mmol) and triethylamine (368 ml, 2.78 mmol) in ethyl acetate (5 ml) was heated under reflux for 18 hrs. The cooled mixture was washed with brine (15 ml), dried over MgSO4 and evaporated under reduced pressure. The residual oil was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol (100:0 to 99:1) to afford the title compound as a colourless oil, (248 mg, 76%).