Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][N:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:26][C:27]=3[CH3:28])=[CH:17][CH:16]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:41](Br)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.CN(C)C=O>O>[CH2:41]([O:1][C:2]1[C:6]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][N:4]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[O:26][C:27]=3[CH3:28])=[CH:19][CH:20]=2)[N:3]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
A mixture of ethyl 3-[3-hydroxy-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (500 mg), potassium carbonate (165 mg), benzyl bromide (205 mg), and N,N-dimethylformamide (10 ml) was stirred at 80° C. for one hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-benzyloxy-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (385 mg, yield: 64%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:9]=2[NH2:10])[CH:2]=1.N1C=CC=CC=1.Cl[C:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27]>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:16])[F:18])=[CH:11][C:9]=2[NH:10][C:26](=[O:27])[O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:2]=1
Reactant: Nc1cc(C(F)(F)F)ccc1Oc1cccnc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1cc(C(F)(F)F)ccc1Oc1cccnc1)Oc1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A yellow solution of 2-(pyridin-3-yloxy)-5-(trifluoromethyl)aniline (263 mg, 1.035 mmol) and pyridine (108 μL, 1.341 mmol) in dry THF (8 mL) was treated dropwise with phenyl chloroformate (156 μL, 1.242 mmol) during 5 min at 0° C. The resulting suspension yellow suspension was stirred at 0° C. for an additional 5 min and then allowed to warm up to room temperature and stirred for 3 h. The yellow suspension was filtered over cotton, washed with Et2O and diluted with EtOAc. The yellow solution was washed with sat. aqueous NaHCO3 (30 mL) and H2O (30 mL), dried and concentrated to dryness to give a yellow oil. Purification by column gave a tan solid. Yield: 300 mg (77%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:21](Cl)=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:29]=[C:30]([O:32][CH3:33])[CH:31]=1)[NH2:28].C1(C)C=CC=CC=1>CCOCC>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:21]([NH:28][C:27]3[CH:29]=[C:30]([O:32][CH3:33])[CH:31]=[C:25]([O:24][CH3:23])[CH:26]=3)=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Nc1nc2ccccc2nc1Cl)c1ccc(Cl)nc1
Reactant: COc1cc(N)cc(OC)c1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2ccc(Cl)nc2)cc(OC)c1
Temperature: 125 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
6-Chloro-N-(3-chloroquinoxalin-2-yl)pyridine-3-sulfonamide (775 mg, 2.2 mmol), 3,5-dimethoxyaniline (355 mg, 2.3 mmol) and toluene (12 mL) were combined and heated to 125° C. with stirring overnight. The reaction was allowed to cool to room temperature and diluted with Et2O with vigorous stirring. The resulting solids were filtered, washed with Et2O and dried to give 6-chloro-N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)pyridine-3-sulfonamide (920 mg, 89%). 1H NMR (400 MHz, DMSO-d6) δ 12.20 (br s, 1H), 9.12 (d, 1H), 9.01 (br s, 1H), 8.53 (dd, 1H), 7.91 (br d, 1H), 7.77 (d, 1H), 7.60 (dd, 1H), 7.40 (m, 4H), 6.26 (m, 1H), 3.78 (s, 6H). MS (EI) m/z for C21H18ClN5O4S: 472.0 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C@H:9]3[C@@H:11]([O:30][C:31](=[O:33])[CH3:32])[C@@H:12]([O:26][C:27](=[O:29])[CH3:28])[C@@H:13](OS(C4C=CC(C)=CC=4)(=O)=O)[O:14][C@H:8]3[N:7]([CH2:34][CH2:35][N:36]([CH2:39][CH3:40])[CH2:37][CH3:38])[C:6]=2[CH:41]=1.[C:42]([O-:45])(=[S:44])[CH3:43].[K+]>CC(C)=O>[C:42]([S:44][C@H:13]1[O:14][C@@H:8]2[C@@H:9]([S:10][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:41][C:6]=3[N:7]2[CH2:34][CH2:35][N:36]([CH2:37][CH3:38])[CH2:39][CH3:40])[C@@H:11]([O:30][C:31](=[O:33])[CH3:32])[C@H:12]1[O:26][C:27](=[O:29])[CH3:28])(=[O:45])[CH3:43]
Reactant: CCN(CC)CCN1c2cc(Cl)ccc2S[C@H]2[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H](OS(=O)(=O)c3ccc(C)cc3)O[C@H]21
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CC(C)=O
Product: CCN(CC)CCN1c2cc(Cl)ccc2S[C@H]2[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H](SC(C)=O)O[C@H]21
Yield: 97.4 %

Procedure:
To the solution of 2.0 g of the compound (36) obtained in Example 35 in 100 ml of acetone, 1.0 g of potassium thioacetate was added, and the mixture was heated with refluxing for 6.5 hours. The solvent was removed under reduced pressure, and the residue was dissolved in ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to obtain 1.65 g (yield 96.8% ) of the title compound.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH:7]([C:9]1[CH:14]=[CH:13][C:12]([N:15]([C:25]2[CH:30]=[CH:29][C:28]([CH:31]=[O:32])=[CH:27][CH:26]=2)[C:16]2[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[C:18]([OH:24])[CH:17]=2)=[CH:11][CH:10]=1)=[O:8].Br[CH:34]([CH2:40][CH3:41])[C:35]([O:37][CH2:38][CH3:39])=[O:36]>CN(C=O)C>[CH:7]([C:9]1[CH:14]=[CH:13][C:12]([N:15]([C:25]2[CH:26]=[CH:27][C:28]([CH:31]=[O:32])=[CH:29][CH:30]=2)[C:16]2[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[C:18]([CH:17]=2)[O:24][CH2:41][CH2:40][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:11][CH:10]=1)=[O:8]
Reactant: O=Cc1ccc(N(c2ccc(C=O)cc2)c2ccc(C=O)c(O)c2)cc1
Reactant: CCOC(=O)C(Br)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1cc(N(c2ccc(C=O)cc2)c2ccc(C=O)cc2)ccc1C=O
Reaction time: 0.25 h
Yield: 65.4 %

Procedure:
K2CO3 (1.1 g, 8.0 mmol, 10 eq.) is added to a solution of compound 10 (280 mg, 810 μmol) in dry DMF (12 mL). The reaction is stirred for 15 minutes and ethyl bromobutanoate (175 μL, 1.22 mmol, 1.5 eq.) is slowly added. The mixture is stirred for 24 hours at room temperature and then concentrated. The residue is taken up in dichloromethane and water. The two-phase mixture is allowed to separate by settling, and the organic phase is washed several times with water. After drying and concentrating, a solid is obtained which is purified by chromatography (elution with a methanol gradient from 0 to 1% in dichloromethane) to give 275 mg (530 μmol) of compound 11 in the form of an orange powder (yield: 75%).
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]([Cl:8])=[C:5]([Cl:7])[N:6]=1.CI.[C:11](=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[Br:1][C:2]1[N:3]([CH3:11])[C:4]([Cl:8])=[C:5]([Cl:7])[N:6]=1
Reactant: Clc1nc(Br)[nH]c1Cl
Reactant: O=C([O-])[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: Cn1c(Br)nc(Cl)c1Cl
Temperature: 75 °C
Reaction time: 1 h

Procedure:
A mixture of 2-bromo-4,5-dichloroimidazole (1 g, 4.6 mmol), methyl iodide (346 μL, 5.56 mmol), potassium carbonate (1.27 g, 9.2 mmol) and tetrabutylammonium bromide (148 mg, 0.46 mmol) in acetonitrile (2 mL) was stirred vigorously at 70-80° C. for 1.0 h. After cooling to room temperature, the inorganic salts were filtered off and washed with acetonitrile. The filtrate was evaporated and the residue was purified by flash chromatography (Si) to afford 2-bromo-4,5-dichloro-1-methyl-1H-imidazole as a white solid. LCMS calc.=230.89; found=230.9 (M+1)+. 1H NMR (500 MHz, CDCl3) δ 3.61 (s, 3 H).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6](=[O:12])[NH:7][CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.Cl.[F:16][C:17]1[CH:18]=[C:19]([CH:23]([NH2:34])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[CH:20]=[CH:21][CH:22]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:7][CH2:8][C:9](=[O:11])[NH:34][CH:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([F:16])[CH:18]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[CH:25]=2)=[O:12])=[CH:13][CH:14]=1
Reactant: NC(c1cccc(F)c1)c1cccc(C(F)(F)F)c1
Reactant: O=C(O)CNC(=O)c1ccc(F)cc1
Agent: Cl
Product: O=C(CNC(=O)c1ccc(F)cc1)NC(c1cccc(F)c1)c1cccc(C(F)(F)F)c1

Procedure:
Prepared in analogy to example 1.1 from 4-fluoro-hippuric acid (CA [366-79-0]) and rac-C-(3-fluoro-phenyl)-C-(3-trifluoromethyl-phenyl)-methylamine hydrochloride (example 4.10).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.Cl.CN(C)CCCN=C=NCC.[O:33]1[CH2:37][CH2:36][O:35][CH:34]1[CH2:38][CH:39]([C:41]1([OH:45])[CH2:44][NH:43][CH2:42]1)[OH:40].C(OCC)(=O)C>CN(C)C1C=CN=CC=1.CN(C=O)C>[F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])=[C:4]([C:5]([N:43]2[CH2:42][C:41]([CH:39]([OH:40])[CH2:38][CH:34]3[O:33][CH2:37][CH2:36][O:35]3)([OH:45])[CH2:44]2)=[O:7])[CH:8]=[CH:9][C:10]=1[F:11]
Reactant: O=C(O)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: OC(CC1OCCO1)C1(O)CNC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(c1ccc(F)c(F)c1Nc1ccc(I)cc1F)N1CC(O)(C(O)CC2OCCO2)C1
Reaction time: 0.17 h
Yield: 35.9 %

Procedure:
3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (287 mg, 0.730 mmol), prepared using procedures similar to those described in U.S. Pat. No. 7,019,033, 4-(dimethylamino)pyridine (178 mg, 1.46 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (168 mg, 0.88 mmol) were dissolved in DMF (3 mL). The mixture was stirred at ambient for 10 minutes and then 3-[2-(1,3-dioxolan-2-yl)-1-hydroxyethyl]azetidin-3-ol (0.729 mmol) in DMF (2 mL) was added and the mixture was stirred for 15 h. The mixture was partitioned between ethyl acetate and 5% lithium chloride. The organic portion was washed with 20% citric acid, saturated sodium bicarbonate and brine, then was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, gradient 90% ethyl acetate in hexanes to 100% ethyl acetate) gave 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[2-(1,3-dioxolan-2-yl)-1-hydroxyethyl]azetidin-3-ol (148 mg, 0.262 mmol, 36% yield): MS (EI) for C21H20F3IN2O5: 565 (MH+).
Reaction SMILES: C([NH:4][N:5]=[CH:6][C:7]1[C:8](F)=[N:9][C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[CH:11][CH:12]=1)(=O)C.O>O.NN>[CH3:19][N:16]1[CH2:17][CH2:18][N:13]([C:10]2[N:9]=[C:8]3[NH:4][N:5]=[CH:6][C:7]3=[CH:12][CH:11]=2)[CH2:14][CH2:15]1
Reactant: CC(=O)NN=Cc1ccc(N2CCN(C)CC2)nc1F
Agent: NN
Solvent: O
Product: CN1CCN(c2ccc3cn[nH]c3n2)CC1
Reaction time: 0.5 h

Procedure:
2-Fluoro-6-(4-methyl-1-piperazinyl)pyridine-3-carboxaldehyde acetylhydrazone (2.30 g, 8.23 mmole) was warmed at 90° C. in 20 mL of hydrazine hydrate. After 30 minutes, water was added to the reaction mixture and the product was filtered off. The aqueous filtrate was concentrated under reduced pressure and the resulting solid triturated with water. This product was combined with the product that had been previously filtered off and the two were recrystallized together from EtOAc, giving 1.15 g, (64%), mp 196°-197° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]3[C:13]([C:14]4[C:15]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)=[N:16][O:17][C:18]=4Cl)=[N:12][N:11]=[C:8]32)=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[NH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1>CO>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]3[C:13]([C:14]4[C:15]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)=[N:16][O:17][C:18]=4[C:38]4[C:33]([CH2:32][NH2:31])=[N:34][CH:35]=[CH:36][CH:37]=4)=[N:12][N:11]=[C:8]32)=[CH:4][CH:3]=1
Reactant: NCc1ccccn1
Reactant: Clc1onc(-c2ccccc2)c1-c1nnc2n1Cc1ccc(Br)cc1-2
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: NCc1ncccc1-c1onc(-c2ccccc2)c1-c1nnc2n1Cc1ccc(Br)cc1-2
Yield: 18.9 %

Procedure:
8-Bromo-3-(5-chloro-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole (50 mg, 0.12 mmol) (prepared in Example 39), sodium acetate (30 mg) and 2-(aminomethyl)pyridine (13 mg) in 5 ml methanol were heated to reflux for 18 h. The reaction was cooled, concentrated and partitioned between H2O—CH2Cl2. The organic phase and extracts were combined, dried over (MgSO4) and concentrated. The residue was purified by preparative TLC using 3% MeOH—CH2Cl2 as eluent. Trituration with 1PrOH gave the title compound as a beige solid (11 mg). 1H NMR (400 MHz, d6-DMSO) δ 8.53–8.54 (1H, m), 8.38–8.40 (1H, m), 8.1 (1H, s), 7.75–7.8 (1H, m), 7.65–7.68 (1H, m), 7.55–7.60 (2H, m), 7.38–7.5 (4H, m), 7.28–7.30 (2H, m), 4.68–4.7 (2H, m), 4.45 (2H, s). m/z (ES+) 485/487 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([CH2:12][C:13]([OH:15])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([O:23][N:24]1[C:30](=[O:31])[N:29]2[CH2:32][C@H:25]1[CH2:26][CH2:27][C@H:28]2[C:33]([NH:35][NH2:36])=[O:34])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:16]([O:23][N:24]1[C:30](=[O:31])[N:29]2[CH2:32][C@H:25]1[CH2:26][CH2:27][C@H:28]2[C:33]([NH:35][NH:36][C:13](=[O:15])[CH2:12][C:9]1([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][CH2:11]1)=[O:34])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)NC1(CC(=O)O)CC1
Reactant: NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(CC(=O)NNC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Yield: 71.3 %

Procedure:
A solution of 2-(1-(tert-butoxycarbonylamino)cyclopropyl)acetic acid (1.5 g, 6.9 mmol), (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbohydrazide (3.1 g, 7.6 mmol), DIPEA (2.7 g, 21.0 mmol), and HATU (3.9 g, 10.45 mmol) in DMF (20 mL) was stirred at 0° C. for 1 hr. The mixture was quenched with saturated sodium chloride (150 mL) and EtOAc (150 mL). The organic layer was separated and washed with saturated sodium chloride (2×), dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (0˜80% gradient elution EtOAc/petroleum ether) to afford tert-butyl 1-(2-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)hydrazinyl)-2-oxoethyl)cyclopropylcarbamate (2.4 g, 70%) as a white solid. ESI-MS (EI+, m/z): 488 [M+H]+.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([C:13]1[C:14](=[O:25])[O:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([OH:23])=[C:18]([OH:24])[CH:17]=2)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(OCC)(=O)C>[C:5]([C:13]1[C:14](=[O:25])[O:15][C:16]2[C:21]([CH:22]=1)=[C:20]([N+:1]([O-:4])=[O:2])[C:19]([OH:23])=[C:18]([OH:24])[CH:17]=2)(=[O:12])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=[N+]([O-])O
Reactant: O=C(c1ccccc1)c1cc2cc(O)c(O)cc2oc1=O
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1)c1cc2c([N+](=O)[O-])c(O)c(O)cc2oc1=O

Procedure:
Nitric acid solution (1.6 ml, 2 M in CH2Cl2) was added to a solution of 3-benzoyl-6,7-dihydroxy-chromen-2-one (0.89 g) in ethyl acetate (50 ml) at −16-10° C. The solvent was evaporated and the product run through a silica column with toluene-ethyl acetate acetic acid (8:1:1) as the solvent. The product was crystallized from ether. Yield: 40 mg, melting point 94-96° C.
Reaction SMILES: C([C:8]1[CH:13]=[CH:12][N:11]=[C:10]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=O)=[CH:16][CH:15]=2)[N:9]=1)CCCCCC.[CH2:23](Cl)[CH2:24]Cl.P(Cl)(Cl)(Cl)=O>CCOCC>[CH2:16]([C:13]1[CH:12]=[N:11][C:10]([C:14]2[CH:15]=[CH:16][C:17]([C:18]#[N:20])=[CH:21][CH:22]=2)=[N:9][CH:8]=1)[CH2:15][CH2:14][CH2:22][CH2:21][CH2:23][CH3:24]
Reactant: CCCCCCCc1ccnc(-c2ccc(C(N)=O)cc2)n1
Reactant: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Product: CCCCCCCc1cnc(-c2ccc(C#N)cc2)nc1

Procedure:
1.9 g. of 4-(4-n-heptylpyrimid-2-yl)benzoic acid amide are left for 80 minutes under reflux in a mixture of 40 ml. of ethylene chloride and 0.63 ml. of phosphorus oxychloride, with stirring. The reaction mixture, diluted with ether, is washed with 2N sodium hydroxide solution and then with water until neutral. After evaporation of the organic phase, drying over sodium sulfate, 1.9 g. of 5-n-heptyl-2-(4-cyanophenyl)-pyrimidine result, which are distilled in a high vacuum, having a m.p. of 44.2°-44.7°; cl.p. 50.1°-50.4°.
Reaction SMILES: C(OC([NH:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:24][C:25]([NH:27][C@@H:28]2[CH2:43][C:42]3=[CH:44][CH:45]=[C:39]([CH:40]=[CH:41]3)[O:38][CH2:37][CH2:36][CH2:35][CH2:34][O:33][CH2:32][C@H:31]([CH:46]([CH3:48])[CH3:47])[NH:30][C:29]2=[O:49])=[O:26])[C:17]([O:19]C(C)(C)C)=[O:18])=[CH:11][CH:10]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:24][C:25]([NH:27][C@@H:28]2[CH2:43][C:42]3=[CH:41][CH:40]=[C:39]([CH:45]=[CH:44]3)[O:38][CH2:37][CH2:36][CH2:35][CH2:34][O:33][CH2:32][C@H:31]([CH:46]([CH3:47])[CH3:48])[NH:30][C:29]2=[O:49])=[O:26])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1
Reactant: CC(C)[C@H]1COCCCCOc2ccc(cc2)C[C@@H](NC(=O)N[C@@H](Cc2ccc(NC(=O)OC(C)(C)C)nc2)C(=O)OC(C)(C)C)C(=O)N1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H]1COCCCCOc2ccc(cc2)C[C@@H](NC(=O)N[C@@H](Cc2ccc(N)nc2)C(=O)O)C(=O)N1
Temperature: 25 °C
Reaction time: 5 h
Yield: 89 %

Procedure:
160 mg (0.23 mmol) of tert-butyl (S)-3-(6-tert-butoxycarbonylaminopyridin-3-yl)-2-[3-((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17),14(18),15-trien-12-yl)ureido]propionate were dissolved in 6 ml of dichloromethane and, after addition of the same volume of TFA, stirred at RT. After 5 h, the mixture was concentrated and purified by preparative HPLC. The required fractions were combined, freed of acetonitrile, mixed with 1N hydrochloric acid, concentrated further and finally freeze dried. 108 mg of the title compound were obtained as hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:10](=[O:12])[CH3:11])[C:7]([C:13]([F:16])([F:15])[F:14])=[CH:6][C:5]=1[NH:17][C:18](=[O:20])[CH3:19]>C1COCC1.[Pd]>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([CH:10]([OH:12])[CH3:11])[C:7]([C:13]([F:16])([F:15])[F:14])=[CH:6][C:5]=1[NH:17][C:18](=[O:20])[CH3:19]
Reactant: COC(=O)c1cc(C(C)=O)c(C(F)(F)F)cc1NC(C)=O
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(C)O)c(C(F)(F)F)cc1NC(C)=O
Yield: 90.8 %

Procedure:
A solution of 5-acetyl-2-acetylamino-4-trifluoromethyl-benzoic acid methyl ester (4 g, 13.2 mmol) in THF (40 mL) was hydrogenated at r.t. for 2 h over Pd—C (10%, 250 mg). The reaction mixture was filtered on a sintered funnel The filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, 2:1 hexanes/EtOAc) to give the title product (3.66 g, 91% yield) as colorless crystals. m.p.: 120-123° C., ESI-MS: m/z 306 [M+H]+.
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[CH:5]=1.[CH3:18][C:19]1[NH:20][CH:21]=[CH:22][N:23]=1>>[ClH:2].[Cl:17][C:12]1[CH:11]=[C:10]([C:6]2[CH:5]=[C:4]([CH2:3][N:20]3[CH:21]=[CH:22][N:23]=[C:19]3[CH3:18])[CH:9]=[CH:8][N:7]=2)[CH:15]=[CH:14][C:13]=1[Cl:16]
Reactant: Cc1ncc[nH]1
Reactant: ClCc1ccnc(-c2ccc(Cl)c(Cl)c2)c1
Agent: Cl
Product: Cc1nccn1Cc1ccnc(-c2ccc(Cl)c(Cl)c2)c1

Procedure:
The title compound, MS: m/e=317.0 (M+) was obtained as a beige solid (51% yield) by the reaction of 4-chloromethyl-2-(3,4-dichloro-phenyl)-pyridine hydrochloride (1:1) with 2-methylimidazole, using sodium hydride and triethylamine as base followed by formation of the hydrochloride salt.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:7]([CH3:20])([CH3:19])[CH:6]=[C:5]2[CH3:21].C([Li])(C)(C)C.[B:27](OC)([O:30]C)[O:28]C>C1COCC1>[C:15]([O:14][C:12]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([B:27]([OH:30])[OH:28])=[CH:11][CH:10]=2)[C:5]([CH3:21])=[CH:6][C:7]1([CH3:20])[CH3:19])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC1=CC(C)(C)N(C(=O)OC(C)(C)C)c2ccc(Br)cc21
Reactant: COB(OC)OC
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC1=CC(C)(C)N(C(=O)OC(C)(C)C)c2ccc(B(O)O)cc21
Yield: 43.8 %

Procedure:
A 25 mL r.b. flask, equipped with a magnetic stirring bar, was charged with Compound 8 (3.765 g, 10.67 mmol) under N2. The oil was dissolved in 11 mL THF (anhydrous) and cooled to −78° C. tert-Butyllithium (12.6 mL, 21.4 mmol, 1.70 M) was added by syringe over a period of 10 min (maintaining temperature below −70° C.) turning the reaction mixture from pale yellow to bright yellow. The reaction was allowed to continue at −75° C. until all of the starting material had been consumed as judged by TLC (15% ethyl acetate/hexane). Trimethyl borate (1.22 g, 1.33 mL, 11.7 mmol, 1.1 equiv) was added by syringe over 5-10 minutes (temperature between −70° C. and −65° C.). The reaction was monitored by TLC. Upon completion, the product mixture was quenched with saturated NH4Cl (200 mL). Addition of ethyl acetate (200 mL) partitioned the mixture into 2 phases. The organic phase was washed with saturated NH4Cl (100 mL) and brine (100 mL). The combined aqueous layers were extracted with ethyl acetate (100 mL). The organic layers were combined and dried (Na2SO4). The crude mixture was applied to a small column containing 200 mL silica and 15% ethyl acetate/hexane. The higher Rf impurities were eluted with 2 L of 10% ethyl acetate/hexane. The boronic acid, Compound 9, was eluted with 500 mL ethyl acetate followed by 750 mL ethanol to provide 1.483 g (44%) of Compound 9. Data for Compound 9: 1H NMR (400 MHz, acetone-d6) 7.73 (d, J=1.2, 1H), 7.66 (dd, J=8, 1.2, 1H), 7.13 (d, J=8, 1H), 5.49 (s, 1H), 2.01 (d, J=1.6, 3H), 1.50 (s, 9H), 1.46 (s, 6H).
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([CH2:9][N:10]=[N+]=[N-])=[CH:5][CH:4]=1)#[N:2].O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:1]([C:3]1[N:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(CN=[N+]=[N-])cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(CN)cn1
Reaction time: 8 h

Procedure:
The compound obtained in (a) was dissolved in 45 ml of THF and 1.2 ml of water and, while stirring, 11.2 g of triphenylphosphine were added in portions. The reaction mixture was left to stand at RT overnight.