Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:17]([NH:18][CH:19]2[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20]2)=[CH:16][C:5]2[N:6]3[CH:11]([CH3:12])[C:10](=[O:13])[NH:9][N:8]=[C:7]3[CH2:14][O:15][C:4]=2[CH:3]=1.[CH2:30]([O:32]/[CH:33]=[CH:34]/B1OC(C)(C)C(C)(C)O1)[CH3:31].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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].C(Cl)Cl>[CH2:33]([O:32]/[CH:30]=[CH:31]/[C:2]1[C:17]([NH:18][CH:19]2[CH2:20][N:21]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:22]2)=[CH:16][C:5]2[N:6]3[CH:11]([CH3:12])[C:10](=[O:13])[NH:9][N:8]=[C:7]3[CH2:14][O:15][C:4]=2[CH:3]=1)[CH3:34]
Reactant: CCO/C=C/B1OC(C)(C)C(C)(C)O1
Reactant: CC1C(=O)NN=C2COc3cc(Br)c(NC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CCO/C=C/c1cc2c(cc1NC1CN(C(=O)OC(C)(C)C)C1)N1C(=NNC(=O)C1C)CO2
Temperature: 100 °C
Reaction time: 8 h
Yield: 50.8 %

Procedure:
To a solution of tert-butyl 3-((8-bromo-1-methyl-2-oxo-1,2,3,5-tetrahydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-9-yl)amino)azetidine-1-carboxylate (Example 1, Step B, 0.20 g, 0.43 mmol), (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.1 g, 0.5 mmol) in dioxane (6 mL) and water (1 mL) was added PdCl2(dppf)-CH2Cl2 adduct (0.035 g, 0.043 mmol) and K2CO3 (0.118 g, 0.85 mmol). The reaction mixture was stirred at 100° C. overnight. The reaction mixture was cooled to ambient temperature, the solvent was removed in vacuo and the residue was purified by chromatography on silica gel (eluting with 2% MeOH in DCM) to give (E)-tert-butyl 3-((8-(2-ethoxyvinyl)-1-methyl-2-oxo-1,2,3,5-tetrahydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-9-yl)amino)azetidine-1-carboxylate (0.10 g, 51%) as a yellow solid. LC/MS (Table 1, Method 2) Rt=1.352 min.; MS m/z: 458 [M+H]+.
Reaction SMILES: [Br-].[CH3:2]C(C)([O-])C.[K+].[CH2:8]([O:10][C:11](=[O:32])[CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][C:24]=1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:21][CH2:20][C:19]2=O)[CH3:9].O>O1CCCC1>[CH2:8]([O:10][C:11](=[O:32])[CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][C:24]=1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:21][CH2:20][C:19]2=[CH2:2])[CH3:9]
Reactant: CC(C)(C)[O-]
Reactant: CCCCCCc1cc2c(cc1OCCCC(=O)OCC)C(=O)CC2
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=C1CCc2cc(CCCCCC)c(OCCCC(=O)OCC)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5.4 g (15.3 mmol) of methyltriphenylphosphate [sic] bromide are added to a suspension of 1.75 g (14.9 mmol) of potassium tert-butoxide in 20 ml of tetrahydrofuran. The reaction medium is stirred for 1 hour at 25° C. and then cooled to 0° C. A solution of 4.5 g (12.9 mmol) of ethyl4-(6-hexyl-3-oxoindan-5-yloxy)butyrate is added. The mixture is stirred for 16 hours at 25° C., poured into water and extracted with ether. The organic phase is dried (Na2SO4) and concentrated under reduced pressure (oil). Purification by flash chromatography (80/20 heptane/ethyl acetate) gives an orange oil (3.5 g; 79%).
Reaction SMILES: [CH:1]([N:3]([C:16](=[CH:22]O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:14][CH3:15])=O.Cl.C([NH2:27])=O>>[CH2:14]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([F:13])([F:12])[F:11])[C:4]=1[N:3]1[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:22][N:27]=[CH:1]1)[CH3:15]
Reactant: CCOC(=O)C(=CO)N(C=O)c1c(CC)cccc1C(F)(F)F
Reactant: NC=O
Agent: Cl
Product: CCOC(=O)c1cncn1-c1c(CC)cccc1C(F)(F)F

Procedure:
1.3 g (3.9 mmol) of ethyl 2-(N-formyl-2-ethyl-6-trifluoromethylanilino)-3-hydroxyacrylate were heated for 4 hours at 150° C. with 20 ml of formamide and 5 ml of concentrated hydrochloric acid. After cooling, the mixture was extracted twice with diisopropyl ether, and the organic phase was washed with water, dried over sodium sulfate and evaporated. After chromatographic purification, 0.7 g (57% of theory) of ethyl 1-(2-ethyl-6-trifluoromethylphenyl)imidazole-5-carboxylate, a colorless oil, was obtained. The compound was identified by NMR spectroscopy.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=2)=[C:5]([CH3:7])[N:6]=1.[C:15]([N:23]=[C:24]=[S:25])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(C)=O>[CH3:7][C:5]1[N:6]=[C:2]([NH:1][C:24]([NH:23][C:15](=[O:22])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[S:25])[S:3][C:4]=1[C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Cc1ccnc(-c2sc(N)nc2C)c1
Solvent: CC(C)=O
Product: Cc1ccnc(-c2sc(NC(=S)NC(=O)c3ccccc3)nc2C)c1

Procedure:
To a suspension of 2-amino-4-methyl-5-(4-methylpyridin-2-yl)-thiazole (615 mg) in acetone (5 ml) was added a solution of benzoyl isothiocyanate (0.443 ml) in acetone (5 ml) dropwise, and the mixture was heated under reflux for 3 hours. After cooling, the resulting precipitate was collected by filtration and dried to give N-(4-methyl-5-(4-methylpyridin-2-yl)thiazol-2-yl)-N′-benzoylthiourea (490 mg).
Reaction SMILES: BrC[C:3]1[C:12]2[C:7](=[CH:8][C:9](OC)=[CH:10][CH:11]=2)OC(=O)C=1.[C:16]([O-:19])(=[O:18])[CH3:17].[Ca+2].[C:21]([O-])(=[O:23])C.Cl>C(O)(=O)C.C(O)C>[OH:23][C:21]1[C:9]2[C:10](=[CH:11][C:12]([CH3:3])=[CH:7][CH:8]=2)[O:18][C:16](=[O:19])[CH:17]=1
Reactant: COc1ccc2c(CBr)cc(=O)oc2c1
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [Ca+2]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1ccc2c(O)cc(=O)oc2c1
Reaction time: 2.5 h

Procedure:
10 g of 4-bromomethyl-7-methoxycoumarin [produced according to Secrist et al., Biochem. Biophys. Res. Commun., 45, 1262 (1971)] are heated to boiling for 2.5 hours under reflux in 40 ml of glacial acetic acid together with 6 g of calcium acetate (free of water). The solution is brought to dryness in vacuo. The residue is heated to boiling in 50 ml of ethanol and 50 ml of concentrated hydrochloric acid for 1.5 hours under reflux. The volatile components are removed under reduced pressure. The residue is dissolved in chloroform. The resulting solution is made free of acids by extraction with diluted aqueous ammoniac and water and dried over annealed potassium carbonate. After removing the chloroform in vacuo, the residue is recrystallized from ethylacetate. In this manner 1.9 g (24.8 percent of the theoretically-calculated amount) of the title compound with a melting point of 179° to 182° C. are obtained.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:13]=[C:12]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+].FC(F)(F)C1C=CC(B(O)O)=CC=1>C1COCC1>[CH2:18]([N:14]1[C:15]2[CH2:16][CH2:17][NH:8][CH2:9][CH2:10][C:11]=2[C:12]([C:25]2[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:29][CH:30]=2)=[N:13]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(-c3ccc(C(F)(F)F)cc3)nn(Cc3ccccc3)c2CC1
Agent: O=P([O-])([O-])[O-]
Agent: OB(O)c1ccc(C(F)(F)F)cc1
Agent: [K+]
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(-c2nn(Cc3ccccc3)c3c2CCNCC3)cc1

Procedure:
1-Benzyl-3-(4-trifluoromethyl-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester. To a solution of the compound from step C (0.17 g) in 5 mL of THF was added 0.12 g of K3PO4, 0.08 g of 4-trifluoromethylphenylboronic acid and 0.03 g of PdCl2dppf. The mixture was heated at reflux for 12 h. The mixture was cooled, filtered through diatomaceous earth, and concentrated in vacuo. Chromatography on SiO2 (5 to 40% EtOAc/hexanes) afforded 0.05 g of the desired compound. TLC (SiO2, 25% EtOAc/hexanes): Rf=0.49.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:20]([NH:22][C@@H:23]([C:25]([NH:27][CH2:28][C@@H:29]([NH:37]C(OCC1C=CC=CC=1)=O)[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:26])[CH3:24])=[O:21])[CH2:10][C:11]1[C:16]([CH3:17])=[CH:15][C:14]([OH:18])=[CH:13][C:12]=1[CH3:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>CO.[OH-].[Pd+2].[OH-]>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:20]([NH:22][C@@H:23]([C:25]([NH:27][CH2:28][C@@H:29]([NH2:37])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:26])[CH3:24])=[O:21])[CH2:10][C:11]1[C:16]([CH3:17])=[CH:15][C:14]([OH:18])=[CH:13][C:12]=1[CH3:19])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(O)cc(C)c1C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C)C(=O)NC[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1cc(O)cc(C)c1C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C)C(=O)NC[C@@H](N)Cc1ccccc1
Temperature: 60 °C
Yield: 95 %

Procedure:
To a solution of N-(tert-butoxycarbonyl)-2,6-dimethyl-L-tyrosyl-N-[(2S)-2-{[(benzyloxy)carbonyl]amino}-3-phenylpropyl]-D-alaninamide (450 mg, 0.70 mmol) from preparation 2 in methanol (10 mL) was added palladium hydroxide (40 mg) and ammonium formate (231 mg, 3.48 mmol) at room temperature. The reaction was then heated at 60° C. for 3 hours, after this time the reaction was allowed to cool and then filtered through a pad of Arbocel. The filtrate was concentrated under reduced pressure, the residue dissolved in methanol (5 mL) and loaded onto a 20 g SCX2 cartridge (pre-wetted with methanol). The cartridge was eluted with methanol to remove non-basic impurities and then eluted with 3M NH3 in methanol. Fractions containing the title compound were combined and concentrated under reduced pressure to afford the title compound as a white amorphous solid in 95% yield, 338 mg. 1H NMR (400 MHz, MeOH-d4) δ : 1.09 (d, 3H), 1.36 (s, 9H), 2.23 (s, 6H), 2.51-2.61 (m, 1H), 2.72-2.89 (m, 2H), 3.01-3.28 (m, 4H), 3.96-4.06 (m, 1H), 4.14-4.28 (m, 2H), 6.46 (s, 2H), 7.11-7.35 (m, 5H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][CH:9]([Cl:48])[C:10]([N:12]([CH2:32][CH2:33][C:34](=[O:47])[CH:35]([NH:39]C(=O)OC(C)(C)C)[CH:36]([CH3:38])[CH3:37])[C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]2[O:23][N:22]=[C:21]([C:24]3[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:31])[CH:20]=2)[CH:14]=1)=[O:11]>C(Cl)Cl>[NH2:39][CH:35]([CH:36]([CH3:38])[CH3:37])[C:34](=[O:47])[CH2:33][CH2:32][N:12]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]2[O:23][N:22]=[C:21]([C:24]3[C:25]([Cl:31])=[CH:26][CH:27]=[CH:28][C:29]=3[Cl:30])[CH:20]=2)[CH:14]=1)[C:10](=[O:11])[CH:9]([Cl:48])[Cl:8]
Reactant: CC(C)C(NC(=O)OC(C)(C)C)C(=O)CCN(C(=O)C(Cl)Cl)c1ccnc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C(N)C(=O)CCN(C(=O)C(Cl)Cl)c1ccnc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (1 mL) was added to a solution of tert-butyl 6-(2,2-dichloro-N-(2-(3-(2,6-dichlorophenyl)isoxazol-5-yl)pyridin-4-yl)acetamido)-2-methyl-4-oxohexan-3-ylcarbamate (185 mg, 0.29 mmol) in methylene chloride (2 mL) at 0° C. The resulting mixture was allowed to stir at 0° C. for 2 hours, then concentrated under reduced pressure. The residue was dissolved in methylene chloride (2 mL) and concentrated under reduced pressure, twice more. Then lyophilized to produce N-(4-amino-5-methyl-3-oxohexyl)-2,2-dichloro-N-(2-(3-(2,6-dichlorophenyl)isoxazol-5-yl)pyridin-4-yl)acetamide (Cpd. No. 3, lot 2, 150 mg) as a light orange solid. 1H NMR (CD3OD): 8.90 (d, 1H), 8.28 (s, 1H), 7.80-7.75 (m, 1H), 7.65-7.55 (m, 3H), 7.38 (s, 1H), 6.62 (s, 1H), 4.38-4.11 (m, 3H), 3.19-3.08 (m, 2H), 2.55-2.41 (m, 1H), 1.15 (d, 3H), 0.90 ppm (d, 3H). MW=544 confirmed by LC-MS, tr=10.55 min (Method Y) MH+=542-546.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][N:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][C:10]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:12]=2)[C:7]1=[O:20].Cl.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][C:35]([CH3:41])([C:38](O)=[O:39])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][C:35]([C:38]([NH:1][C:2]2[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=2)[CH2:5][N:6]2[CH:15]=[CH:14][C:13]3[C:8](=[CH:9][C:10]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:12]=3)[C:7]2=[O:20])=[O:39])([CH3:41])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)O)CC1
Reactant: COC(=O)c1ccc2ccn(Cc3cccc(N)c3)c(=O)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)c1ccc2ccn(Cc3cccc(NC(=O)C4(C)CCN(C(=O)OC(C)(C)C)CC4)c3)c(=O)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
To a solution of methyl 2-(3-aminobenzyl)-1-oxo-1,2-dihydroisoquinoline-7-carboxylate.HCl (0.22 g, 0.64 mmol) in pyridine (5 mL) was added 1-(tert-butoxycarbonyl)-4-methylpiperidine-4-carboxylic acid (0.17 g, 0.70 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.37 g, 1.9 mmol). The reaction mixture was stirred at rt overnight. The reaction mixture was then concentrated and the crude residue was purified by flash silica gel chromatography (0% to 5% EtOAc/DCM) to afford methyl 2-[3-({[1-(tert-butoxycarbonyl)-4-methylpiperidin-4-yl]carbonyl}amino)benzyl]-1-oxo-1,2-dihydroisoquinoline-7-carboxylate (0.29 g, 83%). LC-MS: (FA) ES+ 434.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]1([CH3:19])[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][C:16](Cl)=[O:17]>>[C:8]1([CH3:19])[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][C:16]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:17]
Reactant: Oc1ccccc1
Reactant: Cc1ccccc1CCC(=O)Cl
Product: Cc1ccccc1CCC(=O)Oc1ccccc1
Yield: 91.9 %

Procedure:
The procedure as described in Example 4a) was repeated with phenol (48 mmol) and 3-o-tolylpropanoyl chloride (55 mmol). The crude product (12.4 g, 97%) was short path distilled at 127-129° C./0.05 mbar to yield 10.6 g (93%) of product as a colourless, semicrystalline oil.
Reaction SMILES: [CH:1]([N:4]([CH:17]([CH3:19])[CH3:18])[CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][N+:9]=1[O-])([CH3:3])[CH3:2]>C(O)(=O)C.[Fe]>[CH:17]([N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][N:9]=1)([CH3:18])[CH3:19]
Reactant: COc1cc[n+]([O-])c(NCCN(C(C)C)C(C)C)c1
Agent: [Fe]
Solvent: CC(=O)O
Product: COc1ccnc(NCCN(C(C)C)C(C)C)c1

Procedure:
2-(2-diisopropylaminoethylamino)-4-methoxypyridine-N-oxide (4.3 g., 15 mmole) dissolved in glacial acetic acid (32 ml.) is refluxed with iron powder (8.2 g.) for three hours. The reaction mixture is filtered to remove insoluble salts and then the solvent evaporated. The residue is dissolved in methanol, treated with excess potassium hydroxide pellets and filtered to remove more insoluble salts. The concentrate solution is dissolved in chloroform, washed with water, dried over sodium sulfate, filtered through a pad of charcoal and evaporated to give oily product.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[S:27][C:26]([C:28]([O:30]C(C)(C)C)=[O:29])=[CH:25][C:9]=3[N:10]([CH2:20][C:21](OC)=O)[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:18]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:35][NH2:36].[BH4-].[Na+].B.CSC.Cl>CO.CCOC(C)=O.C1COCC1>[CH:1]1([C:7]2[C:8]3[S:27][C:26]([C:28]([OH:30])=[O:29])=[CH:25][C:9]=3[N:10]3[CH2:20][CH2:21][N:36]([CH3:35])[CH2:18][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[C:11]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)Cn1c(-c2ccccc2C=O)c(C2CCCCC2)c2sc(C(=O)OC(C)(C)C)cc21
Reactant: CN
Agent: B
Agent: Cl
Agent: [BH4-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN1CCn2c(c(C3CCCCC3)c3sc(C(=O)O)cc32)-c2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of tert-butyl 6-cyclohexyl-5-(2-formylphenyl)-4-(2-methoxy-2-oxoethyl)-4H-thieno[3,2-b]pyrrole-2-carboxylate (1 eq., prepared as described in Example 1, Step 4) in dry methanol (0.05 M) was treated with methylamine (1.5 eq., 2 M solution in THF) at RT for 1 h. Sodium borohydride (2 eq.) was then added and the mixture stirred overnight at RT. The residue was diluted with EtOAc and washed with a saturated NaHCO3 solution and with brine, then dried over sodium sulfate and evaporated in vacuo. The foregoing compound (1 eq.) was dissolved in dry THF (0.14M) was treated with borane-dimethylsulfide complex (20 eq., 2M solution in THF) overnight at RT. The reaction mixture was then treated with HCl in methanol (40 eq., 1.25 M solution) and heated to reflux for 1 h. The volatiles were evaporated in vacuo and the residue purified by RP-HPLC (column: Waters XTERRA PREP MS C18, 10 μm; solvents: A: water+0.1% trifluoroacetic acid; B: MeCN+0.1% trifluoroacetic acid; 25% B in A isocratic for 3 min, linear to 20% A in B in 12 min) to afford the title compound after lyophilisation as a colourless powder (39%). 1H-NMR (400 MHz, DMSO-d6, 300 K, δ) 12.83 (bs, 1H), 9.86 (bs, 1H), 8.05 (s, 1H), 7.94-7.90 (m, 1H), 7.65-7.60 (m, 2H), 7.48-7.45 (m, 1H), 4.66 (d, J 15.3, 1H), 4.39 (d, J 12.7, 1H), 3.70-3.20 (m, 4H, partially hidden by H2O signal), 3.06 (s, 3H), 2.50 (m, 1H, hidden by DMSO signal), 2.03-1.36 (m, 10H). MS (ES+) m/z: 395 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](=O)[CH:11]([CH3:15])[CH2:12][CH:13]=O.[NH2:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28]>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:17]([N:18]2[C:22](=[O:23])[C:21]3[C:20](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:19]2=[O:28])[CH:13]=[CH:12][C:11]=1[CH3:15]
Reactant: NN1C(=O)c2ccccc2C1=O
Reactant: COc1ccc(C(=O)C(C)CC=O)c(Cl)c1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(-c2c(C)ccn2N2C(=O)c3ccccc3C2=O)c(Cl)c1
Temperature: 100 °C
Yield: 93.1 %

Procedure:
A mixture of 4-(2-chloro-4-methoxyphenyl)-3-methyl-4-oxobutanal (6.40 g, 27.0 mmol) and N-aminophthalimide (5.32 g, 29.0 mmol) in HCl (5N, 3.90 mL) and dioxane (100 mL) was heated at 100° C. for 1 h. After cooling down to room temperature, the mixture was concentrated in vacuo and the residue was recrystalized from CH2Cl2/hepatene to give 9.22 g (95%) of pink solid as the title compound: mp 202.0–208.5° C.; 1H NMR (400 MHz, Acetone-d6) δ 7.95–7.86 (m, 4H), 7.17 (d, J=8.6 Hz, 1H), 7.01 (d, J=3.1 Hz, 1H), 6.99 (d, J=2.6 Hz, 1H), 6.82 (dd, J=8.6, 2.6 Hz, 1H), 6.20 (d, J=3.1 Hz, 1H), 3.77 (s, 3H), 1.98 (s, 3H); IR (diffuse reflectance) 2072, 2014, 1981, 1906, 1747, 1463, 1293, 1275, 1214, 1047, 881, 820, 719, 712, 705 cm−1; HRMS (FAB) calcd for C20H15N2O3Cl+H 367.0849. found 367.0832. Anal. Calcd for C20H15N2O3Cl: C, 65.49; H, 4.12; N, 7.64. Found: C, 65.16; H, 3.99; N, 7.58.
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17](Br)=[CH:18]4)=[CH:13][C:12]=3[O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C([Li])CCC.[B:35](OC)([O:38]C)[O:36]C.Cl>C1COCC1>[C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([B:35]([OH:38])[OH:36])=[CH:18]4)=[CH:13][C:12]=3[O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: Brc1ccc2cc(OCc3ccccc3)c(C34CC5CC(CC(C5)C3)C4)cc2c1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc2cc(OCc3ccccc3)c(C34CC5CC(CC(C5)C3)C4)cc2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3 g (6.7 mmol) of 7-(1-adamantyl)-6-benzyloxy-2-bromonaphthalene and 50 ml of THF were introduced into a three-necked flask under a stream of nitrogen. 3.2 ml (8 mmol) of n-butyllithium (2.5M in hexane) were added dropwise at -78° C. and stirring was carried out for 15 minutes, at the same temperature. 2.1 g (20 mmol) of trimethyl borate were added and stirring was carried out for 2 hours. 23 ml of hydrochloric acid (1N) were added at -50° C. and the temperature was permitted to increase to room temperature. The reaction mixture was extracted with ethyl ether and the organic phase was separated by settling, dried over magnesium sulfate and evaporated. The residue obtained was triturated in heptane, filtered and dried. 2.8 g (100%) of the expected boronic acid were collected, which acid was used, as is, in the synthesis to follow.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[C:5]([F:29])([F:28])[CH:6]([C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:27])[CH2:14][CH2:15][C:16](=[O:26])[N:17]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:18])[OH:7])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.CCOCC>[CH2:1]([O:3][C:4](=[O:30])[C:5]([F:28])([F:29])[C:6]([C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:27])[CH2:14][CH2:15][C:16](=[O:26])[N:17]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:18])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(F)(F)C(O)[C@@H]1CCCN1C(=O)CCC(=O)N(C)Cc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)C(F)(F)C(=O)[C@@H]1CCCN1C(=O)CCC(=O)N(C)Cc1ccccc1
Reaction time: 3 h
Yield: 95.7 %

Procedure:
A solution of (3RS)-3-[(2S)-l-[3-(N-benzyl-N-methylcarbamoyl) propanoyl]pyrrolidin-2-yl]-3-hydroxy-2,2-difluoropropionic acid ethyl ester (250 mg) in methylene chloride (1.5 ml) was added dropwise to a suspension of Dess-Martin reagent (448 mg) in methylene chloride (6 ml). The mixture was stirred for 3 hrs. The reaction mixture was diluted with ether. A saturated aq. solution of sodium bicarbonate (30 ml) wherein sodium thiosulfate (2.26 g) was dissolved was added to the diluted solution. The mixture was stirred for 10 mins, and extracted with EtOAc. The extract was washed, dried and evaporated. The residue was purified by column chromatography on silica gel (hexane - EtoAc) to give the title compound (238 mg) having the following physical data:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:11][C:12](=[O:22])[CH2:13][CH:14]2[CH:19]3[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]3)[CH2:15]2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:2]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:7]=[CH:6][C:5]([C:8]([NH:11][C:12](=[O:22])[CH2:13][CH:14]2[CH:19]3[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]3)[CH2:15]2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(NC(=O)CC1CN2CCC1CC2)c1ccc(Br)cc1
Product: CC(C)(NC(=O)CC1CN2CCC1CC2)c1ccc(-c2ccccc2)cc1
Yield: 29.1 %

Procedure:
Using general procedure E, N-(2-(4-bromophenyl)propan-2-yl)-2-(quinuclidin-3-yl)acetamide (200 mg, 0.550 mmol), phenylboronic acid (134 mg, 1.00 mmol) and [PdCl2(pddf)]CH2Cl2 gave the title compound as a viscous brown oil (58 mg, 32%). 1H NMR (500 MHz, CDCl3) δ 7.58-7.50 (m, 4H), 7.44-7.37 (m, 4H), 7.31 (t, J=7.0 Hz, 1H), 6.50 (s, 1H), 3.16 (m, 1H), 3.02 (m, 1H), 2.92-2.78 (m, 3H), 2.60 (m, 1H), 2.40-2.20 (m, 3H), 1.47-1.90 (m, 11H) ppm. 13C NMR (125 MHz, CDCl3) δ 170.5, 146.1, 140.7, 139.2, 128.8, 127.2, 127.0 125.2, 55.6, 53.1, 46.8, 46.2, 40.3, 31.7, 29.3, 29.2, 26.0, 24.4, 19.7 ppm. Purity: 100% LCMS (214 nm & 254 nm); retention time 1.55 min; (M+1) 363.
Reaction SMILES: [Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][NH2:16].CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O>CN(C=O)C.CCOC(C)=O>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][NH:16][C:7]([C:4]1[CH:3]=[C:2]([Br:1])[S:6][CH:5]=1)=[O:9]
Reactant: O=C(O)c1csc(Br)c1
Reactant: COc1cccc(CN)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cccc(CNC(=O)c2csc(Br)c2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
5-Bromothiophene-3-carboxylic acid (70%) (200 mg, 0.6 mmol of monobromide) was dissolved in DMF with 3-methoxybenzyl amine (0.3 g, 2.2 mmol), EDCI (0.42 g, 2.2 mmol), and HOBt hydrate (0.06 g, 0.4 mmol). The reaction mixture was stirred at room temperature for 3 days, diluted with EtOAc and the organic layer washed with 10% citric acid, saturated sodium bicarbonate, and brine. The organic layer was then dried over sodium sulfate and concentrated to an oil, which was purified by column chromatography on silica (10 to 30 5 EtOAc/hexanes) to give the product as a colorless oil, 195 mg, 0.6 mmol, 100%. 1H NMR 500 MHz (CDCl3) 7.81 (1H, s), 7.35 (1H, s), 7.28 (1H, m), 6.93 (1H, m), 6.87 (2H, m), 6.23 (1H, br s), 4.57 (2H, d), 3.84 (3H, s).