Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC1SC(C(O)=[O:13])=CC=1C)CC)C.C(C1C=CC(C(NO)=N)=CC=1)C=C.C([C:32]1[CH:37]=[CH:36][C:35]([C:38]2[N:42]=[C:41]([C:43]3[S:47][C:46]([CH2:48][N:49]([CH2:52][CH3:53])[CH2:50][CH3:51])=[C:45]([CH3:54])[CH:44]=3)[O:40][N:39]=2)=[CH:34][CH:33]=1)C=C.C[N+]1([O-])CCOCC1.[CH3:63][C:64]([CH3:66])=[O:65]>O.O=[Os](=O)(=O)=O.C(O)CCC.C(Cl)Cl>[CH2:50]([N:49]([CH2:48][C:46]1[S:47][C:43]([C:41]2[O:40][N:39]=[C:38]([C:35]3[CH:36]=[CH:37][C:32]([CH2:63][CH:64]([OH:65])[CH2:66][OH:13])=[CH:33][CH:34]=3)[N:42]=2)=[CH:44][C:45]=1[CH3:54])[CH2:52][CH3:53])[CH3:51]
Reactant: CCN(CC)Cc1sc(C(=O)O)cc1C
Reactant: C=CCc1ccc(-c2noc(-c3cc(C)c(CN(CC)CC)s3)n2)cc1
Reactant: CC(C)=O
Agent: O=[Os](=O)(=O)=O
Agent: C=CCc1ccc(C(=N)NO)cc1
Agent: C[N+]1([O-])CCOCC1
Solvent: O
Solvent: CCCCO
Solvent: ClCCl
Product: CCN(CC)Cc1sc(-c2nc(-c3ccc(CC(O)CO)cc3)no2)cc1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
{5-[3-(4-Allyl-phenyl)-[1,2,4]oxadiazol-5-yl]-3-methyl-thiophen-2-ylmethyl}-diethyl-amine (625 mg) is obtained as a yellow oil starting from 5-diethylaminomethyl-4-methyl-thiophene-2-carboxylic acid (1.50 g, 6.60 mmol) and 4-allyl-N-hydroxy-benzamidine (1.28 g, 7.26 mmol) according to Method A; LC-MS: tR=0.64 min; [M+1]+=368.20. b) To a solution of {5-[3-(4-allyl-phenyl)-[1,2,4]oxadiazol-5-yl]-3-methyl-thiophen-2-ylmethyl}-diethyl-amine (550 mg, 1.50 mmol) in acetone (7.5 mL) and water (0.5 mL), OsO4 (38 mg, as a 2.5% solution in butanol) followed by N-methyl morpholine-N-oxide (243 mg, 1.80 mmol) is added. The mixture is stirred at rt for 16 h. The clear yellow solution is diluted with DCM, washed with water (3×50 mL), dried over MgSO4, filtered, concentrated and dried to give crude title compound (619 mg) as yellow oil; LC-MS: tR=0.48 min; [M+1]+=401.70; 1H NMR (CDCl3): δ1.11 (t, J=7.0 Hz, 6H), 2.25 (s, 3H), 2.63 (q, J=7.3 Hz, 4H), 2.84-2.92 (m, 2H), 3.55 (dd, J=11.0, 7.0 Hz, 1H), 3.69-3.76 (m, 4H), 3.96-4.04 (m, 1H), 7.37 (d, J=7.8 Hz, 2H), 7.66 (s, 1H), 8.08 (d, J=7.8 Hz, 2H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C@@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:11][C:10](=[O:19])[NH:9]2)[CH:5]=[CH:4][CH:3]=1.[Br:20]C1C=CN=C(C=O)C=1>>[Br:20][C:4]1[CH:3]=[CH:2][N:7]=[C:6]([C@@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:11][C:10](=[O:19])[NH:9]2)[CH:5]=1
Reactant: O=C1N[C@H](c2cccc(Br)n2)[C@@H](c2ccccc2)O1
Reactant: O=Cc1cc(Br)ccn1
Product: O=C1N[C@H](c2cc(Br)ccn2)[C@@H](c2ccccc2)O1

Procedure:
Prepared according to the same procedure as (±)-(4R,5R)-4-(6-bromopyridin-2-yl)-5-phenyloxazolidin-2-one, starting with 4-bromopicolinaldehyde. 1H-NMR (CDCl3, 500 MHz) δ 8.49 (d, J=5.5, 1H), 7.63 (d, J=1.8, 1H), 7.50 (dd, J=5.2, 1.8, 1H), 7.36-7.48 (m, 5H), 6.77 (bs, 1H), 5.60 (d, J=5.5, 1H), 4.93 (d, J=5.5, 1H). 13C-NMR (CDCl3, 126 MHz) δ 160.2, 159.1, 151.0, 138.3, 134.3, 129.12, 129.09, 127.0, 125.7, 124.3, 83.7, 64.6. Mass spec.: 319.1 (MH)+.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=[O:4].[Br:13][C:14]1[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[CH:16][C:15]=1[OH:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:42]1[CH2:46][O:45]C[CH2:43]1>>[Br:13][C:14]1[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[CH:16][C:15]=1[O:22][C@@H:42]([CH3:43])[C:46]([OH:45])=[O:4]
Reactant: N#Cc1ccc(O)c(Br)c1
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: C1CCOC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C[C@H](Oc1ccc(C#N)cc1Br)C(=O)O
Reaction time: 20 h

Procedure:
Diethyl azodicarboxylate (2.12 g) was added to a stirred solution of 2-bromo-4-cyanophenol (2.0 g), methyl-R-lactate (1.47 g) and triphenylphosphine (2.65 g) in THF (80 ml). After 20 h, the mixture was filtered through silica using isohexane/EtOAc as solvent and the filtrate evaporated to dryness. The residue was dissolved in DCM (50 ml), treated with TFA (10 ml) and stirred for 2 h. The solution was evaporated and the residue partitioned between EtOAc and aqueous sodium bicarbonate. The aqueous was acidified with 2M hydrochloric acid, extracted with EtOAc, dried (MgSO4) and evaporated to give the subtitle compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].[F:17][C:18]([F:28])([F:27])[C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1>C(#N)C>[F:17][C:18]([F:27])([F:28])[C:19]1[CH:26]=[CH:25][C:22]([CH2:23][O:1][C:2]2[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=2)[C:5]([NH2:7])=[O:6])=[CH:21][CH:20]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: NC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)c1cccc(OCc2ccc(C(F)(F)F)cc2)c1

Procedure:
3-hydroxybenzamide (0.137 g; 1 mmol) was dissolved in anhydrous acetonitrile (20 ml) under a nitrogen atmosphere. To this was added potassium carbonate (0.138 g; 1 mmol) and 4-(trifluoromethyl)benzyl bromide (0.155 ml; 1 mmol). This mixture was left to reflux for 17 hours.
Reaction SMILES: [C:1](Cl)(=[O:10])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br.[Cl:13][C:14]1[C:23]([OH:24])=[C:22]([OH:25])[C:21]([Cl:26])=[C:20]2[C:15]=1[CH2:16][CH2:17][NH:18][CH2:19]2.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[Cl:13][C:14]1[C:23]([OH:24])=[C:22]([OH:25])[C:21]([Cl:26])=[C:20]2[C:15]=1[CH2:16][CH2:17][N:18]([C:1](=[O:10])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:19]2
Reactant: O=C(Cl)/C=C/c1ccccc1
Reactant: Oc1c(O)c(Cl)c2c(c1Cl)CCNC2
Agent: Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(/C=C/c1ccccc1)N1CCc2c(Cl)c(O)c(O)c(Cl)c2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.8 %

Procedure:
trans-Cinnamoyl chloride (79 mg, 0.476 mmol) was suspended in DMF (7 mL) together with 5,8-dichloro-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrobromide (150 mg, 0.476 mmol) followed by triethylamine (133 μL, 0.952 mmol). The resulting mixture was stirred at room temperature for 16 hours and then diluted with ethyl acetate (50 mL). The resulting mixture was washed twice with saturated sodium bicarbonate (2×40 mL), dried (MgSO4) and evaporated into a yellowish mass. Purification with column chromatography (petroleum ether/ethyl acetate 1/1→1/2) yielded 69 mg (40%) of the title compound as a yellowish solid.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:5]=2[N:6]=1.Cl[C:16]1[C:21]([Cl:22])=[CH:20][C:19]([N+:23]([O-:25])=[O:24])=[CH:18][C:17]=1[C:26](=[O:28])[CH3:27].[H-].[Na+]>CN(C=O)C>[Cl:22][C:21]1[C:16]([S:1][C:2]2[S:3][C:4]3[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:5]=3[N:6]=2)=[C:17]([C:26](=[O:28])[CH3:27])[CH:18]=[C:19]([N+:23]([O-:25])=[O:24])[CH:20]=1
Reactant: CC(=O)c1cc([N+](=O)[O-])cc(Cl)c1Cl
Reactant: FC(F)(F)c1ccc2sc(S)nc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1cc([N+](=O)[O-])cc(Cl)c1Sc1nc2cc(C(F)(F)F)ccc2s1
Yield: 86.6 %

Procedure:
The title compound was prepared using the method of example 258, starting with 5-trifluoromethyl-benzothiazole-2-thiol (239) (470 mg, 2.0 mmol), 1-(2,3-dichloro-5-nitro-phenyl)-ethanone (248) (466 mg, 2.0 mmol) and NaH (Aldrich, 60% suspension, 80 mg, 2.0 mmol) in DMF (20 mL). Compound 259 (750 mg, 87%) was obtained as a yellow solid.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH:26]=[CH2:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:30](Br)[CH:31]=[CH2:32]>CN(C=O)C.CCOC(C)=O>[CH2:32]([N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[CH:11]=2)[C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:8]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]=[CH2:27])[CH:31]=[CH2:30]
Reactant: C=Cc1ccccc1-c1[nH]c2cc(C(=O)OC)ccc2c1C1CCCCC1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCn1c(-c2ccccc2C=C)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a 0.3M solution of methyl 3-cyclohexyl-2-(2-vinylphenyl)1H-indole-6-carboxylate in dry DMF, 60% NaH (1.5 eq) in mineral oil was added at 0° C., after 1 h allyl bromide (1.5 eq) was added and the suspension was stirred at RT for 2 h. The mixture was diluted with EtOAc, washed with 1N HCl, water and brine, dried over Na2SO4 and concentrated in vacuo to give the title compound (100% as crude); MS (ES+) m/z 400 (M+H)+.
Reaction SMILES: [H-].[Na+].F[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:5]=1[S:14]([NH:17][C:18]1[N:26]=[C:25]2[N:20]([C:21]([O:29][CH3:30])=[N:22][CH:23]=[C:24]2[O:27][CH3:28])[N:19]=1)(=[O:16])=[O:15].[F:31][CH:32]([F:35])[CH2:33][OH:34].Cl>>[F:31][CH:32]([F:35])[CH2:33][O:34][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:11])([F:12])[F:13])[C:5]=1[S:14]([NH:17][C:18]1[N:26]=[C:25]2[N:20]([C:21]([O:29][CH3:30])=[N:22][CH:23]=[C:24]2[O:27][CH3:28])[N:19]=1)(=[O:16])=[O:15]
Reactant: OCC(F)F
Reactant: COc1cnc(OC)n2nc(NS(=O)(=O)c3c(F)cccc3C(F)(F)F)nc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: COc1cnc(OC)n2nc(NS(=O)(=O)c3c(OCC(F)F)cccc3C(F)(F)F)nc12
Temperature: 10 °C
Yield: 83 %

Procedure:
Sodium hydride (1.21 g, 30 mmol, as a 60% suspension in mineral oil) was charged into a round bottom flask equipped with magnetic stirring and a nitrogen blanket, washed twice with 10 mL hexanes, dried of residual hexanes under a nitrogen stream, and suspended in 1,2-dimethoxyethane (20 mL). After cooling in an ice bath to about 10° C., 2-fluoro-6-trifluoromethyl-N-(5, 8-di-methoxy[ 1,2,4]triazolo[1,5-c]pyrimidin-2-yl)benzenesulfonamide (4.21 g, about 98.5% purity, 10 mmol) was added over about 5 min, rinsing in with 1 mL 1,2-dimethoxyethane. A slight exotherm to about 13° C. occurred. Continued ice bath cooling lowered temperature to about 6° C. over about 10 min. To the off-white suspension was added 2,2-difluoroethanol (0.815 niL, 13 mmol) over about 5 min. A slight exotherm to about 13° C. occurred. The light tan suspension was stirred at about 5-10° C. for about 1 hr, then the ice bath was removed. The temperature peaked at about 28° C. (about 2° C. above room temperature) about 0.5 hr later. The tan suspension was stirred overnight (about 20 hr total reaction time), then worked up by addition of the reaction mixture over about 7 min into 5% hydrochloric acid (80 mL, 112 mmol) at about 5-10° C. with ice bath cooling. The suspension was stirred about 18 min at about 9° C., then filtered, washed twice with 15 mL water each, washed twice with 15 mL methanol each, air-dried for about 2 hr, and finally vacuum-dried at about 0.02 mm Hg for about 2 hr over phosphorus pentoxide to afford the product as a white powder (4.34 g, about 92.8% purity, 8.3 mmol, about 83% yield).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH2:9]([O:16][C:17]1[CH:18]=[CH:19][C:20]([CH3:26])=[C:21](/[CH:23]=[N:24]/[OH:25])[CH:22]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>CN(C=O)C>[CH2:9]([O:16][C:17]1[CH:18]=[CH:19][C:20]([CH3:26])=[C:21]([C:23]([Cl:1])=[N:24][OH:25])[CH:22]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1ccc(OCc2ccccc2)cc1/C=N/O
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(OCc2ccccc2)cc1C(Cl)=NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.7 %

Procedure:
N-Chlorosuccinimide (3.72 g) was added in small portions to a solution of (E)-1-(5-(benzyloxy)-2-methylphenyl)-N-hydroxymethanimine (6.40 g) in DMF (60 mL) at room temperature, and the obtained mixture was stirred at room temperature for 2 hours. To the reaction mixture, water was added, followed by extraction with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (6.05 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]([OH:15])([CH3:14])[CH2:12][OH:13])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.C(N(CC)C(C)C)(C)C.[CH3:25][N:26]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][C:38]([F:41])([F:40])[F:39])=[CH:33][CH:32]=1)[C:27](Cl)=[O:28]>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:25][N:26]([CH2:30][C:31]1[CH:32]=[CH:33][C:34]([O:37][C:38]([F:39])([F:40])[F:41])=[CH:35][CH:36]=1)[C:27](=[O:28])[O:13][CH2:12][C@@:11]([OH:15])([CH3:14])[CH2:10][N:3]1[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=[C:2]1[Cl:1]
Reactant: CN(Cc1ccc(OC(F)(F)F)cc1)C(=O)Cl
Reactant: C[C@](O)(CO)Cn1cc([N+](=O)[O-])nc1Cl
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1ccc(OC(F)(F)F)cc1)C(=O)OC[C@](C)(O)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 76.7 %

Procedure:
(R)-2-Chloro-1-(2,3-dihydroxy-2-methylpropyl)-4-nitroimidazole prepared in Example 10 (2.16 g, 9.18 mmol), N,N-diisopropylethylamine (2.67 ml, 15.30 mmol) and 4-dimethylaminopyridine (0.19 g, 1.53 mmol) were added to a suspension of N-methyl-N-(4-trifluoromethoxybenzyl)carbamoylchloride (2.05 g, 7.65 mmol) in toluene (40 ml) followed by stirring at 100° C. for 3.5 hours. The reaction mixture was diluted with ethyl acetate, and the solution washed with 10% hydrochloric acid, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=9/1) to afford (R)-3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl N-methyl-N-(4-trifluoromethoxybenzyl)carbamate (2.74 g, yield 77%) as a colorless oil.
Reaction SMILES: [C:1]1([S:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]1([CH3:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[S:22]([O:29]S(C(F)(F)F)(=O)=O)([C:25]([F:28])([F:27])[F:26])(=[O:24])=[O:23]>ClCCl.CCOCC>[O-:29][S:22]([C:25]([F:28])([F:27])[F:26])(=[O:24])=[O:23].[C:9]1([S+:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:18]2[CH:19]=[CH:20][C:15]([CH3:21])=[CH:16][CH:17]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1ccccc1
Reactant: O=S(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1ccc([S+](c2ccccc2)c2ccccc2)cc1
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 25 °C
Yield: 95.3 %

Procedure:
Both 1 g of phenyl sulfoxide and 0.51 g of toluene dissolved in 50 mL dichloromethane was stirred and then, 1.48 g of triflic anhydride was slowly added to the mixture. The reacting mixture was stirred at the same temperature for 30 minutes, and the reaction temperature was slowly increased up to room temperature. Then, the reacting mixture was washed with distilled water. After the complete removal of organic solvent contained in the washed organic layer under vacuum drying, an oil phase with larger viscosity was obtained. The oil phase, so formed, was completely dissolved in dichloromethane and with a slow addition of ether, a white precipitate was obtained. The precipitate was filtered, and dried by vaccum oven to obtain 2.01 g of diphenyl(4-methyl phenyl)sulfonium triflate (yield: 94%) in a white solid. The formula was shown in the table 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[CH2:9]([NH2:12])[CH2:10][NH2:11].[CH3:13][O-:14].[Na+]>C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[ClH:1].[NH2:11][CH2:10][CH2:9][NH:12][C:13]([C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1)=[O:14]
Reactant: Clc1ccc(Cl)nc1
Reactant: NCCN
Reactant: C[O-]
Agent: [Na+]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Product: Cl
Product: NCCNC(=O)c1ccc(Cl)cn1
Yield: 74.8 %

Procedure:
The amidation of 5 g (33.8 mmol) of 2,5-dichloropyridine in the presence of 12.1 g (202 mmol) of ethylenediamine, 8.8 mg of palladium-dichloro-bis(acetonitrile) and 21 mg of 1,3-bis(diphenylphosphino)propane is carried out at 110° in a manner analogous to Example 1. After the addition of 1.91 g (35.5 mmol) of sodium methylate and evaporation of the reaction mixture there are obtained, by extraction with 3N hydrochloric acid and subsequent basification of the acidic-aqueous solution, 5.05 g (75%) of N-(2-aminoethyl)-5-chloropyridine-2-carboxamide; content according to HPLC: 98.2 wt. %, content of N,N'-ethylene-bis(5-chloro-2-pyridinecarboxamide): <1% (GC). Conversion of the free base with hydrogen chloride in methanol into the hydrochloride and crystallization from methanol/ether yields N-(2-aminoethyl)-5-chloropyridine-2-carboxamide hydrochloride as white crystals, m.p. 191°-195°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:22])[O:10][CH2:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16](SC)=[CH:15][C:14]=2[F:21])=[CH:4][CH:3]=1.O[O:24][S:25]([O-:27])=O.[K+].[CH3:29]C(C)=O>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9](=[O:22])[O:10][CH2:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([S:25]([CH3:29])(=[O:27])=[O:24])=[CH:15][C:14]=2[F:21])=[CH:6][CH:7]=1
Reactant: CSc1ccc(C2=C(c3ccc(F)cc3)C(=O)OC2)c(F)c1
Reactant: O=S([O-])OO
Reactant: CC(C)=O
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)c1ccc(C2=C(c3ccc(F)cc3)C(=O)OC2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a solution of 3-(4-fluorophenyl)-4-(2-fluoro-4-methylsulfanylphenyl)-2,5-dihydro-2-furanone (6 g, 18.8 mmol) (obtained in step 2) in acetone (150 ml) was added a solution of oxone (34.8 g, 56.6 mmol) in water (75 ml). The reaction mixture was stirred vigorously for 2 h at 25° C. After completion of the reaction solvent was removed under low vacuum and water (200 ml) was added to it. The mixture was then extracted with EtOAc (2×100 ml), organic layers collected, combined, dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was then treated with MeOH (2×20 ml) and filtered to give 5.6 g of title compound in 85% yield as off white powder. m.p. 160°-162° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][C@H:13]2[CH2:17][CH2:16]C(=O)[C@@H:14]2[C:19]2[CH:24]=[CH:23][C:22]([CH:25]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:21][CH:20]=2)=[CH:8][CH:9]=1)=[O:4].CCN(CC)CC.[CH:48]([Cl:51])(Cl)[Cl:49]>CO>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][C@H:13]2[CH2:17][CH2:16][C:48]([Cl:51])([Cl:49])[C@@H:14]2[C:19]2[CH:20]=[CH:21][C:22]([CH:25]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:23][CH:24]=2)=[CH:8][CH:9]=1)=[O:4]
Reactant: CCCCCC(OCc1ccc(OC)cc1)c1ccc([C@H]2C(=O)CC[C@@H]2CCCc2ccc(C(=O)OC)s2)cc1
Reactant: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CCCCCC(OCc1ccc(OC)cc1)c1ccc([C@@H]2[C@@H](CCCc3ccc(C(=O)OC)s3)CCC2(Cl)Cl)cc1
Reaction time: 1 h
Yield: 49 %

Procedure:
A solution of Hydrazone 2 (prepared from 0.11 mmol of ketone as described above) in 1 mL CHCl3 was cannula transferred to a mixture of CuCl2 (107 mg, 0.80 mmol) and Et3N (50 μL, 0.36 mmol) in MeOH (1.2 mL), rinsing with 1 mL CHCl3. After 1 h, a solution of 10% conc. NH4OH/saturated NH4Cl (8 mL) was added and the mixture was extracted with CH2Cl2 (3×30 mL). The combined CH2Cl2 solution was dried (Na2SO4), filtered and evaporated. Purification by flash chromatography (0%→20% ethyl acetate/hexanes) gave compound 4 (34 mg, 49%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C@H:9]([NH:16][C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:10][C@H:11]([CH3:15])[NH:12]2)=[CH:7][C:6]=1[O:27][CH3:28])=[O:4].N1C=CC=CC=1.Cl[C:36]([O:38][CH2:39][CH3:40])=[O:37].ClC(OC)=O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C@H:9]([NH:16][C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:10][C@H:11]([CH3:15])[N:12]2[C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:7][C:6]=1[O:27][CH3:28])=[O:4]
Reactant: COC(=O)c1cc2c(cc1OC)[C@H](NC(=O)OCc1ccccc1)C[C@H](C)N2
Reactant: CCOC(=O)Cl
Agent: COC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)N1c2cc(C(=O)OC)c(OC)cc2[C@H](NC(=O)OCc2ccccc2)C[C@@H]1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
To a solution of cis-4-benzyloxycarbonylamino-6-methoxy-2-methyl-1,2,3,4-tetrahydro-quinoline-7-carboxylic acid methyl ester (0.99 g, 2.6 mmol) in anhydrous dichloromethane (30 mL) was added pyridine (0.27 mL, 3.35 mmol). The mixture was cooled to 0° C., and ethyl chloroformate (0.29 mL, 3.1 mmol) was slowly added. The reaction was stirred at 0° C. for 30 min, then at room temperature for 2.5 h. Additional aliquots of pyridine and methyl chloroformate were added to drive the reaction to completion. The reaction mixture was evaporated to dryness, and the residue was partitioned between ethyl acetate (75 ml) and water (25 ml). The organic layer was washed with water (25 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to give the crude product. Purification by silica gel chromatography using 25% ethyl acetate/hexanes as eluent afforded the title product (1.06 g). MS m/z 457 (M++1); 1H NMR (DMSO-d6) δ 1.45 (d, 3H), 6.68 (s, 1H).
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[Br:9][C:10]1[N:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][CH:11]=1>CS(C)=O>[CH2:21]([O:20][C:18]([C@@H:17]1[CH2:2][C@H:16]1[C:13]1[CH:14]=[N:15][C:10]([Br:9])=[CH:11][CH:12]=1)=[O:19])[CH3:22]
Reactant: CCOC(=O)/C=C/c1ccc(Br)nc1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccc(Br)nc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Trimethyl sulfoxonium iodide (20.8 g, 94.7 mmol) was added in small portions to a suspension of sodium hydride (4 g, 170.6 mmol) in dry DMSO (400 mL) at rt., stirred for 1 h until clear solution was obtained. A solution of (E)-ethyl 3-(6-bromopyridin-3-yl)acrylate (Intermediate F, 20 g, 78.7 mmol) in dry DMSO (20 mL) was added and stirred for 4 h. After completion, the reaction mixture was poured into ice water (700 mL), extracted with EtOAc (2×350 mL). The combined organic extracts were washed with water (250 mL), brine (250 mL) and dried over anhydrous Na2SO4, filtered and evaporated to give (trans)-ethyl-2-(6-bromopyridin-3-yl)cyclopropanecarboxylate (10 g, 47° A)) as brown liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[C:15]([C:18]4[O:19][C:20]([CH3:23])=[N:21][N:22]=4)[CH:16]=[CH:17][C:12]=3[O:11][CH:10]=2)=[CH:5][CH:4]=1.O1CCCC1.[H][H]>[C].[Pd].CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:13]3[CH:14]=[C:15]([C:18]4[O:19][C:20]([CH3:23])=[N:21][N:22]=4)[CH:16]=[CH:17][C:12]=3[O:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2coc3ccc(-c4nnc(C)o4)cc23)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(C2COc3ccc(-c4nnc(C)o4)cc32)cc1
Yield: 74.4 %

Procedure:
A mixture of 2-[3-(4-methoxyphenyl)-1-benzofuran-5-yl]-5-methyl-1,3,4-oxadiazole (447 mg, 1.46 mmol), 10% palladium carbon (50% containing water, 450 mg), tetrahydrofuran (5 mL) and methanol (15 mL) was stirred at room temperature for 48 hr under 1 atm hydrogen atmosphere. Palladium on carbon was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate), and crystallized from hexane/ethyl acetate to give the title compound (335 mg, yield 74%) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1B(O)O.Cl[C:15]1[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1.[IH:22]>>[I:22][C:15]1[CH:20]=[C:19]([C:3]2[CH:4]=[CH:5][C:6]([O:9][CH3:10])=[C:7]([F:8])[C:2]=2[F:1])[N:18]=[CH:17][N:16]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: I
Reactant: COc1ccc(B(O)O)c(F)c1F
Product: COc1ccc(-c2cc(I)ncn2)c(F)c1F

Procedure:
The compound was prepared according to Example 1 using 2,3-difluoro-4-methoxyphenylboronic acid and 4,6-dichloropyrimidine. The resultant chloro compound was converted to iodo with hydroiodic acid as described in the general procedure.