Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)[N:6]=1.[C:27]([Cl:31])(=[O:30])[CH2:28][CH3:29].[ClH:32]>O1CCCC1.N1C=CC=CC=1>[ClH:31].[ClH:32].[CH:14]([N:11]1[CH2:12][CH2:13][N:8]([CH2:7][C:5]2[N:6]=[C:2]([NH:1][C:27](=[O:30])[CH2:28][CH3:29])[S:3][CH:4]=2)[CH2:9][CH2:10]1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1nc(CN2CCN(C(c3ccccc3)c3ccccc3)CC2)cs1
Reactant: CCC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCC(=O)Nc1nc(CN2CCN(C(c3ccccc3)c3ccccc3)CC2)cs1

Procedure:
To a solution of 2-amino-4-(4-benzhydrylpiperazin-1-ylmethyl)thiazole (1.1 g) in tetrahydrofuran (10 ml) and pyridine (5 ml) was added dropwise propionyl chloride (0.92 ml) under ice-cooling with stirring, and the stirring was continued at the same temperature for an hour. After concentration of the reaction mixture the residue was extracted with ethyl acetate, followed by washing with an aqueous solution of sodium bicarbonate and water and drying over anhydrous magnesium sulfate. Removal of the solvent gave an oil, which was transformed into its hydrochloride in a conventional manner, followed by recrystallization from a mixture of methanol and diethyl ether to obtain white crystals (0.8 g) of 4-(4-benzhydrylpiperazin-1-ylmethyl)-2-propionamidothiazole dihydrochloride, mp 181°-184° C. (dec.).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:7]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]([Br:23])[CH:17]=3)[C:14](=[O:24])[O:13][N:12]=2)=[N:8][O:9][N:10]=1.Cl[S:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])(=[O:28])=[O:27].C(N(CC)CC)C>ClCCl>[Br:23][C:18]1[CH:17]=[C:16]([N:15]2[C:14](=[O:24])[O:13][N:12]=[C:11]2[C:7]2[C:6]([NH:5][CH2:4][CH2:3][NH:2][S:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])(=[O:27])=[O:28])=[N:10][O:9][N:8]=2)[CH:21]=[CH:20][C:19]=1[F:22]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)Cl
Reactant: NCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NS(=O)(=O)NCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Temperature: -15 °C
Reaction time: 0.17 h

Procedure:
A 22 L flask was charged with 3-{4-[(2-aminoethyl)amino]-1,2,5-oxadiazol-3-yl}-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one hydrochloride (661 g, 1.57 mol) and 8.5 L dichloromethane. After cooling to −15° C. with an ice/salt bath, the solution of tert-butyl [chlorosulfonyl]carbamate (prepared as above) was added at a rate so that the temperature did not exceed −10° C. (addition time 7 min). After stirring for 10 min, triethylamine (1085 mL, 7.78 mol) was added at a rate so that the temperature did not exceed −5° C. (addition time 10 min). The cold bath was removed, the reaction was allowed to warm to 10° C., split into two portions, and neutralized with 10% conc HCl (4.5 L each portion). Each portion was transferred to a 50 L separatory funnel and diluted with ethyl acetate to completely dissolve the white solid (˜25 L). The layers were separated, and the organic layer was washed with water (5 L), brine (5 L), and the solvents removed in vacuo to afford an off-white solid. The solid was triturated with MTBE (2×1.5 L) and dried to a constant weight to afford a white solid. A total of 4113 g starting material was processed in this manner (5409 g, 98%). 1H NMR (400 MHz, DMSO-d6): δ 10.90 (s, 1H), 8.08 (dd, J=6.2, 2.5 Hz, 1H), 7.72 (m, 1H), 7.59 (t, J=8.6 Hz, 1H), 6.58 (t, J=5.7 Hz, 1H), 3.38 (dd, J=12.7, 6.2 Hz, 2H), 3.10 (dd, J=12.1, 5.9 Hz, 2H), 1.41 (s, 9H).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].C[N:7]([CH:9]=O)[CH3:8].N1[C:12](=[O:20])[CH:13]=[C:14]2C=1[CH:18]=[CH:17][CH:16]=[CH:15]2.C([O-])(O)=O.[Na+]>ClCCl.N1C=CC=CC=1>[Cl:3][C:9]1[NH:7][C:8]2[C:14]([C:13]=1[CH:12]=[O:20])=[CH:15][CH:16]=[CH:17][CH:18]=2
Reactant: CN(C)C=O
Reactant: O=C1C=c2ccccc2=N1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=Cc1c(Cl)[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
POCl3 (100 ml) was added dropwise to a mixture of dry DMF (100 ml) and dichloromethane (100 ml) kept at 0° C. Indolone (50 g) dissolved in dichloromethane (200 ml) and pyridine (50 ml) was added dropwise at 0° C. over a period of 1.5 h. Subsequent stirring at 0° C. for 1 h. The mixture was poured onto icewater (2000 ml) neutralised with NaHCO3 whereafter the mixture was stirred overnight. The aqueous phase was decanted and the organic phase evaporated followed by extraction with ethanol (boiling). The ethanolic phase was evaporated and the crystalline residue recrystallized from ethanol yielding 70 g of (1), m.p. 227° C.
Reaction SMILES: C(O[C:9]([N:11]1[CH2:15][C@H:14]([CH2:16][CH3:17])[C@H:13]([NH:18]C(OC(C)(C)C)=O)[CH2:12]1)=O)C1C=CC=CC=1.F[C:27]1[C:36](C)=[C:35]2[C:30]([C:31](=[O:45])[C:32]([C:42]([OH:44])=[O:43])=[CH:33][N:34]2[C@@H:38]2[CH2:40][C@@H:39]2[F:41])=[CH:29][CH:28]=1.C(N(CC)CC)C>[C].[Pd].CO>[NH2:18][C@H:13]1[C@@H:14]([CH2:16][CH3:17])[CH2:15][N:11]([C:9]2[C:36]([CH3:27])=[C:35]3[C:30]([C:31](=[O:45])[C:32]([C:42]([OH:44])=[O:43])=[CH:33][N:34]3[C@@H:38]3[CH2:40][C@@H:39]3[F:41])=[CH:29][CH:28]=2)[CH2:12]1
Reactant: CC[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1NC(=O)OC(C)(C)C
Reactant: Cc1c(F)ccc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: CC[C@H]1CN(c2ccc3c(=O)c(C(=O)O)cn([C@@H]4C[C@@H]4F)c3c2C)C[C@H]1N
Temperature: 65 °C
Reaction time: 192 h
Yield: 50.1 %

Procedure:
A 10% palladium carbon catalyst (27 mg) was added to a solution of (3S,4S)-1-(benzyloxycarbonyl)-3-(tert-butoxycarbonylamino)-4-ethylpyrrolidine (270 mg, 775 μmol) in methanol (7.75 mL), and the resultant mixture was stirred under a hydrogen atmosphere at room temperature for 15 hours. After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in dimethyl sulfoxide (3 mL), and 7-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (216 mg, 775 μmol) and triethylamine (130 μL, 930 μmol) were added to the solution, followed by stirring in an oil bath at 65° C. for 8 days. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (50 mL). The solution was washed sequentially with a 10% aqueous citric acid solution (30 mL), water (30 mL×2), and saturated brine (30 mL), followed by drying over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. Subsequently, concentrated hydrochloric acid (2 mL) was added to the obtained residue at room temperature, and the resultant mixture was transferred to a separatory funnel with water (20 mL), followed by washing by chloroform (30 mL×2). The pH of the obtained aqueous layer was adjusted to 12.0 with a 10 mol/L aqueous sodium hydroxide solution under cooling with ice. The pH was adjusted again to 7.4, and the resultant mixture was extracted with chloroform (100 mL×3). The combined organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained residue was recrystallized from hot ethanol, and dried under reduced pressure, to thereby yield the title compound as pale yellow crystals (145 mg, 50.1%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:15][CH2:16][CH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][C:18]1=[O:26])[CH2:12][CH2:13][OH:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36].O>ClCCl>[CH2:1]([O:8][C:9]([N:11]([CH2:15][CH2:16][CH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][C:18]1=[O:26])[CH2:12][CH2:13][O:14][S:35]([CH3:34])(=[O:37])=[O:36])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1Nc2ccccc2C1CCN(CCO)C(=O)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)OCCN(CCC1C(=O)Nc2ccccc21)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 51 %

Procedure:
3-[2-[N-(Benzyloxycarbonyl)-N-(2-hydroxyethyl)amino]ethyl]-2,3-dihydro-1H-indol-2-one (256 mg) was dissolved in dichloromethane (5 ml), added with triethylamine (0.20 ml) and methanesulfonyl chloride (0.11 ml) with ice cooling and stirred at room temperature for 1.5 hours. The reaction mixture was added with water (5 ml) and extracted twice with dichloromethane (5 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate=1:2) to obtain 158 mg of the title compound. Yield: 51%.
Reaction SMILES: O.C[N+]1([O-])CC[O:6]CC1.[Br:10][C:11]1[CH:12]=[CH:13][C:14]([F:38])=[C:15]([C@:17]23[CH2:26][O:25][C@@H:24]([CH2:27][OH:28])[CH2:23][C@H:22]2[CH2:21][S:20][C:19]([NH:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[N:18]3)[CH:16]=1.CC(O)C>C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[C:30]([NH:29][C:19]1[S:20][CH2:21][C@@H:22]2[CH2:23][C@H:24]([C:27]([OH:6])=[O:28])[O:25][CH2:26][C@:17]2([C:15]2[CH:16]=[C:11]([Br:10])[CH:12]=[CH:13][C:14]=2[F:38])[N:18]=1)(=[O:37])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C(NC1=N[C@@]2(c3cc(Br)ccc3F)CO[C@@H](CO)C[C@H]2CS1)c1ccccc1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: CC(C)O
Solvent: O
Solvent: CC#N
Product: O=C(NC1=N[C@@]2(c3cc(Br)ccc3F)CO[C@@H](C(=O)O)C[C@H]2CS1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 113.7 %

Procedure:
N-Methylmorpholine N-oxide monohydrate (3.38 g, 25.0 mmol) and tetrapropylammonium perruthenate (0.147 g, 0.417 mmol) were added to a solution of N-[(4aR,6R,8aS)-8a-(5-bromo-2-fluorophenyl)-6-(hydroxymethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C33) (2.0 g, 4.17 mmol) in acetonitrile (75 mL). The reaction mixture was allowed to stir at room temperature for 16 hours. 2-Propanol (200 mL) was added to the reaction mixture and the resulting solution was left stirring at room temperature for 35 minutes. After that time, the reaction mixture was concentrated under reduced pressure. The oily residue was partitioned between aqueous 0.25 M sodium hydroxide (200 mL) and a 1:1 solution of diethyl ether:ethyl acetate (200 mL each). The layers were isolated and the organic layer was washed with aqueous 0.25 M sodium hydroxide (3×200 mL). The combined aqueous layers were then acidified to pH 1 with 2 M aqueous hydrochloric acid (300 mL). The now heterogeneous mixture was extracted with ethyl acetate (4×200 mL). The combined organics were then dried over sodium sulfate, filtered and concentrated under reduced pressure to give the product (2.34 g) as a purple solid, which was taken directly to the following step. LCMS m/z 495.1 [M+H+]. 1H NMR (400 MHz, CD3OD) δ 8.08-8.11 (m, 1H), 7.50-7.64 (m, 4H), 7.17-7.22 (m, 1H), 4.39 (dd, J=11.8, 2.8 Hz, 1H), 4.20 (d, J=12.1 Hz, 1H), 4.04-4.07 (m, 1H), 3.06 (dd, J=12.9, 4.3 Hz, 1H), 2.92 (dd, J=13.7, 3.1 Hz, 1H), 2.13-2.18 (m, 1H), 2.05-2.09 (m, 1H), 1.99-2.02 (m, 4H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([OH:24])[CH2:15][C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(OCC)(=O)C.[Pd]>[ClH:23].[F:22][C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:23])[C:16]=1[CH2:15][C:14]([CH:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[OH:24]
Reactant: OC(Cc1c(F)cccc1Cl)(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: Cl
Product: OC(Cc1c(F)cccc1Cl)(c1ccccc1)C1CNCCO1
Temperature: 25 °C
Yield: 74.8 %

Procedure:
To a solution of 1-(4-Benzyl-morpholin-2-yl)-2-(2-chloro-6-fluoro-phenyl)-1-phenyl-ethanol (450 mg, 1 equiv.) in ethyl acetate (15 mL) at room temperature under nitrogen atmosphere was added ammonium formate (1.69 g, 25 equiv.) followed by addition of palladium on charcoal (10%, 450 g.). The reaction mixture was heated to reflux for 1.5 hours, cooled to room temperature and then filtered through Celite. All volatiles were evaporated under vacuum, and the resulting solid was purified via preparative HPLC. The isolated white solid was taken up in ethanol. Hydrogen chloride was added (large excess of 2M solution in diethyl ether) and the mixture was stirred until it became a clear solution. Then all the volatiles were evaporated “in vacuo”, to give 147 mg of the title compound as white solid. 1H NMR (300 MHz, CD3OD D4) δ: 2.51-2.61 (d, 1H), 2.79-2.91 (t, 1H), 2.96-3.09 (m, 1H), 3.09-3.16 (m, 1H), 3.32-3.54 (q, 2H), 3.82-3.97 (t, 1H), 4.09-4.24 (t, 2H), 6.73-6.84 (t, 1H), 6.93-7.08 (m, 2H), 7.08-7.21 (m, 5H). LCMS (12 minutes method) [M+H]+=336 @ Rt 4.44 min. single major peak.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][NH2:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[N+](C1C=CC(NN[CH:23]=[O:24])=CC=1)([O-])=O>>[N+:1]([C:4]1[CH:5]=[C:6]([NH:10][NH:11][CH:23]=[O:24])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NNc1cccc([N+](=O)[O-])c1
Reactant: O=CNNc1ccc([N+](=O)[O-])cc1
Product: O=CNNc1cccc([N+](=O)[O-])c1

Procedure:
By reacting 3-nitrophenylhydrazine as in the same manner as (1), 430 g of 2-(3-nitrophenyl)-1-formylhydrazine was obtained. Melting point: 168° to 169° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[C:14]1([C:20]2[O:24][N:23]=[CH:22][C:21]=2[CH2:25][CH2:26][C:27](O)=[O:28])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[N:6]=[C:2]([NH:1][C:27](=[O:28])[CH2:26][CH2:25][C:21]3[CH:22]=[N:23][O:24][C:20]=3[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[S:3][CH:4]=2)=[CH:12][CH:11]=1
Reactant: Nc1nc(-c2ccc(Cl)cc2)cs1
Reactant: O=C(O)CCc1cnoc1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CCc1cnoc1-c1ccccc1)Nc1nc(-c2ccc(Cl)cc2)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.7 %

Procedure:
A mixture of 2-amino-4-(4-chlorophenyl)thiazole (0.75 g), 3-(5-phenyl-4-isoxazolyl)propionic acid (0.72 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.55 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.70 g) and N,N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-[4-(4-chlorophenyl)-2-thiazolyl]-3-(5-phenyl-4-isoxazolyl)propionamide (0.58 g, yield 43%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 172–173° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[C:16]([C:18]([CH3:20])=[CH2:19])[CH:17]=2)[C:11]([O:13]C)=[O:12])=[N:6][CH:7]=1.[OH-].[Na+:22].Cl>CO>[Cl-:1].[Na+:22].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[C:16]([C:18]([CH3:20])=[CH2:19])[CH:17]=2)[C:11]([OH:13])=[O:12])=[N:6][CH:7]=1
Reactant: C=C(C)c1cc(C(=O)OC)cc(-c2ccc(Cl)cn2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=C(C)c1cc(C(=O)O)cc(-c2ccc(Cl)cn2)c1
Product: [Cl-]
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
To a solution of methyl 3-(5-chloropyridin-2-yl)-5-isopropenylbenzoate (0.13 g, 0.46 mmol) in methanol (3.1 mL) was added 1 M aqueous sodium hydroxide (0.92 mL, 0.92 mmol) and the mixture was heated to 60° C. After 45 min, hydrochloric acid (76 uL, 092 mmol) was added and the mixture was concentrated to dryness gave the bis sodium chloride salt of the title compound. MS 274.0 (M+1).
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1)(=[O:3])[CH3:2].C([O-])(=O)C.[K+].[C:18](=[S:20])=[S:19].[CH2:21](Cl)[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23]>CO>[C:1]([NH:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:22]([OH:23])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:21][S:19][C:18]2=[S:20])=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: S=C=S
Reactant: O=C(CCl)c1ccccc1
Reactant: CC(=O)NNc1ccc(N)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CO
Product: CC(=O)NNc1ccc(N2C(=S)SCC2(O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-Acetyl-2-(4-aminophenyl)hydrazine (8.25 g., 0.05 mole) was added to a solution of potassium acetate (4.9 g., 0.05 mole) in methanol (50 ml). The temperature was maintained below 10° C throughout the remainder of the reaction. Carbon disulfide (3.8 g., 0.05 mole) mixed with methanol (5 ml) was added dropwise to the stirred suspension which was stirred for one hour. Phenacyl chloride (3.9 g., 0.02 mole) dissolved in methanol (15 ml) was added dropwise with stirring and the reaction mixture stirred for one and one-half hours. The resulting solution was allowed to warm to room temperature; most of the methanol was removed under vacuum. The solution was diluted with water. The product separated out as a white gummy material which crystallized on stirring and chilling. The white solid was collected by filtration, washed with water, and allowed to dry at room temperature. Yield 8.7 g (97%), m.p. 80°-84° C.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]([C:11]1[C:16]([C:17]([F:20])([F:19])[F:18])=[N:15][C:14]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[C:13]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=2)[N:12]=1)=[O:10].COC(C1C(C(F)(F)F)=NC(Br)=C(C2C=CC([Cl:55])=C(Cl)C=2)N=1)=O>>[OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]([C:11]1[C:16]([C:17]([F:18])([F:19])[F:20])=[N:15][C:14]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[C:13]([C:27]2[CH:32]=[CH:31][C:30]([Cl:55])=[C:29]([Cl:33])[CH:28]=2)[N:12]=1)=[O:10]
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1nc(-c2cccc(Cl)c2)c(OCC(F)(F)F)nc1C(F)(F)F
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(Cl)c2)c(Br)nc1C(F)(F)F
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1nc(-c2ccc(Cl)c(Cl)c2)c(OCC(F)(F)F)nc1C(F)(F)F

Procedure:
In analogy to example 4 (6-(3-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-3-trifluoromethyl-pyrazine-2-carboxylic acid ((1R,2R)-2-hydroxy-cyclohexyl)-amide) the title compound was prepared by substituting 5-bromo-6-(3-chloro-phenyl)-3-trifluoromethyl-pyrazine-2-carboxylic acid methyl ester with 5-bromo-6-(3,4-dichloro-phenyl)-3-trifluoromethyl-pyrazine-2-carboxylic acid methyl ester.
Reaction SMILES: O[C:2]1([CH:9]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)[C:10]2[NH:11][CH:12]=[CH:13][N:14]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.S(Cl)(Cl)=O>ClCCl>[C:2]1(=[C:9]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)[C:10]2[NH:14][CH:13]=[CH:12][N:11]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: N#Cc1ccc(C(c2ncc[nH]2)C2(O)CCCCCC2)cc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: N#Cc1ccc(C(=C2CCCCCC2)c2ncc[nH]2)cc1
Reaction time: 18 h
Yield: 21.6 %

Procedure:
At 0°, 10 g of crude 4-[1-hydroxycyclohept-1-yl-1-(imidazolyl)methyl]benzonitrile is dissolved in 100 ml of dichloromethane and stirred with 10 ml of thionyl chloride for 4 hours. Then the mixture is concentrated to dryness under an oil pump vacuum, taken up in 100 ml of dichloromethane, and stirred with 40 ml of triethylamine for 18 hours at 25°. For working up purposes, the mixture is combined with water, extracted twice with dichloromethane, dried over sodium sulfate, concentrated to dryness under vacuum, and chromatographed on silica gel with hexane/ethyl acetate, thus producing 2.03 g of 4-[1-cycloheptylidene-1-(imidazolyl)methyl]benzonitrile as the oily, free base.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[C:29]2[N:28]=[C:26]([NH2:27])[NH:25][C:23](=[O:24])[C:22]=2[N:21]=[CH:20]1)(=[O:3])[CH3:2].C=O.[CH3:32][C:33]1[CH:38]=[CH:37][C:36]([SH:39])=[CH:35][CH:34]=1.[C:40](O)(=O)C>C(O)C>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[C:29]2[N:28]=[C:26]([NH:27][CH2:40][S:39][C:36]3[CH:37]=[CH:38][C:33]([CH3:32])=[CH:34][CH:35]=3)[NH:25][C:23](=[O:24])[C:22]=2[N:21]=[CH:20]1)(=[O:3])[CH3:2]
Reactant: Cc1ccc(S)cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(=O)O
Agent: C=O
Solvent: CCO
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(NCSc4ccc(C)cc4)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 75 %

Procedure:
2′,3′,5′-Tri-O-acetylguanosine 1 (4.6 g, 11.2 mmol, 1.0 eq), 37% aqueous formaldehyde (4.7 mL, 156 mmol, 14 eq), p-thiocresol (4.6 g, 37 mmol, 3.3 eq), and acetic acid (2 mL) were added into 50 mL of ethanol. The mixture was heated under reflux for 4 h. The mixture was cooled and the white precipitate was collected by filtration. Product was recrystallized from water to obtain the pure solid compound 2 in 75% yield (4.58 g, 8.4 mmol). TLC (CH2Cl2:MeOH, 9:1 v/v): Rf=0.57; 1H NMR (DMSO-d6, 400 MHz) δ (ppm): 2.03 (s, 6H), 2.09 (s, 3H), 2.25 (s, 3H), 4.26-4.29 (m, 1H), 4.30-4.34 (m, 1H), 4.9 (br.s, 2H), 5.48 (br.s, 1H), 5.77 (t, 1H), 5.97 (d, J=6.4 Hz, 1H), 6.1 (br.s, 1H), 6.54 (br.s, 1H), 7.11 (d, J=7.2 Hz, 2H), 7.3 (d, J=7 Hz, 2H), 7.9 (s, 1H), 10.7 (br.s, 1H); 13C NMR (DMSO-d6, 400 MHz) δ (ppm): 20.2, 20.4, 20.5, 63.5, 67.2, 70.3, 72.06, 79.55, 84.44, 129.53, 129.54, 135.67, 153.94, 156.69, 169.31, 169.49.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[C:10](=[C:12]([C:16]([OH:18])=O)[CH:13]=[CH:14][CH:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.C(=O)(O)[O-].[Na+].[CH3:35][C:36]1[N:37]([CH2:41][CH2:42][CH2:43][NH2:44])[CH:38]=[CH:39][N:40]=1>C(Cl)Cl>[CH3:35][C:36]1[N:37]([CH2:41][CH2:42][CH2:43][NH:44][C:16]([C:12]2[CH:13]=[CH:14][CH:15]=[C:9]3[O:8][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:11][C:10]=23)=[O:18])[CH:38]=[CH:39][N:40]=1
Reactant: Cc1nccn1CCCN
Reactant: O=C(O)c1cccc2oc(-c3ccccc3)nc12
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nccn1CCCNC(=O)c1cccc2oc(-c3ccccc3)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 14 %

Procedure:
A 100-mL one-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 2-phenylbenzoxazole-4-carboxylic acid (0.190 g, 0.79 mmol), DMF (0.588 g, 8.00 mmol) and anhydrous methylene chloride (15 mL). The resulting solution was treated with oxalyl chloride (1.46 g, 11.5 mmol) dropwise over 5 min and stirred at ambient temperature under nitrogen for 2 h. After this time, the reaction mixture was evaporated to a solid residue which was dissolved in anhydrous methylene chloride (15 mL). The resulting solution was treated with sodium bicarbonate (0.672 g, 8.00 mmol) and stirred at ambient temperature under nitrogen for 15 min. After this time, a solution of 3-(2-methylimidazol-1-yl)propylamine (0.332 g, 2.39 mmol) in anhydrous methylene chloride (5 mL) was added and the mixture stirred for a further 20 h. The reaction mixture was then diluted with methylene chloride (50 mL) and washed with 10% aqueous potassium carbonate (10 mL) followed by water (20 mL). The organic phase was dried over sodium sulfate, filtered and evaporated to a solid residue which was further purified by preparative HPLC to give 0.040 g (14% yield) of N-[3-(2-methylimidazol-1-yl)propyl]-2-phenylbenzoxazole-4-carboxamide as a white solid: mp 145-148° C.; 1H NMR (300 MHz, CD3OD) δ 8.33 (m, 2H), 8.03 (dd, J=7.8, 0.9 Hz, 1H), 7.86 (dd, J=8.2, 0.9 Hz, 1H), 7.69-7.59 (m, 4H), 7.52 (t, J=8.0 Hz, 1H), 7.38 (d, J=2.1 Hz, 1H), 4.32 (t, J=7.1 Hz, 2H), 3.67 (t, J=7.1 Hz, 2H), 2.65 (s, 3H), 2.31 (m, 2H); MS (ESI) m/z 361 [M+H]+.