Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Ca+2].[I:14](Cl)(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1>ClCCl.CO>[NH2:1][C:2]1[C:7]([I:14])=[N:6][C:5]([Cl:8])=[CH:4][CH:3]=1
Reactant: O=I(=O)Cl
Reactant: Nc1ccc(Cl)nc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Solvent: ClCCl
Product: Nc1ccc(Cl)nc1I
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.1 %

Procedure:
23.2 g (180.5 mM) of 5-amino-2-chloropyridine are mixed in 70 ml of dichloro-methane (DCM) and 180 ml of methanol, and 21.6 g (216 mM) of calcium carbonate and 75.3 g (226 mM) of benzyltrimethylammonium dichloroiodate are added. The reaction mixture is stirred at room temperature for 16 hours, and then filtered to remove the mineral salts. The filtrate is diluted with water and extracted with DCM. The organic phase obtained is washed with sodium chloride solution, and then with saturated sodium thiosulfate solution, dried over magnesium sulfate and concentrated under reduced pressure. An oil is obtained, which is purified by chromatography on silica gel, eluting with a cyclohexane/ethyl acetate mixture (80/20 and then 70/30; v/v). 13.9 g of the expected product are thus obtained in the form of an orange-colored solid (yield=30%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=O)(=[O:13])=[O:12].[N:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[N:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:28][CH2:29][N:30]([C:18]([CH2:17][CH2:16][CH2:15][NH:14][S:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)(=[O:12])=[O:13])=[O:20])[CH2:31][CH2:32]2)=[CH:23][CH:22]=1
Reactant: O=C(O)CCCNS(=O)(=O)c1ccc2ccccc2c1
Reactant: c1cc(N2CCNCC2)ccn1
Product: O=C(CCCNS(=O)(=O)c1ccc2ccccc2c1)N1CCN(c2ccncc2)CC1
Yield: 15 %

Procedure:
Using an analogous procedure to that described in Example 36, 4-(2 -naphthalenesulphonamido)butyric acid was reacted with 1-(4 -pyridyl)piperazine to give N-{3-[4-(4-pyridyl)piperazin-1-ylcarbonyl]propyl]naphthalene-2-sulphonamide in 15% yield as a foam;
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1>C(#N)C>[CH:5]1[C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=[C:9]2[C:4]=1[C:3]1[C:2]([NH:1]2)=[C:2]2[NH:1][C:9]3[CH:8]=[CH:7][C:6]([C:10]([OH:12])=[O:11])=[CH:5][C:4]=3[C:3]2=[C:2]2[NH:1][C:9]3[CH:8]=[CH:7][C:6]([C:10]([OH:12])=[O:11])=[CH:5][C:4]=3[C:3]=12
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Solvent: CC#N
Product: O=C(O)c1ccc2[nH]c3c4[nH]c5ccc(C(=O)O)cc5c4c4c5cc(C(=O)O)ccc5[nH]c4c3c2c1
Reaction time: 0.25 h
Yield: 89.9 %

Procedure:
15 ml of acetonitrile was poured into a 200 ml three-neck flask, and 1.61 g of indole-5-carboxylic acid was dissolved therein. On the other hand, preparation of an oxidant solution was performed by dissolving 47.4 g of cupric tetrafluoroborate n-hydrate (Cu content: 20%) in 100 ml of acetonitrile and agitating the mixture for 15 minutes. pH of the reaction solution was less than 1. Then the prepared oxidant solution was dripped over 60 minutes into the indole-5-carboxylic acid solution, and the resultant mixture solution was agitated for 5 hours at the temperature of 30° C. Color of the reaction solution changed from yellow to blue-green with slight heat generation. After the end of the reaction, the reaction liquid was suction-filtered with a perforated funnel, and the filtrate was washed with acetonitrile and then methanol, and was dried to obtain 1.43 g of 6,11-dihydro-5H-diindolo [2,3-a:2′,3′-c]carbazole-2,9,14-tricarboxylic acid (indole-5-calboxylic acid trimer) with a blue-green color (yield: 89%). The resultant trimer was pressure-molded with a tablet molding machine and the mold was cut into a piece with the diameter of 10 mm and thickness of 1 mm. A conductivity thereof was measured by the four terminal method, and found to be 0.40 S/cm. The result of elemental analysis was: <C9.00H4.95N0.98O1.99Cl0.13>3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[Cl:15][C:16]1[N:24]=[C:23]2[C:19]([NH:20][CH:21]=[N:22]2)=[C:18]([Cl:25])[N:17]=1>>[Cl:15][C:16]1[N:24]=[C:23]2[C:19]([N:20]=[CH:21][N:22]2[C@@H:12]([C@@:9]2([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])[CH2:11][O:10]2)[CH3:13])=[C:18]([Cl:25])[N:17]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](n1cnc2c(Cl)nc(Cl)nc21)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 17.5 %

Procedure:
Using (1S)-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol (578 mg) and 2,6-dichloropurine (490 mg), (2S)-2-[(1R)-1-[2,6-dichloro-9(9H)-purinyl]ethyl]-2-(2,4-difluorophenyl)oxirane (168 mg) was obtained by the same way as in Reference Example 2.
Reaction SMILES: [C:1]([O:5][CH:6]([CH2:15][S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:7][S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:4])[CH:2]=[CH2:3].[CH2:23]([SH:35])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].O>C(O)C>[CH2:23]([S:35][CH2:3][CH2:2][C:1]([O:5][CH:6]([CH2:7][S:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:15][S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:4])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: C=CC(=O)OC(CSc1ccccc1)CSc1ccccc1
Reactant: CCCCCCCCCCCCS
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCSCCC(=O)OC(CSc1ccccc1)CSc1ccccc1

Procedure:
A solution of 15 grams of 1,3-bis-(phenylthio)-2-propyl acrylate, 9.2 grams of dodecanethiol, and 1 milliliter of "Triton B" in 75 milliliters of ethanol was heated under reflux for 53/4 hours. The reaction mixture was allowed to cool and was then poured into water. The oil which precipitated was separated by extraction with toluene and the toluene solution was stripped on a rotary evaporator. There remained 24.0 grams of a light colored oil which was identified as 1,3-bis-(phenylthio)-2-propyl 3-(dodecylthio)propionate by means of its NMR spectrum.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][N+:8]([O-])=[C:7]([CH3:12])[C:6]=1[CH3:13])(=[O:4])=[O:3].C(O)(=[O:16])C.C(OC(=O)C)(=O)C>CO>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:12][OH:16])[C:6]=1[CH3:13])(=[O:4])=[O:3]
Reactant: CC(=O)O
Reactant: Cc1c(S(C)(=O)=O)cc[n+]([O-])c1C
Solvent: CC(=O)OC(C)=O
Solvent: CO
Product: Cc1c(S(C)(=O)=O)ccnc1CO
Temperature: 80 °C

Procedure:
To a mixture of (4-Methanesulfonyl-2,3-dimethyl-pyridine)-1-oxide (24 g) and acetic acid (50 ml) was added acetic anhydride (28.2 ml), followed by heating to reflux and maintaining the same temperature for about 3 hrs. The reaction mass was cooled to 80° C. and methanol (25 ml) was added followed distilling off the solvent completely under vacuum. THF:methanol (125:25 ml), LiOH (7.5 g) was added to the crude at 25-30° C. followed by adding DCM (100 ml) to the reaction mixture and extraction with (2×150 ml) DCM. All the organic layers were combined and washed with saturated sodium chloride solution (25 ml). The organic layer was dried over sodium sulphate and distilled off completely under vacuum. Subsequently, n-hexane (100 ml) was added to the reaction mass, the compound filtered and washed with n-hexane (10 ml). The wet compound was then dried at 50-55° C. to yield 14 g of the title compound characterized by 1HNMR data (300 MHz): δ 2.58 (s, 3H), 3.13 (s, 3H), 4.62 (s, 1H), 4.80 (s, 2H), 7.86 (d, 1H), 8.68 (d, 1H) and mass [M]+: 202.06.
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[C:14]1([C:20]2[CH:24]=[CH:23][S:22][C:21]=2[CH:25]=[O:26])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O)(C)C>CC(C)=O>[C:14]1([C:20]2[CH:24]=[CH:23][S:22][C:21]=2[C:25]([OH:3])=[O:26])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)=O
Reactant: O=Cc1sccc1-c1ccccc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: O=C(O)c1sccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46 %

Procedure:
8N Jones' reagent (ca. 10 ml) was added dropwise to a solution of 3-phenylthiophen-2-aldehyde (5) (0.58 g, 3.1 mmol) in 32 ml of acetone, until an orange colour persisted. The mixture was stirred at room temperature for 18 hrs. Isopropanol (5 ml) was added to remove the excess Jones' reagent and the mixture was then filtered, the organic solvents were evaporated under vacuum and extracted with ethyl acetate (4×100 ml). The combined organic layer was washed with a saturated solution of NaCl, dried (Na2SO4), and evaporated under reduced pressure. The mixture was then chromatographed using 95/5 chloroform/methanol, thus giving the compound (6) (0.44 g, 1.36 mmol, 46% yield) (M.Pt. 200-202° C.). 1H-NMR (CDCl3) ä 6.87-7.37 (m, 5H, Ph-H), 7.05 (d J=5.0 Hz, 1H, th-H4), 7.53 (d J=5.0 Hz, 1H, th-H5).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[C:15]=1[CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][C:11]1[CH:23]=[CH:24][CH:25]=[CH:26][C:10]2=1)=[O:5])[CH3:2].[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30]>C(Cl)Cl>[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[C:15]=1[CH2:14][NH:13][CH2:12][C:11]1[CH:23]=[CH:24][CH:25]=[CH:26][C:10]2=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncn2c1CN(C(=O)OC(C)(C)C)Cc1ccccc1-2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1ncn2c1CNCc1ccccc1-2
Reaction time: 2 h
Yield: 93 %

Procedure:
To a solution of 4H,6H-2,5,10b-Triaza-benzo[e]azulene-3,5-dicarboxylic acid 5-tert-butyl ester 3-ethyl ester (300 mg, 1.14 mmol) in DCM (30 mL), was added trifluoroacetic acid (3.42 mL, 3 ml/mmol) and the reaction mixture was stirred for 2 h. After the completion of the reaction as confirmed by TLC, excess of trifluoroacetic acid and DCM were removed in vacuo to afford 5,6-dihydro-4H-2,5,10b-triaza-benzo[e]azulene-3-carboxylic acid ethyl ester trifluoroacetate (295 mg, 93%) as a gummy solid which was used without any further purification for the next step.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][C:19](=[O:29])[C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=2)=[N:2]1.[Cl-].[NH4+].C(O)C>[Fe].O>[NH2:26][C:23]1[CH:22]=[CH:21][C:20]([C:19]([NH:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2/[CH:11]=[CH:10]/[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][N:2]=2)=[O:29])=[CH:25][CH:24]=1
Reactant: O=C(Nc1ccccc1/C=C/c1n[nH]c2ccccc12)c1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(C(=O)Nc2ccccc2/C=C/c2n[nH]c3ccccc23)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 32.6 %

Procedure:
Compound 65 (60 mg, 0.13 mmol), iron powder (436 mg, 7.80 mmol) and ammonium chloride (42 mg, 0.78 mmol) were added with ethanol (1.0 mL) and water (1.0 mL) at room temperature, stirred at 50° C. for 1 hour and then the reaction mixture was filtered through Celite. The filtrate was extracted with ethyl acetate and the organic layer was sequentially washed with water and saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was triturated in ethanol to obtain Compound 70 (15 mg, 28%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[H-].[Na+].[CH3:17]I>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([N:11]([CH3:17])[C:12](=[O:14])[CH3:13])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: CI
Reactant: CC(=O)Nc1cc(Br)cc([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N(C)c1cc(Br)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
31.0 g (0.1197 mol) of N-(3-bromo-5-nitrophenyl)-acetamide were dissolved in 240 ml of dimethylformamide and added dropwise within 20 min. to a suspension, cooled at 5° C., of 5.8 g (0.1325 mol) of NaH (60%) in 120 ml of dimethylformamide. Subsequently, the mixture was stirred at room temperature for 1 hr., again cooled to 0-5° C. and 22.30 ml (0.358 mol) of MeI were added thereto. The mixture was stirred at room temperature for 18 hrs., then freed from solvent and the residue was partitioned in water and dichloromethane. The organic phase was washed with sat. sodium chloride solution, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel with ethyl acetate/hexane. There were obtained 29.0 g (88.7%) of N-(3-bromo-5-nitrophenyl)-N-methylacetamide as a brown oil. MS (El): me/e=274,272 (C9H9BrN2O3+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].C(=O)([O-])[O-:34].[K+].[K+].OO>CS(C)=O>[CH2:1]([O:3][C:4](=[O:32])[C:5]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30](=[O:34])[NH2:31])=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:13][CH:14]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(C#N)cc3)oc2C)cc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(C(N)=O)cc3)oc2C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
2-(4-{2-[2-(4-Cyanophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester (60 mg, 0.14 mmol) and potassium carbonate (30 mg, excess) were dissolved in dimethylsulfoxide (1 mL). After cooling to 0° C., the mixture was treated with hydrogen peroxide (120 •L of a 30% aqueous solution) and then warmed to ambient temperature. After stirring for 1 h, the mixture was partitioned between EtOAc (15 mL) and H2O. The aqueous phase was extracted with EtOAc (3×), and then the combined organic phases were dried (MgSO4), filtered and concentrated to provide the product as a white solid (58 mg, 93%): mp 112° C.; 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J=8.4 Hz, 2H), 7.87 (d, J=8.4 Hz, 2H), 6.81-6.77 (m, 4H), 6.12 (br s, 1H), 5.66 (br s, 1H), 4.22 (q, J=6.8 Hz, 2H), 4.18 (t, J=6.4 Hz, 2H), 2.95 (t, J=6.4 Hz, 2H), 2.38 (s, 3H), 1.52 (s, 6H), 1.27 (t, J=7.2 Hz, 3H); MS (EI) 475.2 (M+Na)+, 453.2 (M+H)+.
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:20][C@H:21]([C:26]([O:28][CH3:29])=[O:27])[CH2:22][CH:23]([CH3:25])[CH3:24].C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:16]([O:15][C:13]([NH:1][CH:2]([CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:10]([NH:20][CH:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:26]([O:28][CH3:29])=[O:27])=[O:12])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(CC(C)C)NC(=O)C(Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
Boc-Phe-OH (2 g, 13.77 mmol), H-Leu-OMe (11 g, 41.32 mmol), HOBt (5.58 g, 41.32 mmol), and HBTU (15.67 g, 41.32 mmol) were dissolved in DMF (69 mL) and then DIPEA (7.2 mL, 41.32 mmol) was added under argon. The reaction was stirred for 8 hrs at room temperature. The reaction was extracted by EtOAc and wash with 5% NaHSO3, sat. NaHCO3 and brine. The organic layer was dried over Na2SO4, and concentrated by rotary evaporation. The crude was purified by chromatography (silica, 4/1: Hexane/EtOAc, Rf=0.3) to give methyl 2-(2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoylamino)-4-methylpentanoate as white solid (4.5 g, 8%).
Reaction SMILES: [OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1.CCN(C(C)C)C(C)C.[OH:34][C:35]([C@@H:38]1[CH2:42][CH2:41][NH:40][CH2:39]1)([CH3:37])[CH3:36]>>[OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:40]4[CH2:41][CH2:42][C@@H:38]([C:35]([OH:34])([CH3:37])[CH3:36])[CH2:39]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1
Reactant: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Reactant: CC(C)(O)[C@@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(N4CC[C@@H](C(C)(C)O)C4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid ((1R,3R)-1-hydroxy-3methyl-cyclohexylmethyl)-amide, DIPEA and (R)-3-(1-hydroxy-1-methyl-ethyl)-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 4.40 (s, 1H), 4.14 (s, 1H), 3.74 (m, 1H), 3.65 (m, 1H), 3.36 (m, 2H), 3.28 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.15 (m, 6H), 1.03 (m, 1H), 0.83 (d, 3H), 0.74 (m, 1H). m/z: 460 [M+H]
Reaction SMILES: CS(O[CH:6]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)[CH2:7][CH3:8])(=O)=O.[Li+].[Br-:19]>CC(C)=O>[CH3:17][O:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][CH:6]([Br:19])[CH2:7][CH3:8])[CH:11]=1
Reactant: CCC(Cc1cccc(OC)c1)OS(C)(=O)=O
Reactant: [Br-]
Agent: [Li+]
Solvent: CC(C)=O
Product: CCC(Br)Cc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.3 %

Procedure:
To a solution of 1-{[3-(methyloxy)phenyl]methyl}propyl methanesulfonate (52) (4.66 g, 18.0 mmol) in acetone (60 mL) was added LiBr (3.13 g, 36.1 mmol). The reaction mixture was refluxed under nitrogen for 8 h. Another 0.80 g of LiBr was added, and the reflux was continued for 1 h. Cooled to room temperature, the solid was filtered off and washed with acetone. The filtrate was concentrated to give the crude product as a brown oil. The crude product was purified by flash chromatography over SiO2 with hexanes:EtOAc (100:1) to give 2.07 g (47%) of the title compound (53) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 1.06 (t, J=7.2 Hz, 3H), 1.70-1.82 (m, 1H), 1.83-1.95 (m, 1H), 3.10-3.20 (m, 2H), 3.80 (s, 3H), 4.10-4.20 (m, 1H), 6.75-6.85 (m, 3H), 7.22 (t, J=7.9 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18]O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:44]I>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][I:44])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: II
Reactant: O=C(OCc1ccccc1)N1CCC(CCO)CC1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C(OCc1ccccc1)N1CCC(CCI)CC1
Temperature: 0 °C

Procedure:
A solution of 3-2(263 g, 116 mmol) was treated with triphenylphosphine (33.5 g, 128 mmol), imidazole (11.9 g, 175 mmol) and cooled to 0° C. Iodine (32.4 g, 128 mmol) was added and the ice bath was removed. The reaction was filtered into a separatory funnel and the solution was washed with H2O and brine, dried over MgSO4 and concentrated. The residue was chromatographed (10% EtOAc/Hexanes) to give 3-3 as a colorless oil. Rf (20% EtOAc/Hexanes) 0.56 1H NMR (300 MHz, CDCl3) δ 7.4-7.1 (m, 5H), 5.2-5.05 (bs, 2H), 4.3-4.1 (bs, 2H), 3.2 (t, 2H), 2.8 (bs, 2H), 1.8-1.5 (m, 5H), 1.15 (m, 2H). ##STR31## 2(N-t-Butyloxycarbonylaminopiperidin-4-yl)ethanol (4-1)
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11](=[S:14])[NH:12][N:13]=2)=[CH:5][CH:4]=1)[CH3:2].Br.Br[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[NH:13][N:12]=[C:11]([S:14][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[N:10]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: BrCc1ccccn1
Reactant: CCc1ccc(-c2n[nH]c(=S)[nH]2)cc1
Agent: Br
Product: CCc1ccc(-c2nc(SCc3ccccn3)n[nH]2)cc1
Yield: 71 %

Procedure:
Prepared in a similar manner to example 1 using 5-(4-ethylphenyl)-2H-1,2,4-triazole-3(4H)-thione (example 4a) and 2-(bromomethyl)pyridine hydrobromide. Yield 71%. 1H NMR (500 MHz, dMSO): δ 1.18-1.22 (t, 3H), 2.64-2.66 (t, 2H), 4.52 (s, 2H), 7.30-7.88 (m, 8H), 14.3 (bs, 1H). MS (M+H, 297).
Reaction SMILES: CO[C:3]([C:5]1[S:9][C:8](/[CH:10]=[CH:11]/[C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:7][C:6]=1[CH3:22])=[O:4].[NH2:23][CH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[O:27]1[CH2:28][CH2:29][CH:24]([NH:23][C:3]([C:5]2[S:9][C:8](/[CH:10]=[CH:11]/[C:12]3[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=3[CH3:17])=[N:7][C:6]=2[CH3:22])=[O:4])[CH2:25][CH2:26]1
Reactant: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)OC)s1
Reactant: NC1CCOCC1
Product: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)NC2CCOCC2)s1
Yield: 75 %

Procedure:
As described for example 93d, 2-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-4-methyl-thiazole-5-carboxylic acid methyl ester (60 mg, 0.19 mmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (55 mg, 75%) which was obtained as a white solid. MS: m/e=390.3 [M+H]+.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[C:5]#[N:6].[CH3:14][C:15]1[NH:16][CH:17]=[CH:18][N:19]=1>CN(C)C(=O)C>[CH3:14][C:15]1[N:16]([C:2]2[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=2)[C:5]#[N:6])[CH:17]=[CH:18][N:19]=1
Reactant: Cc1ncc[nH]1
Reactant: N#Cc1cc(F)cc(C(F)(F)F)c1
Solvent: CC(=O)N(C)C
Product: Cc1nccn1-c1cc(C#N)cc(C(F)(F)F)c1
Temperature: 145 °C
Reaction time: 19 h

Procedure:
A mixture of 3-fluoro-5-(trifluoromethyl)-benzonitrile (Lancaster Synthesis GmbH; 17 g, 89 mmol) and 2-methylimidazole (Fluka, Buchs, Switzerland; 22.2 g, 270 mmol) in N,N-dimethylacetamide (80 mL) is stirred at 145° C. for 19 h. The solvent is evaporated off under reduced pressure and the residue is dissolved in ethyl acetate (200 mL). The solution is washed with brine (200 mL), dried (Na2SO4) and the solvent is evaporated off under reduced pressure to give the crude product which is purified by recrystallisation from ether-hexane to afford the title compound as yellow crystalline solid, m.p. 132–134° C.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=[CH:11][N:10]3[CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:26]([NH2:29])[C:27]#[N:28])[CH:23]=[CH:24][CH:25]=1.C([O-])(O)=O.[Na+].P(Cl)(Cl)(Cl)=O>C(#N)C>[C:1]1([C:7]2[N:8]=[C:9]3[C:14]([C:15]([NH:29][CH:26]([C:22]4[CH:23]=[CH:24][CH:25]=[C:20]([Cl:19])[CH:21]=4)[C:27]#[N:28])=[O:17])=[CH:13][CH:12]=[CH:11][N:10]3[CH:18]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CC(N)c1cccc(Cl)c1
Reactant: O=C(O)c1cccn2cc(-c3ccccc3)nc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: N#CC(NC(=O)c1cccn2cc(-c3ccccc3)nc12)c1cccc(Cl)c1
Yield: 27.1 %

Procedure:
2-phenyl-imidazo[1,2-a]pyridine-8-carboxylic acid (1.0 g, 4.2 m moles), α-(3-chlorophenyl)-aminoacetonitrile (0.77 g, 4.6 m moles) and NaHCO3 (1.1 g, 13.1 m moles) were added to acetonitrile 110 ml). Phosphorus oxychloride (0.7 ml, 7.51 m moles, dissolved in 5 ml of acetonitrile) was added slowly to the mixture with stirring under ice-cooling. The mixture was reacted at room temperature for 10 hours, and the solvent was removed from the reaction mixture under reduced pressure. Water (50 ml) was added to the residue and the mixture was adjusted to pH 7 with saturated aqueous solution of sodium bicarbonate and then extracted with dichloromethane/ethyl acetate (10/1) (100 ml×2). The extract was dried over anhydrous magnesium sulfate and concentrated. Acetonitrile (5 ml) was added to the concentrate, and the precipitating crystals were collected by filtration to give the object compound (0.44 g, yield 27.2%) as crystals. m.p. 210°-211° C.