Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][C:8]1[CH2:12][S:11][C:10](=[O:13])[N:9]=1.[F:14][C:15]([F:36])([F:35])[C:16]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:17]=1[CH2:18][N:19]1[CH2:24][CH2:23][CH:22]([CH:25]=O)[CH2:21][CH2:20]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:36][C:15]([F:14])([F:35])[C:16]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:17]=1[CH2:18][N:19]1[CH2:24][CH2:23][CH:22](/[CH:25]=[C:12]2/[C:8]([NH:7][CH2:6][C:2]3[O:1][CH:5]=[CH:4][N:3]=3)=[N:9][C:10](=[O:13])[S:11]/2)[CH2:21][CH2:20]1
Reactant: O=C1N=C(NCc2ncco2)CS1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: O=C1N=C(NCc2ncco2)/C(=C/C2CCN(Cc3ccc(C(F)(F)F)cc3C(F)(F)F)CC2)S1
Temperature: 60 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
To a solution of 4-[(1,3-oxazol-2-ylmethyl)amino]-1,3-thiazol-2(5H)-one (357 mg) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (676 mg) in 2-propanol (5 mL) was added piperidinium acetate (289 mg) at room temperature. The reaction mixture was stirred at 60° C. for 5 hr, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) and recrystallized from ethyl acetate/heptane to give the title compound (751 mg)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:14][CH2:15][C:16](=[O:18])[CH3:17])[CH:6]=[CH:7][C:8]=1[O:9][Si](C)(C)C.C(NC(C)C)(C)C.[Li].[CH2:27]([O:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][CH:43]=[O:44])=[CH:37][CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([O:34][C:35]1[CH:36]=[CH:37][C:38]([CH2:41][CH2:42][CH:43]([OH:44])[CH2:17][C:16](=[O:18])[CH2:15][CH2:14][C:5]2[CH:6]=[CH:7][C:8]([OH:9])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:39][CH:40]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=CCCc1ccc(OCc2ccccc2)cc1
Reactant: COc1cc(CCC(C)=O)ccc1O[Si](C)(C)C
Agent: [Li]
Solvent: CC(C)NC(C)C
Product: COc1cc(CCC(=O)CC(O)CCc2ccc(OCc3ccccc3)cc2)ccc1O
Yield: 11.5 %

Procedure:
In a manner similar to Example 3, 2.2 g (10 mmol) of 4-(3-methoxy-4-trimethylsilyloxyphenyl)butan-2-one was treated with 10 mmol of lithium diisopropylamine, followed by 3 g (12 mmol) of 3-(4-benzyloxyphenyl)propan-1-al. Purification of reaction mixture by dry column chromatography (silica gel, hexane: ethyl acetate, 2:1) gave 0.5 g of the desired product as a pale yellow oil. MS(EI):434.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:8]=1[OH:14])([CH3:6])([CH3:5])[CH3:4].[C:15](=[O:17])=[O:16]>COCCOC>[C:3]([C:7]1[CH:12]=[C:11]([CH:10]=[C:9]([CH3:13])[C:8]=1[OH:14])[C:15]([OH:17])=[O:16])([CH3:6])([CH3:5])[CH3:4]
Reactant: Cc1cccc(C(C)(C)C)c1O
Reactant: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1cc(C(=O)O)cc(C(C)(C)C)c1O
Temperature: 5 °C

Procedure:
Charge a reaction vessel with a suspension of sodium hydride (4.74 g, 0.198 mol) in anhydrous ethylene glycol dimethyl ether (150 mL). Add, by dropwise addition, a solution of 2-t-butyl-6-methylphenol (0.1 mol) in ethylene glycol dimethyl ether (150 mL). Warm to 50°-60° C. for 1.5 hours then introduce carbon dioxide through a gas-disparging tube below the surface of the reaction mixture for 20 hours. Cool to 5° C. and destroy the excess sodium hydride carefully with methyl alcohol (30 mL). After hydrogen evolution ceases, adjust the pH of the reaction mixture to 2 with 1N hydrochloric acid. Dilute with water (1.6 L) and collect the title compound by filtration.
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10](Cl)=[N:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].O.[NH2:15][NH2:16]>C(O)C>[C:1]([O:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:15][NH2:16])=[N:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CC(C)(C)OCc1ccc(Cl)nc1
Solvent: O
Solvent: CCO
Product: CC(C)(C)OCc1ccc(NN)nc1

Procedure:
7.9 g (39.6 mmol) 5-(tert-butoxymethyl)-2-chloropyridine together with 19.8 g (395.6 mmol) hydrazine hydrate are divided into three portions of equal size and 15 ml ethanol are added to each portion. Each portion is reacted in a single mode microwave (CEM Explorer) at 170° C. for in each case 4 h. Thereafter, the three mixtures are combined and the solvent is removed. The residue is taken up in ethyl acetate and the mixture is washed once with saturated sodium bicarbonate solution. The aqueous phase is extracted once with ethyl acetate. The two ethyl acetate phases are combined and washed once with saturated sodium chloride solution. The mixture is dried over magnesium sulfate and the solvent is removed. The residue obtained is stirred in petroleum ether and the solid is filtered off.
Reaction SMILES: [Br:1]Br.[O:3]=[C:4]([CH3:12])[CH2:5][CH2:6][C:7]([O:9][CH2:10]C)=[O:8]>CO>[Br:1][CH2:12][C:4](=[O:3])[CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8]
Reactant: CCOC(=O)CCC(C)=O
Reactant: BrBr
Solvent: CO
Product: COC(=O)CCC(=O)CBr
Reaction time: 8 h
Yield: 29.4 %

Procedure:
A solution of bromine (27.71 g, 173.4 mmol) in methanol (40 mL) was added dropwise to a solution of ethyl 4-oxopentanoate (25.0 g, 173.4 mmol) in methanol (200 mL) at room temperature over a period of 30 minute, and the reaction mixture was stirred overnight. The reaction mixture was concentrated, and the residue was partitioned between 3:1 ether:ethyl acetate and water, washed with saturated sodium bicarbonate, water, brine, dried, and concentrated to afford 17 g of a crude clear oil. The oil was purified by MPLC (Biotage) eluting with 8:1 hexane ethyl acetate to afford methyl 5-bromo-4-oxopentanoate (10.65 g, 29.38% yield) as a clear oil. 1H NMR (CDCl3) δ 3.96 (s, 2H), 3.69 (s, 3H), 2.96 (t, 2H), 2.66 (t, 2H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][OH:7].[CH3:8][S:9](Cl)(=[O:11])=[O:10].O>N1C=CC=CC=1>[O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][O:7][S:9]([CH3:8])(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: OC[C@@H]1CCCO1
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)OC[C@H]1CCCO1

Procedure:
To a solution of (S)-1-(tetrahydrofuran-2-yl)methanol (7.95 g) in pyridine (35 ml) was added, at −15° C., methanesulfonyl chloride (7.47 g), and the reaction was stirred at 0° C. for 5 hours. After the addition of water, the mixture was extracted with ethyl acetate. The organic phases were dried over magnesium sulfate and concentrated. The product was thus obtained with the molecular weight of 180.22 (C6H12O4S); MS (ESI): 181 (M+H+). Analogously, methanesulfonic acid (R)-1-(tetrahydrofuran-2-yl)methyl ester was synthesized.
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:23]=[CH:22][CH:21]=[N:20]3)=[CH:15][CH:14]=2)=[C:10]([Cl:24])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:25]([C:37]3[N:41]([CH3:42])[CH:40]=[N:39][CH:38]=3)([C:27]3[CH:28]=[N:29][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:32]=3)[OH:26])[CH:8]=2)[N:3]=1.Cl.[F:44][CH:45]1[CH2:48][NH:47][CH2:46]1.CN(C=O)C>CCOC(C)=O>[Cl:24][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:25]([C:37]3[N:41]([CH3:42])[CH:40]=[N:39][CH:38]=3)([C:27]3[CH:28]=[N:29][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:31][CH:32]=3)[OH:26])[CH:8]=2)[N:3]=[C:2]([N:47]2[CH2:48][CH:45]([F:44])[CH2:46]2)[C:11]=1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH:23]=[CH:22][CH:21]=[N:20]2)=[CH:15][CH:14]=1
Reactant: FC1CNC1
Reactant: Cn1cncc1C(O)(c1ccc(C(F)(F)F)nc1)c1ccc2nc(Cl)c(Cc3ccc(-n4cccn4)cc3)c(Cl)c2c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1cncc1C(O)(c1ccc(C(F)(F)F)nc1)c1ccc2nc(N3CC(F)C3)c(Cc3ccc(-n4cccn4)cc3)c(Cl)c2c1
Temperature: 100 °C

Procedure:
{2,4-Dichloro-3-[4-(1H-pyrazol-1-yl)benzyl]quinolin-6-yl}(1-methyl-1H-imidazol-5-yl)pyrimidin-2-ylmethanol (100 mg, 0.164 mmol, Intermediate 65), 3-fluoroazetidine hydrochloride (183 mg, 1.64 mmol) and DMF (2 mL) were combined in a reaction tube, then sealed and heated to 100° C. and maintained at that temperature for 24 hours. The residue was taken up into EtOAc, transferred to a reparatory funnel and extracted twice with a saturated, aqueous NH4Cl solution. The organic phase was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified via reverse phase chromatography using acetonitrile with ammonium hydroxide in water as eluent to afford the title compound. MS (ESI): mass calcd. for C33H26ClF4N7O, 647.2. m/z found, 648.2 [M+H]+. 1H NMR (600 MHz, CDCl3) δ ppm 8.82 (d, J=1.7 Hz, 1H), 8.09 (d, J=2.0 Hz, 1H), 7.97-7.93 (m, 1H), 7.86 (d, J=2.3 Hz, 1H), 7.76 (d, J=8.8 Hz, 1H), 7.67 (d, J=1.5 Hz, 1H), 7.64 (d, J=8.3 Hz, 1H), 7.59 (d, J=8.6 Hz, 2H), 7.55-7.51 (m, 1H), 7.26 (s, 1H), 7.16 (d, J=8.6 Hz, 2H), 6.46-6.42 (m, 1H), 6.39 (s, 1H), 4.41-4.31 (m, 2H), 4.29 (s, 2H), 4.27-4.18 (m, 3H), 3.44 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:5]=[C:6]([CH2:10][NH2:11])[CH:7]=[CH:8][CH:9]=1.[Br:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([CH:21]=[C:22]([C:24](OCC)=[O:25])[N:23]=2)[CH:20]=1>>[Br:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([CH:21]=[C:22]([C:24]([NH:11][CH2:10][C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:12])([F:13])[F:1])[CH:5]=3)=[O:25])[N:23]=2)[CH:20]=1
Reactant: NCc1cccc(OC(F)(F)F)c1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Product: O=C(NCc1cccc(OC(F)(F)F)c1)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate I, using (3-(trifluoromethoxy)phenyl)methanamine and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: F[C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.CC(C)([O-])C.[K+].[F:17][C:18]([F:22])([F:21])[CH2:19][OH:20]>O.Cl>[F:17][C:18]([F:22])([F:21])[CH2:19][O:20][C:2]1[N:3]=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1cccnc1F
Reactant: OCC(F)(F)F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=C(O)c1cccnc1OCC(F)(F)F
Yield: 32 %

Procedure:
2-Fluoropyridine-3-carboxylic acid (200 mg, 1.42 mmol) was dissolved in 2,2,2-trifluoroethanol (2 mL) and potassium tert-butoxide (477 mg, 4.25 mmol) was added. The mixture was then heated to 90 C for 4 h. The mixture was diluted with water (4 mL), 2M HCl was added to bring the solution to pH 4 and the mixture was extracted with DCM (3×4 mL). 2M HCl was added to the aqueous layer to bring the solution to pH 3 and the mixture was extracted with DCM (4×5 mL). The combined organic extractions were dried over sodium sulfate and evaporated under vacuum to afford the title compound (100 mg, 32%). Method C HPLC-MS: MH+ requires m/z=222. Found: m/z=222, Rt=1.17 min (100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20][O:21]S(C)(=O)=O)[CH2:15]3)=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:26]1[O:30][C:29]2[CH:31]=[C:32](O)[CH:33]=[CH:34][C:28]=2[O:27]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[O:27]1[C:28]2[CH:34]=[CH:33][C:32]([O:21][CH2:20][CH:16]3[CH2:17][CH2:18][CH2:19][N:14]([C:12]([C:8]4([C:5]5[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=5)[CH2:11][CH2:10][CH2:9]4)=[O:13])[CH2:15]3)=[CH:31][C:29]=2[O:30][CH2:26]1
Reactant: Oc1ccc2c(c1)OCO2
Reactant: CS(=O)(=O)OCC1CCCN(C(=O)C2(c3ccc(Cl)cc3)CCC2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=C(N1CCCC(COc2ccc3c(c2)OCO3)C1)C1(c2ccc(Cl)cc2)CCC1
Temperature: 25 °C
Yield: 61.4 %

Procedure:
To a solution of 43 (1.0 g, 2.59 mmol) in acetonitrile (25 mL) was added sesamol (0.36 g, 2.59 mmol) and cesium carbonate (1.27 g, 3.89 mmol). The reaction was stirred and refluxed for 20 h. After cooling to room temperature, the reaction mixture was filtered and most of the solvent was removed by rotary evaporation. The residue was partitioned between dichloromethane and water, and the organic layer was washed with sat. sodium carbonate (2×50 mL) and water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation. The residue was purified by chromatography on silica gel, eluting with dichloromethane/methanol (98:2) to give 0.68 g of the amide 44 as a crystalline solid. C24H26ClNO4, MS (m/z)=428 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][N:3]=1.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>>[Si:13]([O:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([Cl:1])=[N:3][CH:4]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: Oc1cnc(Cl)c2ccccc12
Reactant: CC(C)(C)[Si](C)(C)Cl
Product: CC(C)(C)[Si](C)(C)Oc1cnc(Cl)c2ccccc12

Procedure:
1-Chloroisoquinolin-4-ol was treated with tert-butyldimethylsilyl chloride to produce 4-{[tert-butyl(dimethyl)silyl]oxy}-1-chloroisoquinoline. Halogen exchange gave 4-{[tert-butyl(dimethyl)silyl]oxy}-1-iodoisoquinoline, which was treated with copper iodide and methyl difluoro(fluorosulfonyl)acetate to produce 1-(trifluoromethyl)isoquinolin-4-ol.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][CH2:7][C:8]1[CH:20]=[CH:19][C:11]([O:12][CH2:13][C:14]([O:16]CC)=[O:15])=[CH:10][CH:9]=1)C(C)=O.C(O)C.[OH-].[K+].Cl>O>[NH2:1][CH2:5][CH2:6][CH2:7][C:8]1[CH:20]=[CH:19][C:11]([O:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:10][CH:9]=1
Reactant: CCOC(=O)COc1ccc(CCCNC(C)=O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NCCCc1ccc(OCC(=O)O)cc1

Procedure:
A mixture of 16.2 g. (58 mMol) ethyl 4-(3-acetaminopropyl)-phenoxyacetate, 100 ml. ethanol, 100 ml. water and 32.5 g. (0.58 mol) potassium hydroxide is kept at reflux temperature for 16 hours. The reaction mixture is then cooled, adjusted to pH 6.5 with 6 N hydrochloric acid and the resultant sand-colored precipitate filtered off with suction. After washing with water and drying, there are obtained 12.0 g. (quantitative yield) 4-(3-aminopropyl)-phenoxyacetic acid; m.p. 248° C.
Reaction SMILES: C[O:2][C:3](=[O:43])[C@H:4]([OH:42])[CH2:5][NH:6][C:7](=[O:41])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]([C:32]2[CH:33]=[C:34]3[C:38](=[CH:39][CH:40]=2)[CH2:37][CH2:36][CH2:35]3)[C:16]2[S:17][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=3)[N:20]=2)=[CH:10][CH:9]=1.[OH-].[Na+].Cl.O>CO>[OH:42][C@H:4]([CH2:5][NH:6][C:7](=[O:41])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]([C:32]2[CH:33]=[C:34]3[C:38](=[CH:39][CH:40]=2)[CH2:37][CH2:36][CH2:35]3)[C:16]2[S:17][CH:18]=[C:19]([C:21]3[CH:22]=[CH:23][C:24]([O:27][C:28]([F:30])([F:29])[F:31])=[CH:25][CH:26]=3)[N:20]=2)=[CH:10][CH:9]=1)[C:3]([OH:43])=[O:2]
Reactant: COC(=O)[C@H](O)CNC(=O)c1ccc(CN(c2ccc3c(c2)CCC3)c2nc(-c3ccc(OC(F)(F)F)cc3)cs2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(NC[C@@H](O)C(=O)O)c1ccc(CN(c2ccc3c(c2)CCC3)c2nc(-c3ccc(OC(F)(F)F)cc3)cs2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2(R)-Hydroxy-3-[4-({indan-5-yl-[4-(4-trifluoromethoxyphenyl)thiazol-2-yl]amino}methyl)benzoylamino]propionic acid methyl ester (0.10 g, 0.16 mmol) was dissolved in methanol (5 mL) and 1 N aqueous sodium hydroxide (0.16 mL, 0.16 mmol) was added and the resulting mixture was stirred at room temperature for 16 hours. 1 N hydrochloric acid (0.17 mL) and water (50 mL) were added and the mixture was extracted with ethyl acetate (50 mL). The organic phase was washed with water (50 mL), dried (MgSO4) and concentrated in vacuo. This afforded 0.06 g (61%) of the title compound.
Reaction SMILES: Cl[C:2]1[C:3]([CH2:14][CH3:15])=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cu](C#N)[C:17]#[N:18].N1C=CC=CC=1>C(Cl)Cl>[CH2:14]([C:3]1[C:2]([C:17]#[N:18])=[CH:7][CH:6]=[CH:5][C:4]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:15]
Reactant: N#C[Cu]C#N
Reactant: CCc1c(Cl)cccc1-c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCc1c(C#N)cccc1-c1ccccc1
Temperature: 25 °C

Procedure:
Under a dry nitrogen atmosphere a mixture of 3-chloro-2-ethyl-[1,1'-biphenyl] (2.3 g, 0.0106 mole), copper cyanide (1.4 g, 0.0016 mole) and pyridine (1.2 g, 0.016 mole) was heated at 195° for approximately 18 hours. The reaction mixture was cooled to room temperature to give a solid. The solid was dissolved in 300 ml of methylene chloride and washed with 25% aqueous ammonium hydroxide and the aqueous phase extracted with 250 ml of methylene chloride. The organic phases were combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated to give 2-ethyl-[1,1'-biphenyl]-3-carbonitrile as a solid. A mixture of ethyl-[1,1'-biphenyl]-3-carbonitrile (2.2 g, 0.0106 mole), 40 ml of 10N aqueous sodium hydroxide, and 40 ml of ethanol was heated at reflux for approximately 18 hours. The reaction mixture was cooled and the ethanol evaporated under reduced pressure. The remaining aqueous portion was diluted with 100 ml of water, then extracted with three 150 ml portions of methylene chloride. The organic phases were combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated to give 2-ethyl-[1,1'-biphenyl]-3-carboxamide (2.4 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[NH:11][C:10](=[S:12])[NH:9][N:8]=2)=[CH:3][CH:2]=1.Br[CH2:14][C:15]#[CH:16].C([O-])(=O)C.[Na+].O>CN(C=O)C>[CH2:16]([S:12][C:10]1[NH:11][C:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[N:8][N:9]=1)[C:15]#[CH:14]
Reactant: C#CCBr
Reactant: S=c1[nH]nc(-c2ccncc2)[nH]1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCSc1nnc(-c2ccncc2)[nH]1
Temperature: 25 °C
Reaction time: 6 h
Yield: 61.9 %

Procedure:
A mixture of 3-(pyridin-4-yl)-1H-1,2,4-triazole-5(4H)-thione (2 g, 11.2 mmol), 3-bromoprop-1-yne (1.47 g, 12.3 mmol) and sodium acetate (5.34 g, 65.1 mmol) in DMF (20 mL) was stirred for 6 h at room temperature. The reaction mixture was then poured into water (50 mL) and extracted with DCM. The combined organic layers were washed with water three times, dried with Na2SO4, filtered and concentrated to obtain the title compound (1.5 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[CH2:8][C@H:9]3[CH2:21][C@H:10]3[C:11]=2[N:12]([C:14]2[CH:19]=[N:18][C:17](Br)=[CH:16][N:15]=2)[N:13]=1)=[O:5])C.[CH3:22][O-:23].[Na+].O.Cl>CO>[CH3:22][O:23][C:17]1[N:18]=[CH:19][C:14]([N:12]2[C:11]3[C@@H:10]4[CH2:21][C@@H:9]4[CH2:8][C:7]=3[C:6]([C:4]([OH:3])=[O:5])=[N:13]2)=[N:15][CH:16]=1
Reactant: CCOC(=O)c1nn(-c2cnc(Br)cn2)c2c1C[C@H]1C[C@@H]21
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cnc(-n2nc(C(=O)O)c3c2[C@@H]2C[C@@H]2C3)cn1
Temperature: 140 °C
Yield: 74.7 %

Procedure:
To a reaction vial containing (1aR,5aR)-2-(5-bromopyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ethyl ester (120 mg, 0.344 mmol) in methanol was added sodium methoxide (74 mg, 1.375 mmol). The reaction mixture was heated at 140° C. for 1 h under microwave irradiation, poured into water, acidified with HCl solution and extracted with solution of DCM:IPA (4:1). The combined organics were dried and concentrated to give the title compound (70 mg). LCMS m/z=273.3 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][NH:3]1.[OH-].[Na+].Br[CH2:10][CH2:11][CH2:12][Cl:13]>CC(C)=O>[Cl:13][CH2:12][CH2:11][CH2:10][N:3]1[CH2:4][CH2:5][CH2:6][CH:2]1[CH3:1]
Reactant: ClCCCBr
Reactant: CC1CCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC1CCCN1CCCCl
Yield: 58.4 %

Procedure:
2-Methylpyrrolidine (0.9 g, 10.6 mmol), acetone (18 ml, 20 vol), 5M NaOH solution (2.50 ml) and 1-bromo-3-chloropropane (5 g, 31.8 mmol, 3 eq) were reacted together according to general procedure A to give the title compound (1 g, 59%) as a pale yellow oil.
Reaction SMILES: [S:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[OH:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[C:16]=1[OH:17])[CH:12]=O.N1CCCCC1>C(O)(=O)C>[OH:8][C:9]1[CH:10]=[C:11]([CH:12]=[C:7]2[S:1][C:2](=[S:3])[NH:4][C:5]2=[O:6])[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[C:16]=1[OH:17]
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: O=C1CSC(=S)N1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: O=C1NC(=S)SC1=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Temperature: 100 °C

Procedure:
A solution containing 2.1 g (0.0157 mol) of rhodanine, 2.76 g (0.0151 mol) of 3,4-dihydroxy-5-nitrobenzaldehyde and 0.15 ml of piperidine in 10 ml of acetic acid was heated for 7-8 h at 100° C. After cooling the crystalis were filtered and washed with 2-propanol. Yield 4.0 g (89%), mp>350° C. (decomp.).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][C@H:12]([CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[N:11]1[C:24]1[N:29]=[C:28]([C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-])=O)=[CH:32][CH:31]=2)[N:27]=[C:26]([N:39]2[CH:44]3[CH2:45][CH2:46][CH:40]2[CH2:41][O:42][CH2:43]3)[N:25]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H][H]>[Pd].O1CCCC1>[CH:40]12[N:39]([C:26]3[N:25]=[C:24]([N:11]4[C@@H:12]([CH2:15][O:16][Si:17]([C:20]([CH3:22])([CH3:23])[CH3:21])([CH3:19])[CH3:18])[CH2:13][CH2:14][C@H:10]4[CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2])[N:29]=[C:28]([C:30]4[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=4)[N:27]=3)[CH:44]([CH2:45][CH2:46]1)[CH2:43][O:42][CH2:41]2
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CC[C@@H](CO[Si](C)(C)C(C)(C)C)N1c1nc(-c2ccc([N+](=O)[O-])cc2)nc(N2C3CCC2COC3)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CC[C@@H](CO[Si](C)(C)C(C)(C)C)N1c1nc(-c2ccc(N)cc2)nc(N2C3CCC2COC3)n1
Yield: 54.6 %

Procedure:
A suspension of palladium on charcoal (10%, 50 mg) and 8-(4-((2S,5R)-2,5-bis((tert-butyldimethylsilyloxy)methyl)pyrrolidin-1-yl)-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane (0.55 g, 1.2 mmol) in tetrahydrofuran (20 mL) was stirred under a balloon of hydrogen overnight. The mixture was filtered through a pad of Celite™ diatomaceous earth and concentrated under reduced pressure to provide the title compound as a tan foam (0.42 g, 80%). MS (ES+)=642.4 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([F:18])([F:17])[F:16].C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:16][C:15]([F:17])([F:18])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: FC(F)(F)c1ccccc1CBr
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: FC(F)(F)c1ccccc1CN1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.2 %

Procedure:
1.08 g (12.5 mmol) of piperazine are placed in the presence of 1 g (4.2 mmol) of 1-bromomethyl-2-trifluoromethyl-benzene and 0.64 mL (4.6 mmol) of triethylamine in 10 mL of toluene. The reaction medium is stirred for 30 min at room temperature and then heated to 110° C. for 6 h. After dry concentration, the obtained residue is taken up with AcOEt and washed with water. After drying on MgSO4, the organic phases are dry concentrated, the obtained residue is purified by flash chromatography on silica (CH2Cl2-MeOH—NH4OH: 90-9-1). 0.7 g of intermediate 7a are thereby isolated as a clear oil (yield 68%).
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([CH2:8][N:9]2[C:13]([CH2:14][CH:15]=[CH:16][OH:17])=[C:12]([Cl:18])[N:11]=[C:10]2[CH2:19][CH2:20][CH2:21][CH3:22])=[CH:6][CH:5]=1)([O-])=O.C(O)(=O)C>C(O)C.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[C:13]([CH2:14][CH:15]=[CH:16][OH:17])=[C:12]([Cl:18])[N:11]=[C:10]2[CH2:19][CH2:20][CH2:21][CH3:22])=[CH:23][CH:24]=1
Reactant: CCCCc1nc(Cl)c(CC=CO)n1Cc1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: CCCCc1nc(Cl)c(CC=CO)n1Cc1ccc(N)cc1

Procedure:
A mixture of 0.2 g of 3-[1-(4-nitrobenzyl)-2-butyl-4-chloroimidazol-5-yl]propen-1-ol, 0.15 g of iron and 0.3 mL of glacial acetic acid in 10 mL of absolute ethanol was refluxed for 1 hour. The reaction mixture was concentrated to dryness and the residue was dissolved in 20 mL of water and the solution was made basic to pH 8 by adding K2CO3. The mixture was then extracted with ethyl acetate and the ethyl acetate layer was washed with water. The organic layer was concentrated to give a crude product which was purified by flash silica gel column chromatography (ethyl acetate elution). A pure product was obtained as an amorphous solid; NMR (200 MHz, CDCl3): δ6.76 and 6.62 (dd, 4H, J=8.5 Hz); 6.42-6.22 (m, 2H); 2.57 (t, 2H, J=7.3 Hz); 1.65 (m, 2H); 1.33 (m, 2H); 0.87 (t, 2H, J=7.3 Hz).