Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:21])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]1.CCN(C(C)C)C(C)C.[F:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[CH:34][CH:33]=1>CN(C=O)C>[F:31][C:32]1[CH:33]=[CH:34][C:35]([N:38]2[CH2:43][CH2:42][N:41]([C:1]([O:2][CH2:3][CH:4]3[CH2:5][CH2:6][N:7]([CH3:10])[CH2:8][CH2:9]3)=[O:21])[CH2:40][CH2:39]2)=[CH:36][CH:37]=1
Reactant: CN1CCC(COC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Reactant: Fc1ccc(N2CCNCC2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(COC(=O)N2CCN(c3ccc(F)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 11.8 %

Procedure:
(1-Methylpiperidin-4-yl)methyl 4-nitrophenyl carbonate (Intermediate 1; 4.99 g, 16.9 mmol) was dissolved in DMF (40 mL). DIPEA (5.90 mL, 33.9 mmol) and 4-(4-fluoro-phenyl)piperazine (3.21 g, 17.8 mmol) were added. The reaction mixture was stirred at room temperature for 3 h and then concentrated in vacuo. The residue was dissolved in EtOAc (400 mL) and then washed sequentially with 1 M aq NaOH solution (6×150 mL), brine (50 mL), dried (MgSO4) and concentrated in vacuo. The residue was dissolved in DCM (100 mL) and methyl isocyanate resin (1.0 g) was added. The reaction mixture was shaken for 14 h, filtered and then concentrated in vacuo. The residue was purified by reverse phase chromatography (gradient eluting with MeOH in water, with 1% formic acid in each solvent, 0-30%). The resulting residue was dissolved in DCM (70 mL) and stirred with solid K2CO3 for 20 minutes, filtered and concentrated in vacuo to give (1-methylpiperidin-4-yl)methyl 4-(4-fluorophenyl)piperazine-1-carboxylate (0.67 g, 11.8%) as a pale yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=2)[CH:13]=[C:12]([C:23]([OH:25])=O)[CH:11]=1)#[N:2].[NH2:26][C@@H:27]([CH3:30])[CH2:28][OH:29].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CN(C)C=O>>[OH:29][CH2:28][C@@H:27]([NH:26][C:23]([C:12]1[CH:11]=[C:10]([C:4]2[CH:5]=[C:6]([CH3:9])[CH:7]=[CH:8][C:3]=2[C:1]#[N:2])[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=2)[CH:13]=1)=[O:25])[CH3:30]
Reactant: C[C@H](N)CO
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(-c3cc(C)ccc3C#N)c2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(C(=O)N[C@@H](C)CO)cc(-c3cc(C)ccc3C#N)c2)nc1
Temperature: 25 °C

Procedure:
A round bottom flask was charged with 2′-cyano-5′-methyl-5-(5-methylpyridin-2-yl)biphenyl-3-carboxylic acid (30.0 mg, 0.0914 mmol), (2S)-2-Aminopropan-1-ol (13.724 mg, 0.18272 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.14474 g, 0.38068 mmol), N,N-diisopropylethylamine (0.10609 mL, 0.60908 mmol), N,N-dimethylformamide (0.260 mL, 3.35 mmol) and the reaction stirred over night at room temperature. The solvent was removed under reduced pressure and the residue purified by prep HPLC to get the compound as white solid.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19](=[O:30])[CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[CH3:29])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].Cl.[OH:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][C:36]=1[O:43][CH3:44].C(N(CC)CC)C>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:20][C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:40][CH2:39][C:38]4[CH:41]=[CH:42][C:35]([OH:34])=[C:36]([O:43][CH3:44])[CH:37]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:30])=[C:23]([CH3:29])[CH:24]=1
Reactant: COc1cc(CN)ccc1O
Reactant: Cc1cc(Cl)ccc1OCC(=O)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Agent: Cl
Solvent: CCN(CC)CC
Product: COc1cc(CNC(=O)c2ccc3n2Cc2ccccc2N(C(=O)COc2ccc(Cl)cc2C)C3)ccc1O

Procedure:
The title compound was synthesized from 2,2,2-trichloro-1-{10-[(4-chloro-2-methylphenoxy)acetyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 75 (0.3 mmol), 4-hydroxy-3-methoxybenzylamine hydrochloride (2.2 eq.) and triethylamine (2.4 eq.) in the manner of Example 68, m.p. 167-168° C. MS [(+)ESI, m/z]: 546 [M+H]+
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[NH:10][N:9]=[C:8]2[CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])[CH2:19][CH2:18]1.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH2:41]Cl)[CH:36]=[CH:37][C:38]=1[O:39][CH3:40].O>CN(C)C=O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]([CH2:41][C:35]1[CH:36]=[CH:37][C:38]([O:39][CH3:40])=[C:33]([O:32][CH3:31])[CH:34]=1)[N:9]=[C:8]2[CH2:16][N:17]1[CH2:18][CH2:19][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])[CH2:21][CH2:22]1
Reactant: COc1cc2[nH]nc(CN3CCN(c4ccccc4OC)CC3)c2cc1OC
Reactant: COc1ccc(CCl)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(CN3CCN(c4ccccc4OC)CC3)c3cc(OC)c(OC)cc32)cc1OC
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
In dimethylformamide was suspended 61.6 mg of sodium hydride at 0° C., and 590 mg of 5,6-dimethoxy-3-[[4-(2-methoxyphenyl)-1-piperazinyl]methyl]indazole was added thereto, followed by stirring for 30 minutes. To the mixture was added 290 mg of 3,4-dimethoxyphenylmethyl chloride. After 1.5 hours, 2.0 ml of water was added to the reaction mixture, followed by evaporation of the solvent. The residue was purified by silica gel column chromatography (chloroform:ethanol=20:1) and recrystallized from ethanol to yield 654 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[N:11]([CH3:12])[N:10]=[C:9]([CH3:13])[C:8]=2[CH:14]=O)=[CH:4][CH:3]=1.[NH2:18][O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2([CH3:32])[O:31][CH2:30][CH2:29][O:28]2)=[CH:23][CH:22]=1>C(O)C>[F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[N:11]([CH3:12])[N:10]=[C:9]([CH3:13])[C:8]=2[CH:14]=[N:18][O:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3([CH3:32])[O:28][CH2:29][CH2:30][O:31]3)=[CH:25][CH:26]=2)=[CH:4][CH:3]=1
Reactant: CC1(c2ccc(CON)cc2)OCCO1
Reactant: Cc1nn(C)c(Oc2ccc(F)cc2)c1C=O
Solvent: CCO
Product: Cc1nn(C)c(Oc2ccc(F)cc2)c1C=NOCc1ccc(C2(C)OCCO2)cc1
Yield: 71.1 %

Procedure:
1.1 Gram (0.0043 mole) of 5-(4-fluorophenoxy)-1,3-dimethylpyrazol-4-carbaldehyde and 0.9 g (0.0043 mole) of 2-[4-(aminooxymethyl)phenyl]-2-methyl-1,3-dioxolane were added to 20 ml of ethanol, and the resulting mixture was heated for 3 hours to carry out reaction. After completion of the reaction, ethanol was removed by evaporation under reduced pressure, after which water was added to the residue and extraction was carried out with ethyl acetate. The ethyl acetate extract was washed with water and dried, and ethyl acetate was removed by evaporation to obtain an oily product. This oily product was column-chromatographed on silca gel to obtain 1.3 g of the desired compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[OH:14])([O-:3])=[O:2].C(=O)([O-])[O-].[Ca+2].Br[C:21]([CH3:25])([CH3:24])[CH:22]=[O:23]>CN(C)C=O>[N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=[CH:6][C:5]=1[O:14][C:21]([CH3:25])([CH3:24])[CH:22]=[O:23])([O-:3])=[O:2]
Reactant: CC(C)(Br)C=O
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1O
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CN(C)C=O
Product: CC(C)(C=O)Oc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 96 h
Yield: 33.1 %

Procedure:
To a mixture of 10 g of 2-nitro-4-trifluoromethylphenol, 8.0 g of anhydrous calcium carbonate and 30 ml of N,N-dimethylformamide was added dropwise a solution of 8.8 g of 2-bromoisobutyraldehyde in 23 ml of N,N-dimethylformamide and the mixture was stirred at room temperature for 4 days. The reaction mixture was then poured in ice-water and extracted with toluene. The organic layer was washed with 0.5 N aqueous sodium hydroxide solution and water in that order and dried over anhydrous magnesium sulfate and the solvent was distilled off. The residue was chromatographed on a silica gel column and elution was carried out with hexane-ethyl acetate (3:1). The Crystals from the eluate were recrystallized from 15 ml of hexane twice to give 4.428 g of 2-(2-nitro-4-trifluoromethylphenoxy)isobutyraldehyde.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([CH2:17]C#N)[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[C:25](=[O:28])(O)[O-:26].[Na+]>O.C(O)(=O)C>[C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([CH2:17][C:25]([OH:26])=[O:28])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C([O-])O
Reactant: N#CCc1ccc2nc(-c3ccccc3)ccc2c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)Cc1ccc2nc(-c3ccccc3)ccc2c1

Procedure:
A mixture of 10 g of 2-phenyl-6-quinolineacetonitrile, 19 ml of water, 19 ml of concentrated sulphuric acid and 19 ml of glacial acetic acid is kept under reflux for 2 hours. Thereafter, ice and water are added and the pH is adjusted to 5-6 with solid sodium bicarbonate. The crystals which thereupon precipitate are filtered off and rinsed with water. Recrystallisation from methanol-ether-petroleum ether yields 2-phenyl-6-quinolineacetic acid of melting point 176°-179°C. 2-(p-Chlorophenyl)-6-quinoline-acetic acid and 2-(p-fluorophenyl)-6-quinolineacetic acid are obtained analogously.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:16][C:15]([C:26]#[N:27])=[N:14]1.ClCCl.[F:31][CH:32]([F:35])[S:33]Cl>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[C:16]([S:33][CH:32]([F:35])[F:31])[C:15]([C:26]#[N:27])=[N:14]1
Reactant: FC(F)SCl
Reactant: N#Cc1cc(NCc2ccccn2)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(NCc2ccccn2)c1SC(F)F
Temperature: 25 °C
Yield: 90 %

Procedure:
Under a nitrogen atmosphere, 500 mg (1.21 mmol) of 1-(2,6-dichloro-4-trifluoromethylphenyl)-5-(pyridin-2-ylmethylamino)pyrazole-3-carbonitrile was suspended into 5.0 mL of dried dichloromethane, and 2.0 mL of dried dichloromethane containing 180 mg (1.52 mmol, 1.25 eq.) of difluoromethylsulfenyl chloride was added dropwise thereto under stirring at room temperature, followed by reaction for 2 hours. Ethyl acetate (100 mL) was added thereto, and the organic layer was washed successively with 20 mL of a saturated aqueous sodium hydrogen carbonate solution and 20 mL of water, followed by drying over anhydrous magnesium sulfate. After magnesium sulfate was filtered off, the solvent was removed by distillation under reduced pressure and the crude product was recrystallized from a mixed solvent of hexane/ethyl acetate (3/1) to thereby obtain 535 mg of 1-(2,6-dichloro-4-trifluoromethylphenyl)-4-difluoromethylthio-5-(pyridin-2-ylmethylamino)pyrazole-3-carbonitrile (yield: 90%, purity: 96%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:16])[C:9](=[O:15])[N:10]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:5]2=[CH:4][CH:3]=1.[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B1OC(C)(C)C(C)(C)O1)#[N:18].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:12]1([CH2:11][N:10]2[C:5]3[C:6](=[N:7][C:2]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[C:17]#[N:18])=[CH:3][CH:4]=3)[N:8]([CH3:16])[C:9]2=[O:15])[CH2:14][CH2:13]1
Reactant: Cn1c(=O)n(CC2CC2)c2ccc(Cl)nc21
Reactant: CC1(C)OB(c2ccccc2C#N)OC1(C)C
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cn1c(=O)n(CC2CC2)c2ccc(-c3ccccc3C#N)nc21
Temperature: 90 °C

Procedure:
5-chloro-1-(cyclopropylmethyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1-4) (35 mg, 0.138 mmol), 2-cyanophenylboronic acid pinacol ester (79 mg, 0.345 mmol), cesium carbonate (135 mg, 0.414 mmol), and bis(tri-t-butylphosphine)palladium(0) (7 mg, 0.014 mmol) were added to a microwave vial, and purged with nitrogen. Dioxane (1.1 ml) and water (0.3 ml) were added and the suspension was heated at 90° C. overnight. The reaction was cooled to room temperature, diluted with methanol, and passed through a syringe filter. The solution was purified using reverse phase chromatography (10-100%, 0.1% TFA in H2O/Acetonitrile) and the desired fractions were collected and concentrated to produce 2-[1-(cyclopropylmethyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]benzonitrile (1-5). HRMS (M+H)+: observed=305.1403, calculated=305.1397.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[CH3:9][O:10][C:11]1[CH:19]=[C:18]([CH2:20][S:21][CH3:22])[CH:17]=[CH:16][C:12]=1[C:13](O)=O>>[CH3:9][O:10][C:11]1[CH:19]=[C:18]([CH2:20][S:21][CH3:22])[CH:17]=[CH:16][C:12]=1[C:13]1[NH:8][C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: COc1cc(CSC)ccc1C(=O)O
Reactant: Nc1ccncc1N
Product: COc1cc(CSC)ccc1-c1nc2cnccc2[nH]1

Procedure:
Prepared analogously to Example 14 from 3,4-diaminopyridine and 2-methoxy-4-methylthiomethyl-benzoic acid.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]#[N:11].[CH2:12]([OH:14])[CH3:13]>>[ClH:1].[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10](=[NH:11])[O:14][CH2:12][CH3:13]
Reactant: N#CCc1ccccc1F
Reactant: CCO
Agent: Cl
Product: CCOC(=N)Cc1ccccc1F
Reaction time: 48 h
Yield: 91.5 %

Procedure:
Dry hydrogen chloride gas (29.8 g, 0.817 mol) was bubbled through a solution of 2-fluorophenylacetonitrile (100 g, 0.743 mol) (Aldrich) in absolute ethanol (37.6 g, 0.817 mol) at 0° C. After uptake of hydrogen chloride was complete, the reaction was kept at 0° C. for 48 hours. The solid was triturated in ether (3×200 mL) and the white solid was collected by suction filtration. Drying for several days under vacuum in a desiccator containing sodium hydroxide pellets and phosphorus pentoxide gave 148 g (91%) of ethyl 2-(2-fluorophenyl)acetimidate hydrochloride, mp. 96°-99° C.; nmr (DMSO-d6)L δ11.58 (br s, 2H, NH2), 6.95-7.50 (complex multiplets, 4H, ArH), 4.40 (q, 2H, OCH2), 4.06 (s, 2H, CH2), 1.24 (t, 3H, CH3); ms: m/e 181 (M+), 162 (M-F+), 153 (M-C2H4 +), 136 (M-OEt+), 109 (C7H6F+).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@H:3]1[N:11]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21].[CH3:22][Si](C)(C)[N-][Si](C)(C)C.[Li+].CI>C1COCC1>[CH3:22][O:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@H:3]1[N:11]1[C:12](=[O:21])[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19]1=[O:20]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: O=C1c2ccccc2C(=O)N1[C@@H]1c2ccccc2C[C@H]1O
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CO[C@@H]1Cc2ccccc2[C@H]1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 46 %

Procedure:
To a solution of 2-[(1R,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-1H-isoindole-1,3(2H)-dione (0.860 g, 0.00308 mol) in THF (30 mL) at 0° C. under an atmosphere of nitrogen was added a 1.0 M solution of lithium hexamethyldisilazide in THF (3.39 mL, 0.00339 mol). The reaction mixture was stirred for 20 minutes, followed by the addition of methyl iodide (0.575 mL, 0.00924 mol). The cold bath was removed, and the reaction mixture was allowed to stir and warm to rt over 18 h. The reaction was monitored by 1H NMR. The reaction mixture was then re-cooled to 0° C. To the reaction mixture was added 1.0 M solution of lithium hexamethyldisilazide in THF (3.39 mL, 0.00339 mol). The reaction mixture was stirred for 15 minutes, followed by addition of methyl iodide (0.575 mL, 0.00924 mol). The cold bath was removed, and the reaction mixture was allowed to stir at rt for 22 h. 1H NMR indicated 80:20 product/starting material. The reaction was quenched with aqueous 1N HCl solution and then concentrated in vacuo. The residue was partitioned between EtOAc and water. The organic phase was washed with saturated NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated. The oil was purified by silica gel chromatography, eluting with a gradient of hexanes to 10% EtOAc in hexanes) to obtain product (4.18 g, 46%). LC/MS: Rt=1.90 min, ES+ 294 (AA standard).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][OH:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[CH2:17](Br)[C:18]#[CH:19]>CN(C=O)C>[CH2:19]([O:14][CH2:13][C@@H:9]1[CH2:10][CH2:11][CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:18]#[CH:17]
Reactant: C#CCBr
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: C#CCOC[C@@H]1CCCN1C(=O)OC(C)(C)C
Yield: 66.9 %

Procedure:
To a stirred solution of 18 (0.40 g, 2 mmol) in dry DMF (10 mL) was added potassium hydroxide (0.56 g, 10 mmol), followed by dropwise addition of propargyl bromide (80 wt. % in toluene) (0.48 g, 4 mmol) over 5 min. After 18 h the reaction mixture was poured onto water (30 mL) and washed with DCM (3×15 mL). The combined organic fractions concentrated in vacuo and the liquid remaining taken up in diethyl ether (15 mL) and washed with water (2×10 mL), then brine (1×10 mL) and dried over Na2SO4. Chromatography (hexanes/ethyl acetate) gave the desired product as a colorless oil (0.32 g, 67%). HRMS (ESI)=240.1597 (M+H)+. Calcd. for C13H22NO3 240.1594. 1H NMR (600 MHz, CDCl3) δ 4.13 (s, 2H), 3.96-3.88 (m, 1H), 3.64 (dd, J=9 Hz, J=3.6 Hz, 1H), 3.49-3.22 (m, 3H), 2.40 (s, 1H), 1.94-1.78 (m, 4H), 1.46 (s, 9H). TLC (I2) Rf=0.67 (1:1 hexanes/ethyl acetate).
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]([NH2:22])=[CH:11][CH:10]=1)C1C=CC=CC=1.[C:23](OC)(OC)(OC)[CH2:24][CH2:25][CH3:26]>C(O)(C(F)(F)F)=O>[C:16]1([N:15]2[C:13]3=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]3[N:22]=[C:23]2[CH2:24][CH2:25][CH3:26])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Nc1ccc(OCc2ccccc2)nc1Nc1ccccc1
Reactant: CCCC(OC)(OC)OC
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2ccc(O)nc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 6-(benzyloxy)-N2-phenylpyridine-2,3-diamine (90 mg, 0.31 mmol), trimethyl orthobutyrate (5 mL), and TFA (20 μL) was stirred at room temperature for 2 h. The mixture was concentrated in vacuo and the residue dissolved in MeOH (5 mL). Palladium on carbon (20% wt./wt., 15 mg,) was added and the mixture was stirred vigorously under H2 (1 atm) for 1 h. The mixture was filtered through Celite® and concentrated to give the title compound as a white solid (26 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.85 (t, J=7.6 Hz, 3H), 1.65 (s, J=7.3 Hz, 2H), 2.62 (t, J=7.6 Hz, 2H), 6.51 (d, J=8.6 Hz, 1H), 7.45-7.56 (m, 3H), 7.60 (t, J=7.6 Hz, 2H), 7.87 (d, J=8.3 Hz, 1H), 10.75 (br s, 1H).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][CH2:20][C:21]#[C:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:15][CH:14]=1>ClCCl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH2:20][C:21]#[C:22][CH2:23][O:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:6])=[CH:15][CH:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Clc1ccc(SCC#CCOc2ccccc2)cc1
Solvent: ClCCl
Product: O=S(CC#CCOc1ccccc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of m-chloroperoxybenzoic acid (55% purity; 81 g) in dichloromethane (1400 ml) was added dropwise over 2.5 hours to a stirred, ice-cold solution of the crude 1-(4-chlorophenylthio)-4-phenoxybut-2-yne (74.5 g) in dichloromethane (600 ml), then the mixture was stirred at ambient temperature for 18 hours and filtered. The filtrate was washed with 5% aqueous sodium carbonate solution (3×750 ml) and water (3×500 ml) then dried (Na2SO4), and the solvent removed in vacuo. The residue was dissolved in hot dichloromethane (40 ml), then petroleum ether (b.p. 60°-80° C.) (75 ml) was added, and the mixture was triturated to give a sticky solid which was collected by filtration, triturated with hot ether (500 ml), collected by filtration, and dried in vacuo to give 1-(4-chlorophenylsulphinyl)-4-phenoxybut-2-yne as a solid (21.73 g), m.p. 102°-103° C.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:22])[C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH3:21])=[CH:15][CH:14]=3)=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].[CH3:25]I>CN(C=O)C>[CH3:25][N:11]([C:8]1[CH:9]=[CH:10][C:4]2[S:3][C:2]([CH3:1])=[N:6][C:5]=2[CH:7]=1)[C:12](=[O:22])[C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][CH3:21])=[CH:17][CH:18]=1
Reactant: CI
Reactant: CCCc1ccc(C(=O)Nc2ccc3sc(C)nc3c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1ccc(C(=O)N(C)c2ccc3sc(C)nc3c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-(2-methylbenzothiazol-5-yl)-4-propylbenzamide (130 mg, 0.4 mmol) in DMF (5 mL) was added sodium hydride (17 mg, 0.44 mmol), followed by methyl iodide (85 mg, 059 mmol). The mixture was stirred at rt overnight, partitioned between water and ethyl acetate. The organic phase was washed with brine, dried over sodium sulphate and concentrated to give a residue that wad purified with flash chromatography (ethyl acetate-hexane gradient elution). A thick syrup (41 mg, 26% was obtained. 1H NMR (400 MHz, CDCl3): δ 7.61-7.79 (3H, m, ArH), 7.22-7.26 (2H, m, ArH), 6.92-7.02 (2H, m, ArH), 3.54 (3H, s, CH3) 2.81 (3H, s, CH3), 2.45 (2H, t J=7.4 Hz, CH2) 1.52 (2H, m, CH2), 0.83 (3H, t, .J=7.4 Hz, CH3); FAB-MS 325 (MH+); FAB-HRMS calcd for C19H21N2OS (MH+) 325.1375, found 325.1992.
Reaction SMILES: CO.[H-].[Na+].[CH3:5][SH:6].Cl[CH2:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([C:19]2[NH:20][C:21](=[O:28])[C:22]([CH:25]([CH3:27])[CH3:26])([CH3:24])[N:23]=2)[N:10]=1>C(O)(=O)C>[CH:25]([C:22]1([CH3:24])[C:21](=[O:28])[NH:20][C:19]([C:11]2[N:10]=[C:9]([CH2:8][S:6][CH3:5])[CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])=[N:23]1)([CH3:27])[CH3:26]
Reactant: COC(=O)c1ccc(CCl)nc1C1=NC(C)(C(C)C)C(=O)N1
Reactant: CS
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1ccc(CSC)nc1C1=NC(C)(C(C)C)C(=O)N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 30 mL of absolute methanol, stirred at -10° under nitrogen, is added in portions 0.9 g of 50% sodium hydride (oil dispersion). A stream of methyl mercaptan is then added to the solution until a pH of 10 is achieved. To this solution is added 3 g of methyl 6-chloromethyl-2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)nicotinate, and stirring is continued at -10° for 1 hour. The reaction is then allowed to warm to room temperature over 1 hour, and is then acidified with glacial acetic acid to pH 4. The mixture is concentrated in vacuo, and the residue is dissolved in methylene chloride, washed with saturated aqueous sodium bicarbonate, dried, and concentrated in vacuo. The residue is dissolved in absolute methanol, washed with hexanes, and concentrated in vacuo to afford the desired product. Recrystallization from methylene chloride-hexane affords a solid, mp 113.5°-115° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[N:12]=[N:11][CH:10]=[N:9]2)=[CH:4][C:3]=1[CH3:13].[I:14]Cl>>[NH2:1][C:2]1[C:3]([CH3:13])=[CH:4][C:5]([N:8]2[N:12]=[N:11][CH:10]=[N:9]2)=[CH:6][C:7]=1[I:14]
Reactant: ClI
Reactant: Cc1cc(-n2ncnn2)ccc1N
Product: Cc1cc(-n2ncnn2)cc(I)c1N

Procedure:
The following compound, m.p. 196°-199° was prepared similarly to the previous Preparation using 2-(4-amino-3-methylphenyl)tetrazole and iodine monochloride as the starting materials: ##STR141##