Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:11])[CH2:8][C:9]#[N:10].C(N(CC)CC)C.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([N:25]=[C:26]=[O:27])[CH:20]=1>C1(C)C=CC=CC=1>[O:11]=[C:7]([C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=1)[CH:8]([C:26](=[O:27])[NH:25][C:21]1[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=1)[C:9]#[N:10]
Reactant: O=C=Nc1cccnc1
Reactant: Cn1cccc1C(=O)CC#N
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cn1cccc1C(=O)C(C#N)C(=O)Nc1cccnc1
Reaction time: 8 h

Procedure:
To the suspension of 12.9 g of 1-methyl-β-oxo-2-pyrrolepropionitrile (U.S. Pat. No. 4,256,759) in 150 ml of dry toluene and 10.1 g of anhydrous triethylamine are added 10.8 g of 3-pyridyl isocyanate while stirring. After all solids are dissolved, the solution is allowed to stand at room temperature overnight. The mixture is evaporated to dryness, the residue taken up in methanol and the solution is neutralized to pH ca. 6 with 3 N hydrochloric acid and diluted with 600 ml of water. The resulting precipitate is collected, washed with water, and dried to yield the β-oxo-α-(3-pyridylcarbamoyl)-β-(1-methyl-2-pyrrolyl)propionitrile.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][OH:8])=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:4]=[N:3]1.[H-].[Na+].Cl[C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][N:19]=1.O>C1COCC1>[CH3:25][O:24][C:22](=[O:23])[C:21]1[CH:26]=[CH:27][C:18]([O:8][CH2:7][C:6]2[N:2]([CH3:1])[N:3]=[N:4][C:5]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:19][CH:20]=1
Reactant: Cn1nnc(-c2ccccn2)c1CO
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(OCc2c(-c3ccccn3)nnn2C)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.4 %

Procedure:
A solution of (3-methyl-5-pyridin-2-yl-3H-[1,2,3]triazol-4-yl)-methanol (158 mg, 0.83 mmol) in THF (2.4 mL) was added dropwise at 0° C. to a suspension of NaH (60% in oil, 40 mg, 0.91 mmol) in THF (1.2 mL) and the reaction mixture was then stirred at room temperature for 30 min. Then a solution of methyl 6-chloronicotinate (157 mg, 0.91 mmol) in THF (2.4 mL) was added dropwise at 0° C. and the reaction mixture stirred at room temperature for 18 h. The mixture was then poured into water extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 100% ethyl acetate in heptane) afforded the title compound (209 mg, 77%) as a white solid. MS: m/e=326.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:23])([CH3:22])[C:20]#[N:21])=[CH:15][CH:14]=1)=[CH:9][C:8]([CH3:24])=[CH:7][CH:6]=2.C(N(CC)CC)C.Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH3:23][C:19]([C:16]1[CH:17]=[CH:18][C:13]([N:12]2[C:11]3[C:10]4[CH:9]=[C:8]([CH3:24])[CH:7]=[CH:6][C:5]=4[N:4]=[CH:3][C:2]=3[NH:1][C:33]2=[O:35])=[CH:14][CH:15]=1)([CH3:22])[C:20]#[N:21]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1ccc2ncc(N)c(Nc3ccc(C(C)(C)C#N)cc3)c2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2ncc3[nH]c(=O)n(-c4ccc(C(C)(C)C#N)cc4)c3c2c1
Reaction time: 0.33 h

Procedure:
A solution of 2-(4-(3-amino-6-methyl-quinolin-4-ylamino)phenyl)-2-methylpropanenitrile (Compound of Preparation J, 190 mg, 0.6025 mmol) and triethylamine (0.12 ml, 0.901 mmol) in CH2Cl2 (10 mL) was added over 40 min to a solution of triphosgene (195 mg, 0.6139 mmol) in 5 mL of CH2Cl2 at 0° C. The reaction mixture was stirred for 20 min at this temperature then was quenched with saturated aqueous NaHCO3, stirred for 5 min and extracted with CH2Cl2. The organic layer was dried over Na2SO4, filtered and evaporated in vacuo to obtain the title compound as brown solid. Yield: 145 mg (70%); 1H NMR (DMSO-d6, 300 MHz): δ 11.641 (s, 1H), 8.678 (s, 1H), 7.864-7.892 (d, 1H, J=8.4 Hz), 7.782-7.810 (d, 2H, J=8.4 Hz), 7.629-7.657 (d, 2H, J=8.4 Hz), 7.342-7.371 (d, 1H, J=8.7 Hz), 6.625 (s, 1H), 2.147 (s, 3H), 1.801 (s, 6H); MS: m/z 343 (M+).
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([B:8]([OH:10])[OH:9])[CH:5]=[CH:6][CH:7]=1.Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1>>[C:20]([CH2:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][S:1][C:2]2[CH:3]=[C:4]([B:8]([OH:10])[OH:9])[CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:15]=1)([OH:22])=[O:21]
Reactant: O=C(O)Cc1ccc(CBr)cc1
Reactant: OB(O)c1cccc(S)c1
Product: O=C(O)Cc1ccc(CSc2cccc(B(O)O)c2)cc1

Procedure:
3-(4-Carboxymethyl-benzylsulfanyl)-phenylboronic acid was prepared from 3-mercaptophenylboronic acid and 4-bromomethylphenyl acetic acid according to the procedure of Example 12;
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:14][C:15]([CH3:17])=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl.C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH:15]([CH3:17])[CH3:14])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)=O
Reactant: Brc1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CC(C)N1CCN(c2ccc(Br)cc2)CC1
Temperature: 25 °C
Yield: 98.9 %

Procedure:
To a mixture of 1-(4-bromophenyl)piperazine (1.20 g, 5 mmol) and acetone (1.47 mL, 20 mmol) in DCE/THF (45 mL/15 mL) was added NaBH(OAc)3 (1.38 g, 6.5 mmol), followed by AcOH (0.5 mL). After addition, the resulting mixture was stirred O/N at rt. The reaction as quenched with NaHCO3 (10 mL) and H2O (10 mL), and was extracted with EtOAc (60 mL×2). The solvents were removed in vacuo to give the crude title compound as a white solid (1.40 g, 99%). 1H NMR (400 MHz, DMSO-d6) δ 7.45 (d, J=7.2 Hz, 2H), 7.21 (d, J=7.2 Hz, 2H), 3.64-3.55 (m, 2H), 3.44 (s, 2H), 2.68 (d, J=11.6 Hz, 2H), 1.75 (t, J=11.0 Hz, 2H), 1.54 (d, J=6.0 Hz, 6H); MS ESI 282.9 [M+H]+, calcd. for [C13H19BrN2+H]+ 283.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:8][C@H:7]([CH3:9])[C@@H:6]([C:10]([O:12][C@H:13]2[C@H:18]([CH:19]([CH3:21])[CH3:20])[CH2:17][CH2:16][C@@H:15]([CH3:22])[CH2:14]2)=[O:11])[C:5](=[O:23])[CH:4]=1.[H-].[Na+].[F:26][C:27]([F:40])([F:39])[S:28]([O:31]S(C(F)(F)F)(=O)=O)(=[O:30])=[O:29]>CCOCC>[OH:23][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH2:8][C@H:7]([CH3:9])[C:6]=1[C:10]([O:12][C@H:13]1[C@H:18]([CH:19]([CH3:21])[CH3:20])[CH2:17][CH2:16][C@@H:15]([CH3:22])[CH2:14]1)=[O:11].[F:26][C:27]([F:40])([F:39])[S:28]([O-:31])(=[O:30])=[O:29]
Reactant: COC1=CC(=O)[C@H](C(=O)O[C@@H]2C[C@H](C)CC[C@H]2C(C)C)[C@@H](C)C1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: COC1=CC(O)=C(C(=O)O[C@@H]2C[C@H](C)CC[C@H]2C(C)C)[C@@H](C)C1
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 23 °C
Reaction time: 5 h
Yield: 288.5 %

Procedure:
A solution of (1R,3R,4S)-p-menth-3-yl(1R,6S)-4-methoxy-6-methyl-2-oxo-3-cyclohexene-1-carboxylate (4, 35.5 g, 110 mmol, 1 equiv) in ether (300 mL) was transferred by cannula over 15 min to a stirring suspension of sodium hydride (3.96 g, 165 mmol, 1.50 equiv) in ether (100 mL) at 0° C. The slurry was allowed to warm to 23° C. over approximately 10 min, and was stirred at that temperature for 5 h. Excess sodium hydride was quenched by the addition of 10-mL aliquots of water to the suspension at 30-min intervals until such point as gas evolution was no longer evident. The reaction mixture was then cooled to -78° C. and trifluoromethanesulfonic anhydride (29.6 mL, 176 mmol, 1.60 equiv) was added by syringe over 10 min. Upon completion of the latter addition, the reaction mixture was placed in an ice bath and was stirred for 30 min. The product solution was partitioned between aqueous phosphate buffer solution (pH 7, 0.05M in sodium hydrogen phosphate and 0.05M in potassium dihydrogen phosphate, 400 mL) and ether (400 mL). The aqueous layer was separated and extracted further with ether (2×400 mL). The combined organic layers were dried over sodium sulfate, and then were concentrated. The residue was purified by flash column chromatography (10% ethyl acetate-hexanes) to afford (1R,3R,4S)-p-menth-3-yl(S)-2-hydroxy-4-methoxy-6-methyl-1,3-cyclohexadiene-1-carboxylate, trifluoromethane-sulfonate (6) as a pale yellow oil (47.3 g, 95%). Due to its instability to storage, product 6 was typically carried directly on to the next step in the sequence. ##STR17##
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.Br[C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][N:12]=1.C([O-])([O-])=O.[K+].[K+].C(O)(C(F)(F)F)=O>CS(C)=O>[Cl:17][C:16]1[C:11]([N:1]2[CH2:2][CH:3]=[C:4]([C:7]([OH:9])=[O:8])[CH2:5][CH2:6]2)=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(O)C1=CCNCC1
Reactant: Clc1cccnc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: O=C(O)C1=CCN(c2ncccc2Cl)CC1
Temperature: 90 °C

Procedure:
1,2,3,6-Tetrahydro-4-pyridinecarboxylic acid (7.0 g, 47 mmol) and 2-bromo-3-chloropyridine (11.0 g, 57 mmol) were combined in DMSO (100 mL) and treated with anhydrous K2CO3 (8.0 g, 58 mmol). The mixture was heated at 90° C. overnight, allowed to cool to room temperature, and then concentrated under reduced pressure. The residue in dichloromethane (200 mL) was cooled to −78° C. and treated with an excess of TFA (10 mL, 130 mmol) dropwise. The mixture was allowed to warm to room temperature and the layers were separated. The organic layer was washed with brine, dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure to provide the title compound which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Si:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1[C:4](Cl)=[O:5].[CH:15]([NH:18][CH:19]([CH3:21])[CH3:20])([CH3:17])[CH3:16]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Si:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1[C:4]([N:18]([CH:19]([CH3:21])[CH3:20])[CH:15]([CH3:17])[CH3:16])=[O:5]
Reactant: C[Si](C)(C)c1cccc(Cl)c1C(=O)Cl
Reactant: CC(C)NC(C)C
Solvent: Cc1ccccc1
Product: CC(C)N(C(=O)c1c(Cl)cccc1[Si](C)(C)C)C(C)C
Yield: 56.1 %

Procedure:
The compound of Example b (2.47 g, 10 mmol), diisopropyl amine (2.23 g, 22 mmol), and toluene (25 mL) were combined according to General Method E2. The crude product was recrystallized from ethanol/water to afford 1.75 g of the title compound as a white solid, a 58% yield. m.p. 96-97.5° C.
Reaction SMILES: CN1CCOCC1.C(OC(Cl)=O)C(C)C.[C:16]([NH:26][C:27]([CH3:32])([C:29]([OH:31])=O)[CH3:28])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].Cl.[CH3:34][NH:35][O:36][CH3:37].Cl>C(Cl)Cl>[CH3:37][O:36][N:35]([CH3:34])[C:29](=[O:31])[C:27]([NH:26][C:16](=[O:17])[O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([CH3:28])[CH3:32]
Reactant: CNOC
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)C(C)(C)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
N-Methylmorpholine (682 mg, 741 μL, 6.74 mmol) and isobutylchloroformate (460 mg, 441 μL, 3.37 mmol) were added successively to a stirred solution of N-carbobenzyloxy-2-methylalanine (0.64 g, 2.69 mmol) in dry CH2Cl2 at 0° C. under N2. The resulting cloudy mixture was stirred at 0° C. for 90 min. N,O-Dimethylhydroxylamine hydrochloride (316 mg, 3.24 mmol) was added portionwise and the mixture was warmed to room temperature and stirred for 3 h. The mixture was poured into 1N HCl (30 mL) and extracted with CH2Cl2 (3×40 mL). The combined extracts were washed with 1N HCl (30 mL), dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 40×160 mm, 0-80% EtOAc in hexanes gradient) to afford benzyl {2-[methoxy(methyl)amino]-1,1-dimethyl-2-oxoethyl}carbamate. Rf=0.47 (50% EtOAc in hexanes). LCMS calc.=303.1; found=303.2 (M+Na)+. 1H NMR (500 MHz, CDCl3) δ 7.37-7.29 (m, 5H), 5.82 (s, 1H), 5.09 (s, 2H), 3.60 (s, 3H), 3.18 (s, 3H), 1.60 (s, 6H).
Reaction SMILES: [O-]S(C(F)(F)F)(=O)=O.C([B+]CCCC)CCC.[CH:18]([C@H:21]1[CH2:25][O:24][C:23](=[O:26])[N:22]1[C:27](=[O:36])[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([CH3:20])[CH3:19].C(N(CC)C(C)C)(C)C.[C:46]([O:50][C:51]([N:53]1[CH2:57][C@H:56]([F:58])[CH2:55][C@@H:54]1[CH:59]=[O:60])=[O:52])([CH3:49])([CH3:48])[CH3:47].P([O-])([O-])([O-])=O>ClCCl>[C:46]([O:50][C:51]([N:53]1[CH2:57][C@H:56]([F:58])[CH2:55][C@@H:54]1[C@@H:59]([OH:60])[C@H:28]([CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:27]([N:22]1[C@@H:21]([CH:18]([CH3:20])[CH3:19])[CH2:25][O:24][C:23]1=[O:26])=[O:36])=[O:52])([CH3:49])([CH3:48])[CH3:47]
Reactant: CC(C)[C@H]1COC(=O)N1C(=O)CCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C[C@H](F)C[C@@H]1C=O
Agent: CCCC[B+]CCCC
Agent: O=P([O-])([O-])[O-]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)[C@H]1COC(=O)N1C(=O)[C@@H](Cc1ccccc1)[C@H](O)[C@H]1C[C@@H](F)CN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 52.3 %

Procedure:
Add dibutylboron triflate (1 M in dichloromethane, 11.8 mL, 11.8 mmol) to a solution of 4-(S)-isopropyl-3-(3-phenylpropionyl)-oxazolidin-2-one (2.8 g, 10.7 mmol) in dichloromethane (40 mL) at 0° C. Stir 5 min. Add N,N-diisopropylethylamine (2.25 mL, 12.87 mmol) and stir 90 min. Cool to −78° C. and add 4-(R)-fluoro-2-(R)-formylpyrrolidine-1-carboxylic acid tert-butyl ester (2.53 g, 11.6 mmol) in dichloromethane (15 mL) over 15 min. Stir 90 min and then warm to room temperature over 18 h. Cool in ice bath and add 0.05 M pH 7 phosphate buffer (15 mL). Extract with dichloromethane and concentrate. Dissolve in methanol (50 mL) and cool in ice bath. Add aqueous hydrogen peroxide (15 mL, 30% solution) and remove ice bath. Stir 5 min and concentrate. Extract with ethyl acetate and wash extract with 1 N HCl, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with hexanes and ethyl acetate) to give the title compound as a foam (2.68 g, 52%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:11]([C:12]3[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=3[F:19])[N:10]=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:31][CH2:30]S[CH2:28][CH2:27]4)=[CH:22][CH:21]=3)[C:4]=2[C:5](=[O:8])[NH:6][CH:7]=1.CO.O[O:35][S:36]([O-:38])=O.[K+]>O>[Cl:1][C:2]1[C:3]2[N:11]([C:12]3[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=3[F:19])[N:10]=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:31][CH2:30][S:36](=[O:38])(=[O:35])[CH2:28][CH2:27]4)=[CH:22][CH:21]=3)[C:4]=2[C:5](=[O:8])[NH:6][CH:7]=1
Reactant: O=c1[nH]cc(Cl)c2c1c(-c1ccc(N3CCSCC3)cc1)nn2-c1c(F)cccc1F
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=c1[nH]cc(Cl)c2c1c(-c1ccc(N3CCS(=O)(=O)CC3)cc1)nn2-c1c(F)cccc1F
Temperature: 80 °C
Reaction time: 16 h
Yield: 17.8 %

Procedure:
To a mixture of 7-chloro-1-(2,6-difluorophenyl)-3-(4-(thiomorpholin-4-yl)phenyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one (30 mg) obtained in Example 236 in a mixed solvent of methanol (3 mL) and water (0.15 mL) was added Oxone (registered trademark) (80 mg) at room temperature. The reaction mixture was stirred at 80° C. for 16 hr. To the reaction mixture was added water, and the mixture was extracted with THF. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (5.7 mg).
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:18][C:19]([O-:22])(C)[CH3:20].[K+].[CH2:24]1COC[CH2:25]1.CN(C=O)C>CCOCC>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])/[N:7]([CH2:18][C@H:19]2[CH2:20][CH2:25][CH2:24][O:22]2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)Nc1nnc(C(C)(C)C)s1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)/N=c1\sc(C(C)(C)C)nn1C[C@H]1CCCO1
Temperature: 75 °C

Procedure:
To a mixture of Example 69A (20.0 g, 78.0 mmol) and Example 39A (21.9 g, 85.0 mmol) in THF/DMF (4/1) was added potassium 2-methylpropan-2-olate (13.1 g, 117 mmol). The mixture was heated at 75° C. for 16 hours then cooled to room temperature, diluted with ether and washed with aqueous NaHCO3. The organic extract was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on SiO2 using an Analogix® Intelliflash280™ (Hexanes:EtOAc, 0 to 50% gradient) to afford the title compound. MS (ESI+) m/z 342 (M+H)+.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[N:7][NH:6][C:5]2=[S:10].[Na].[CH3:12]I>C(O)C>[CH3:12][S:10][C:5]1[N:4]2[CH:3]=[CH:2][N:1]=[C:9]2[CH:8]=[N:7][N:6]=1
Reactant: CI
Reactant: S=c1[nH]ncc2nccn12
Agent: [Na]
Solvent: CCO
Product: CSc1nncc2nccn12

Procedure:
A 66.7 gm. portion of imidazo[1,2-d]-as-triazine-5(6H)-thione is added to 250 ml. of ethanol. A solution of 10.1 gm. of sodium reacted in 250 ml. of ethanol is added with swirling. A 27.7 ml. portion of methyl iodide is added slowly with swirling. The mixture is stored in a chillroom overnight, filtered and dried giving 56.5 gm. of the desired final product, m.p. 147°-149° C.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30].C(N(CC)CC)C>ClCCl>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:29](=[O:30])[C:28]4[CH:32]=[CH:33][C:34]([Cl:36])=[CH:35][C:27]=4[O:26][CH3:25])=[CH:24][CH:23]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: COc1cc(Cl)ccc1C(=O)Cl
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(Cl)ccc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.7 %

Procedure:
As described for Example 9, a mixture of 0.377 g (1 mmol) of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine, 0.295 g of 2-methoxy-4-chloro-benzoyl chloride, and 0.15 g of triethylamine in 10 ml of dichloromethane is stirred at room temperature for 3 hours. An additional 0.148 g of 2-methoxy-4-chlorobenzoyl chloride and 75 mg of triethylamine is added and the mixture stirred overnight. The solution is worked-up as for Example 9 to give 0.38 g of product (crystallized from dichloromethane-hexane) m.p. 237°-239° C.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:20])[CH2:6][O:7][C:8]1[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[CH:11]=[CH:10][C:9]=1[CH2:17][CH2:18][NH2:19])[CH3:3].C(N(CC)CC)C.[C:28]([C:30]1[CH:31]=[CH:32][C:33]([O:40][CH3:41])=[C:34]([S:36](Cl)(=[O:38])=[O:37])[CH:35]=1)#[N:29]>O1CCCC1.O>[CH2:2]([O:4][C:5](=[O:20])[CH2:6][O:7][C:8]1[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[CH:11]=[CH:10][C:9]=1[CH2:17][CH2:18][NH:19][S:36]([C:34]1[CH:35]=[C:30]([C:28]#[N:29])[CH:31]=[CH:32][C:33]=1[O:40][CH3:41])(=[O:38])=[O:37])[CH3:3]
Reactant: CCOC(=O)COc1cc(C(C)C)ccc1CCN
Reactant: COc1ccc(C#N)cc1S(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)COc1cc(C(C)C)ccc1CCNS(=O)(=O)c1cc(C#N)ccc1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 72.5 %

Procedure:
To a stirred solution of 326 mg of ethyl[2-(2-aminoethyl)-5-isopropylphenoxy]acetate hydrochloride and 0.452 mL of triethylamine in a mixture of 10 mL of tetrahydrofuran and 5 mL of water was added 238 mg of 5-cyano-2-methoxybenzenesulfonyl chloride under ice-cooling, and the mixture was stirred at room temperature for 6 hours. To the reaction mixture was added 30 mL of water, and the mixture was extracted with 120 mL of ethyl acetate. The organic layer was washed with 100 mL of water, and 100 mL of brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate-hexane) to give 343 mg of ethyl[2-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]acetate.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[S:14](=[O:16])(=[O:15])[NH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5]1=[O:6])[CH3:3].O.[NH3:18]>ClCCCl>[CH3:3][CH:2]([N:4]1[S:14](=[O:16])(=[O:15])[NH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5]1=[O:6])[CH3:1].[NH4+:18]
Reactant: N
Agent: CC(C)N1C(=O)c2ccccc2NS1(=O)=O
Solvent: O
Solvent: ClCCCl
Product: [NH4+]

Procedure:
A solution of 24 g of bentazone (IIa) in 216 g of 1,2-dichloroethane was treated with stirring at 50°-60° C. with 34 g of ammonia water (5% strength solution of ammonia in water). After addition was complete, the aqueous phase was separated off at 50°-60° C. On cooling the aqueous phase, the bentazone-ammonium was deposited in crystalline form. The solid was separated off at 20° C. by filtration and freed from solvent residues under reduced pressure and at 50° C. 11.8 g of bentazone-ammonium (m.p. 180° C.) were obtained. By evaporating the water from the mother liquor under reduced pressure and at 50°-60° C., a further 13.7 g of bentazone-ammonium were obtained.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][CH:15]([CH3:21])[CH2:16][CH2:17][C:18](Cl)=[O:19]>>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:18](=[O:19])[CH2:17][CH2:16][CH:15]([CH3:21])[CH3:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CCC(=O)Cl
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Product: CC(C)CCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1

Procedure:
27.1 g of the crude title compound (yield: quant.) was obtained in the same manner as in Reference Example 5 using (S)-4-benzyl-2-oxazolidinone and 4-methylpentanoyl chloride.
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:9]O)[N:5]=1)([CH3:3])[CH3:2].S(Cl)([Cl:13])=O>ClCCl>[ClH:13].[CH:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:9][Cl:13])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccn(CO)n1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)c1ccn(CCl)n1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.28 g of 3-i-propyl-1H-pyrazole-1-ylmethanol was dissolved to 20 ml of dichloromethane. 2 ml of thionyl chloride was added to the solution, followed by stirring at room temperature for overnight. The reaction mixture was concentrated under reduced pressure to obtain 1.58 g of 3-i-propyl-1-(chloromethyl)-1H-pyrazole hydrochloride.
Reaction SMILES: FC1C=CC(C(C2C=CC(F)=CC=2)=[C:9](C2N(C)N=NN=2)[CH:10]=[O:11])=CC=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)=[C:33]([C:36]2[N:37]=[N:38][N:39]([CH3:41])[N:40]=2)[CH:34]=O)=[CH:28][CH:27]=1.C1(P(=CC=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[F:48][C:45]1[CH:46]=[CH:47][C:42]([C:32]([C:29]2[CH:28]=[CH:27][C:26]([F:25])=[CH:31][CH:30]=2)=[C:33]([C:36]2[N:37]=[N:38][N:39]([CH3:41])[N:40]=2)[CH:34]=[CH:9][CH:10]=[O:11])=[CH:43][CH:44]=1
Reactant: Cn1nnnc1C(C=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: Cn1nnc(C(C=O)=C(c2ccc(F)cc2)c2ccc(F)cc2)n1
Agent: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: Cn1nnc(C(C=CC=O)=C(c2ccc(F)cc2)c2ccc(F)cc2)n1
Yield: 90.5 %

Procedure:
The general procedure of Example 8 was repeated, except that the 3,3-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propenal utilized therein was replaced by 0.67 g (21.0 mmoles) of 3,3-bis(4-fluorophenyl)-2-(2-methyl-2H-tetrazol-5-yl)-2-propenal [prepared in Example 7]. The reaction was carried out with 0.64 g (21.0 mmoles) of triphenylphosphoranylidene acetaldehyde to yield 0.66 g (90.5%) of the title compound.